Phase 4, Multicenter, Prospective, Interventional, Post-Marketing Study in Hemophilia A Patients in India Receiving ADVATE as On-Demand or Prophylaxis Under Standard Clinical Practice
Phase: PHASE4
Conditions: Hemophilia A
Sponsor: Baxalta now part of Shire

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PROTOCOL AMENDMENT 1: TAK-761-4009 
TITLE: 
Phase 4, Multicenter, Prospective, Interventional, Post-Marketing 
Study in Hemophilia A Patients in India Receiving ADVATE as 
On-Demand or Prophylaxis Under Standard Clinical Practice 
SHORT TITLE: 
ADVATE INDIA PMC Study  
STUDY PHASE: 
Phase 4 (post-marketing) 
DRUG: 
ADVATE (Coagulation Factor VIII (Recombinant) rFVIII, 
Plasma/Albumin Free Method; Octocog Alfa)  
IND NUMBER: 
Non-IND 
EUDRACT NUMBER: 
Non-EUDRACT 
SPONSOR: 
Takeda Biopharmaceuticals India Pvt. Ltd. 
6th Floor, Building 8,  
Tower C, DLF Cyber City,  
Gurgaon 122002, Haryana, India 
 
PRINCIPAL/ 
COORDINATING 
INVESTIGATOR: 
Multicenter study 
PROTOCOL HISTORY: 
Original Protocol: 31 JUL 2019 
 
This document contains confidential and proprietary information of Takeda and is disclosed pursuant to 
confidentiality and non-disclosure obligations. This information should be used solely for the purposes for which it 
was provided and should not be copied, shared with, or disclosed to any third party without the express written 
consent of Takeda. 
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EMERGENCY CONTACT INFORMATION 
In the event of a serious adverse event (SAE), the investigator must fax or e-mail the “Takeda 
Clinical Study Adverse Event Form for Serious Adverse Events (SAEs) and Non-serious AEs as 
Required by Protocol” within 24 hours to the Takeda Global Drug Safety Department. The fax 
number and e-mail address are provided on the form (sent under separate cover). A copy of this 
form must also be sent to the contract research organization (CRO)/Takeda medical monitor using 
the details below. 
Takeda India medical monitor: 
 
 
 
Tel:  
 
Email: 
 
CRO local medical monitor:  
Contact details will be provided separately prior to first site initiation. 
For protocol- or safety-related questions or concerns, the investigator must contact the medical 
monitor: 
Takeda India medical monitor (during business hours 9:00 AM through 5:00 PM IST [India]): 
 
 
 
Tel:  
 
Email: 
 
CRO local medical monitor:  
Contact details will be provided separately prior to first site initiation. 
 
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PRODUCT QUALITY COMPLAINTS 
Investigators are required to report investigational product quality complaints or non-medical 
complaints to Takeda within 24 hours. If requested, defective product(s) will be returned to the 
sponsor for inspection and analysis according to procedures. 
This includes any instances wherein the quality or performance of a Takeda product (marketed or 
investigational) does not meet expectations (eg, inadequate or faulty closure, product 
contamination); or that the product did not meet the specifications defined in the application for 
the product (eg, wrong product such that the label and contents are different products); or a product 
deficiency that relates to identity, quality, durability, reliability, safety and performance of the 
product but did not result in an AE, which include but are not limited to the following: 
• 
A failure of a product to exhibit its expected pharmacological activity and/or design 
function, eg, reconstitution difficulty 
• 
Missing components 
• 
Damage to the product or unit carton 
• 
A mislabeled product (eg, potential counterfeiting/tampering) 
• 
A bacteriological, chemical, or physical change or deterioration of the product causing it 
to malfunction or to present a hazard or fail to meet label claims 
 
For instructions on reporting AEs related to product complaints, see Appendix 3.4. 
Please use the information below as applicable to report the Product Quality Complaint or  
Non-Medical Complaint: 
Origin of Product Quality Complaint 
E-mail Address 
North and South America 
PQC@Takeda.com 
European Union and Rest of World 
PQCROW@Takeda.com 
 
Telephone number (provided for reference if needed): 
Takeda, Lexington, MA (USA) 
1-800-828-2088 
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TABLE OF CONTENTS 
PROTOCOL SIGNATURE PAGE ....................................................................................... 2 
Sponsor’s (Takeda) Approval ............................................................................................ 2 
Investigator’s Acknowledgement ....................................................................................... 2 
EMERGENCY CONTACT INFORMATION ...................................................................... 3 
PRODUCT QUALITY COMPLAINTS ................................................................................ 4 
TABLE OF CONTENTS....................................................................................................... 5 
1. PROTOCOL SUMMARY ............................................................................................... 10 
1.1 Synopsis ...................................................................................................................... 10 
1.2 Schema ....................................................................................................................... 14 
1.3 Schedule of Activities ................................................................................................. 15 
2. INTRODUCTION ........................................................................................................... 17 
2.1 Indication and Current Treatment Options............................................................... 17 
2.2 Product Background and Clinical Information ......................................................... 18 
2.3 Study Rationale .......................................................................................................... 19 
2.4 Benefit/Risk Assessment............................................................................................. 19 
2.5 Compliance Statement ............................................................................................... 20 
3. OBJECTIVES AND ENDPOINTS.................................................................................. 21 
3.1 Study Objectives......................................................................................................... 21 
3.1.1 Primary Objective ............................................................................................... 21 
3.1.2 Secondary Objectives .......................................................................................... 21 
3.2 Study Endpoints ......................................................................................................... 21 
4. STUDY DESIGN ............................................................................................................. 22 
4.1 Overall Design ............................................................................................................ 22 
4.2 Scientific Rationale for Study Design ......................................................................... 22 
4.3 Justification for Dose.................................................................................................. 22 
4.4 Duration of Subject Participation and Study Completion Definition ........................ 22 
4.5 Sites and Regions........................................................................................................ 23 
5. STUDY POPULATION................................................................................................... 24 
5.1 Inclusion Criteria ....................................................................................................... 24 
5.2 Exclusion Criteria ...................................................................................................... 24 
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5.3 Restrictions................................................................................................................. 25 
5.4 Reproductive Potential ............................................................................................... 25 
5.4.1 Female Contraception ......................................................................................... 25 
5.4.2 Male Contraception ............................................................................................. 25 
6. STUDY INTERVENTION .............................................................................................. 26 
6.1 Investigational Product .............................................................................................. 26 
6.1.1 Identity of Investigational Product...................................................................... 26 
6.1.2 Blinding the Treatment Assignment.................................................................... 26 
6.2 Administration of Investigational Product................................................................. 26 
6.2.1 Allocation of Subjects to Treatment .................................................................... 27 
6.2.2 Dosing .................................................................................................................. 27 
6.2.3 Unblinding the Treatment Assignment ............................................................... 27 
6.2.4 Dose Modification................................................................................................ 27 
6.3 Labeling, Packaging, Storage, and Handling of Investigational Product .................. 27 
6.3.1 Labeling ............................................................................................................... 27 
6.3.2 Storage................................................................................................................. 27 
6.4 Drug Accountability ................................................................................................... 28 
6.5 Subject Compliance.................................................................................................... 29 
6.6 Prior and Concomitant Therapy ................................................................................ 29 
6.6.1 Prior Treatment .................................................................................................. 30 
6.6.2 Concomitant Treatment ...................................................................................... 30 
6.6.3 Permitted Treatment ........................................................................................... 30 
6.6.4 Prohibited Treatment .......................................................................................... 31 
7. DISCONTINUATION OF STUDY INTERVENTION AND SUBJECT 
DISCONTINUATION/WITHDRAWAL ........................................................................ 32 
7.1 Discontinuation of Study Treatment .......................................................................... 32 
7.2 Reasons for Discontinuation....................................................................................... 32 
7.3 Withdrawal from the Study ....................................................................................... 33 
7.4 Subjects “Lost to Follow-up” Prior to the Last Scheduled Visit ................................ 33 
8. STUDY ASSESSMENTS AND PROCEDURES ............................................................. 34 
8.1 Informed Consent and Enrollment ............................................................................ 34 
8.2 Subject Identification Code ........................................................................................ 34 
8.3 Study Periods ............................................................................................................. 34 
8.3.1 Screening Period.................................................................................................. 34 
8.3.1.1 Screening Visit .............................................................................................. 34 
8.3.1.2 Baseline Visit (Day 0) .................................................................................... 35 
8.3.2 Treatment Period ................................................................................................ 35 
8.3.2.1 Visit 1 and Visit 2 .......................................................................................... 35 
8.3.2.2 Final Visit (End-of-Treatment Visit / Study Termination Visit) .................. 35 
8.3.3 Follow-up Period ................................................................................................. 35 
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8.3.4 Additional Care of Subjects after the Study........................................................ 35 
8.4 Study Assessments...................................................................................................... 36 
8.4.1 Demographic and Other Baseline Characteristics .............................................. 36 
8.4.1.1 Height and Weight ........................................................................................ 36 
8.4.1.2 Medical and Medication History .................................................................. 36 
8.4.2 Efficacy ................................................................................................................ 36 
8.4.2.1 Effectiveness of ADVATE as On-demand and Prophylactic Treatment ...... 36 
8.4.2.2 Determination of Incremental Recovery....................................................... 38 
8.4.2.3 Blood Sampling for Determination of Factor VIII Level.............................. 38 
8.4.3 Safety ................................................................................................................... 39 
8.4.3.1 Physical Examination ................................................................................... 39 
8.4.3.2 Adverse Events ............................................................................................. 39 
8.4.3.3 Vital Signs ..................................................................................................... 39 
8.4.3.4 Clinical Laboratory Tests ............................................................................. 39 
8.4.3.5 Clinical Pharmacology .................................................................................. 40 
8.4.4 Volume of Blood to Be Drawn from Each Subject .............................................. 40 
8.4.5 Backup Samples and Biobanking ........................................................................ 41 
9. STATISTICAL CONSIDERATIONS ............................................................................. 42 
9.1 Statistical Analysis Process ........................................................................................ 42 
9.2 Planned Interim Analysis, Adaptive Design, and Data Monitoring Committee ........ 42 
9.3 Sample Size and Power Considerations ..................................................................... 42 
9.4 Statistical Analysis Set(s)............................................................................................ 42 
9.4.1 Effectiveness Full Analysis Set (EFAS) ............................................................... 42 
9.4.2 Safety Analysis Set (SAS) .................................................................................... 42 
9.5 Efficacy Analyses........................................................................................................ 43 
9.5.1 Primary Efficacy Endpoint ................................................................................. 43 
9.5.2 Secondary Efficacy Endpoints............................................................................. 43 
9.5.3 Multiplicity Adjustment ...................................................................................... 43 
9.6 Safety Analyses........................................................................................................... 43 
9.7 Other Analyses ........................................................................................................... 43 
10. SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS .. 45 
APPENDIX 1 REGULATORY, ETHICAL, AND STUDY OVERSIGHT 
CONSIDERATIONS ....................................................................................................... 45 
Appendix 1.1 Regulatory and Ethical Considerations .................................................. 45 
Appendix 1.2 Sponsor’s Responsibilities....................................................................... 45 
Appendix 1.3 Investigator’s Responsibilities ................................................................ 46 
Appendix 1.4 Data Management Considerations.......................................................... 49 
Appendix 1.5 Ethical Considerations ............................................................................ 50 
APPENDIX 2 CLINICAL LABORATORY TESTS ........................................................ 54 
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Appendix 2.1 Hematology and Clinical Chemistry ....................................................... 54 
Appendix 2.2 Viral Serology ......................................................................................... 54 
Appendix 2.3 FVIII Antigen ......................................................................................... 55 
Appendix 2.4 Blood Sampling for Determination of FVIII Activity ............................. 55 
Appendix 2.5 Incremental recovery (IR) ...................................................................... 55 
Appendix 2.6 FVIII Inhibitor ....................................................................................... 56 
APPENDIX 3 ADVERSE EVENTS: DEFINITIONS AND PROCEDURES FOR 
RECORDING, EVALUATING, FOLLOW-UP, AND REPORTING ............................ 57 
Appendix 3.1 Adverse Event Definitions....................................................................... 57 
Appendix 3.2 Collection of Adverse Events .................................................................. 60 
Appendix 3.3 Assessment of Adverse Events ................................................................ 60 
Appendix 3.4 Safety Reporting ..................................................................................... 62 
Appendix 3.5 Serious Adverse Event Collection Time Frame ...................................... 63 
Appendix 3.6 Serious Adverse Event Onset and Resolution Dates ............................... 63 
Appendix 3.7 Fatal Outcome......................................................................................... 64 
Appendix 3.8 Pregnancy ............................................................................................... 64 
Appendix 3.9 Abuse, Misuse, Overdose and Medication Error .................................... 65 
Appendix 3.10 Urgent Safety Measures .......................................................................... 66 
Appendix 3.11 Regulatory Agency, Institutional Review Board, Ethics Committee and 
Site Reporting ............................................................................................................ 66 
APPENDIX 4 COUNTRY-SPECIFIC REQUIREMENTS.............................................. 67 
Appendix 4.1 Package Insert......................................................................................... 67 
Appendix 4.2 Undertaking by the Investigator ............................................................. 70 
APPENDIX 5 ABBREVIATIONS.................................................................................... 72 
APPENDIX 6 PROTOCOL HISTORY ........................................................................... 75 
11. REFERENCES .............................................................................................................. 76 
 
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Tables 
Table 1. Schedule of Study Procedures and Assessments ........................................................ 15 
Table 2. Schedule of Clinical Laboratory Assessments............................................................ 16 
Table 3. Objectives and Endpoints ......................................................................................... 21 
Table 4. Overall Effectiveness Assessment for Bleed Treatment.............................................. 38 
Table 5. Overall Effectiveness Assessment for Prophylactic Treatment ................................... 38 
Table 6. Time Points for FVIII Activity Assessment for IR Determination .............................. 56 
Table 7. Adverse Event Relationship Categorization ............................................................... 61 
 
Figures 
Figure 1. Study Design and Visit Schedule ............................................................................. 14 
 
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1. PROTOCOL SUMMARY 
1.1 Synopsis 
Protocol number: TAK-761-4009 
Drug: ADVATE (Coagulation Factor VIII (Recombinant) rFVIII, 
Plasma/Albumin Free Method; Octocog Alfa) 
Title of the study: Phase 4, Multicenter, Prospective, Interventional, Post-Marketing Study in Hemophilia A 
Patients in India Receiving ADVATE as On-demand or Prophylaxis Under Standard Clinical Practice 
Short title: ADVATE INDIA PMC Study 
Study phase: Phase 4 (post-marketing)  
Number of subjects (total and per treatment arm): Total: 50 subjects (single-group assignment) 
Investigator(s): Multicenter study 
Site(s) and Region(s): India (multicenter) 
Study period (planned): 
Q2/Q3 2021 to Q1 2023 
Clinical phase: 
4 (post-marketing) 
Objectives: 
Primary:  
• To assess the safety of ADVATE based on serious adverse events (SAEs) (including FVIII inhibitors) 
Secondary:  
• To assess the safety of ADVATE based on adverse events (AEs) and changes in laboratory parameters 
• To assess the efficacy of prophylactic treatment with ADVATE 
• To assess the efficacy of on-demand treatment with ADVATE in the control of bleeding episodes 
Rationale: 
The purpose of this study is to evaluate the safety and efficacy of ADVATE when used under standard clinical 
practice in previously treated hemophilia A patients (PTPs) in India. 
Investigational product, dose, and mode of administration: 
ADVATE (Coagulation Factor VIII (Recombinant) rFVIII, Plasma/Albumin Free Method; Octocog Alfa) 
Refer to the ADVATE India Product Label for further information. 
Methodology: 
This is a Phase 4, multicenter, prospective, interventional, post-marketing study in previously treated hemophilia 
A patients (PTPs) in India receiving ADVATE under standard clinical practice.  
All enrolled subjects who have met the inclusion and exclusion criteria will be treated with ADVATE according to 
a regimen determined by the treating physician and in accordance with the national product label. The individual 
subject´s duration of participation is expected to be approximately 7-8 months. The period of observation for each 
subject will be 6 months; another 10 to 15 days are anticipated for the study completion visit (“End-of-Treatment 
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Visit”). The starting point of the observation will be an infusion of ADVATE at baseline to determine incremental 
recovery (IR). 
Inclusion and Exclusion Criteria:  
Inclusion Criteria: 
1. The subject or legally authorized representative (in case of study participants <18 years of age) gave written 
informed consent to participate in the study. 
2. Subject of any age with hemophilia A.  
3. Subject is defined as previously treated patient (PTP): 
• 
Subject aged ≥ 6 years that has been previously treated with plasma-derived and/or recombinant FVIII 
concentrate(s) for a minimum of 150 exposure days (EDs). 
• 
Subject aged < 6 years that has been previously treated with plasma-derived and/or recombinant FVIII 
concentrate(s) for a minimum of 50 EDs. 
4. Subject has negative history of FVIII inhibitors and negative inhibitor at screening defined as less than 
0.6 Bethesda units (BU)/mL (Nijmegen-modified Bethesda assay). 
5. Subject is human immunodeficiency virus negative (HIV-); or HIV+ with stable disease and CD4+ count 
≥ 200 cells/mm3, as confirmed by central laboratory at screening. 
6. Subject is hepatitis C virus negative (HCV-) by antibody or polymerase chain reaction (PCR) testing (if 
positive, antibody titer will be confirmed by PCR), as confirmed by central laboratory at screening; or 
HCV+ with chronic stable hepatitis. 
7. The subject is willing and able to comply with the requirements of the protocol. 
 
Exclusion Criteria: 
1. Subject has known hypersensitivity to mouse or hamster proteins or to any of the excipients of FVIII 
concentrates. 
2. Subject has been diagnosed with bleeding disorder(s) other than congenital hemophilia A, such as acquired 
hemophilia A, von Willebrand´s disease or thrombocytopenia (platelet count<100,000/mL). 
3. Subject has received treatment for hemophilia A with non-FVIII products/concentrates (eg, emicizumab 
[Hemlibra®]) in the 6 months prior to screening. 
4. Subject has severe chronic hepatic dysfunction [eg, ≥ 5 times upper limit of normal alanine 
aminotransferase (ALT), aspartate aminotransferase (AST) or INR > 1.5 as confirmed by central laboratory 
at screening]. 
5. Subject has planned, or is likely to have, surgery during the study period. 
6. Subject has a clinically significant medical, psychiatric, or cognitive illness, or recreational drug/alcohol use 
that, in the opinion of the investigator, would affect subject’s safety or compliance. 
7. Subject is currently receiving or is scheduled to receive during the course of the study, an 
immunomodulating drug (eg, corticosteroid agents at a dose equivalent to hydrocortisone greater than 
10 mg/day, or α-interferon) other than antiretroviral chemotherapy. 
8. Subject has participated in another clinical study involving an investigational product (IP) or investigational 
device within 30 days prior to enrollment or is scheduled to participate in another clinical study involving 
an IP or investigational device during the course of this study. 
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9. Subject is a family member or employee of the investigator.  
Maximum duration of subject participation in the study: Approximately 7-8 months 
• Planned duration of screening period: up to 45 days (until Day 0/Baseline Visit) 
• Planned duration of treatment period: 6 months 
• Time allocated for End-of-Treatment Visit: 10-15 days 
• Planned duration of follow-up: Not applicable. There will be no follow-up. 
Sample size calculation: 
According to the WFH Report on the Annual Global Survey 2017i, there were a total of 15,920 cases of 
hemophilia A in India in 2017. Due to the low prevalence of hemophilia A and the difficulty in switching patients 
from their current therapy, the planned sample size is 50 subjects. 
Statistical analysis: 
The statistical analysis for this study will be descriptive in nature. Descriptive statistics will include specifically, 
but not exclusively, arithmetic mean, standard deviation, medians, quartiles and interquartile range, minimum, 
maximum, proportions, frequency counts, and 95% confidence intervals of point estimates.  
Statistical Analysis for Primary Outcome Measure: 
Frequency counts and percentages for possibly or probably related SAEs (including FVIII inhibitor formation) as 
well as for subjects with possibly or probably related SAEs (including FVIII inhibitor formation) that occurred 
during or after first ADVATE infusion will be summarized. The incidence of FVIII inhibitor development will 
also be summarized by high-titer (>5 BU) and low-titer (0.6-5 BU). 
Statistical Analysis for Secondary Outcome Measures: 
Safety: 
See statistical analysis for primary outcome measure. 
All AEs will be cross-tabulated for relatedness, seriousness, and severity. AEs will be categorized according to 
the MedDRA dictionary and summarized by system organ class and preferred term. A listing of all AEs will be 
presented by subject identifier, age, sex, preferred term and reported term of the AE, duration, severity, 
seriousness, action taken, outcome, causality assessment by investigator, onset date, stop date and medication or 
non-drug therapy to treat the AE.  
Shift tables will be presented for the results of clinical laboratory data.  
Efficacy: 
The annualized bleeding rate (ABR) during the prophylactic treatment will be assumed to have a negative 
binomial distribution, and the mean ABR (95% CI) will be estimated using a generalized linear model (GLM). 
The total ABR and ABR by bleed cause/ site, i.e. joint, non-joint, target joints, spontaneous, traumatic, will be 
summarized descriptively as well. 
 
i World Federation of Hemophilia report on the annual global survey 2017. Published by the World Federation of 
Hemophilia. Montréal, Québec, Canada. October 2018. 
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Summary statistics for the total number of infusions, as well as the average number of prophylactic infusions per 
week and per month of prophylaxis will be provided. Similarly, the total body mass adjusted consumption and the 
average consumption of ADVATE per week and per month during prophylactic treatment will be provided. 
For the overall hemostatic efficacy rating at resolution of bleed, for the number of infusions of ADVATE to 
control a bleeding episode, as well as for the body mass adjusted consumption of ADVATE per bleeding event, 
summary statistics will be presented. These tables will be also presented by bleeding site, cause and severity. 
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1.2 Schema 
Figure 1. Study Design and Visit Schedule 
 
 
Screening 
Baseline Assessments 
On-demand/Prophylaxis 
Treatment &  
Follow-up visits 
EOS visit 
6 months 
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1.3 Schedule of Activities 
Table 1. Schedule of Study Procedures and Assessments 
Procedures/ 
Assessments 
Screening  
Visit 
Baseline 
Visit 
Visit 1 
Visit 2 
Unscheduled 
Visit(s)a 
End of Treatment 
Visit 
Study Termination 
Visitb 
Time point 
Up to 45 days 
prior to Day 0 
Day 0 
1 month 
± 1 week 
3 month 
± 1 week 
 
6 month  
± 1 week 
 
Informed Consentc 
X 
 
 
 
 
 
 
Eligibility Criteria 
X 
Xd 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
Hemophilia A Disease History, Bleeding History 
and FVIII Treatment History 
X 
 
 
 
 
 
 
Medications History (other than Hemophilia A) 
X 
 
 
 
 
 
 
Physical Exam 
X 
X 
X 
X 
X 
X 
X 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medications and Non-drug Therapies 
X 
X 
X 
X 
X 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
Laboratory assessments 
See Table 2 
Bleeding Episodes and Treatmente 
X 
X 
X 
X 
X 
X 
X 
Review of Subject Diary 
 
X 
X 
X 
X 
X 
X 
IP Use 
 
X 
X 
X 
X 
X 
X 
IP Dispensef 
 
X 
X 
X 
X 
 
 
a 
Unscheduled visits could be performed for any reason (bleed management, safety event, etc.) as per Investigators’ discretion. 
b 
Study Termination Visit will be performed only if subject is discontinuing the study or withdrawing from the study without completing the End of 
Treatment Visit. 
c  Occurs prior to any study-specific procedure. 
d  Same eligibility criteria to be used as at Screening. 
e  To collect information on the type of bleeding episodes (site, severity, duration) and the treatment used for the bleeding episodes (drug, dose, frequency, 
duration). 
f 
ADVATE should be dispensed to provide sufficient treatment until at least the next scheduled visit, or as appropriate. 
 
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Table 2. Schedule of Clinical Laboratory Assessments   
Procedures/ 
Assessments 
Screening 
Visit 
Baseline 
Visit 
Visit 1 
Visit 2 
Unscheduled 
Visit(s)a 
End of Treatment 
Visit 
Study Termination 
Visitb 
Time point 
Up to 45 days 
prior to Day 0 
Day 0 
1 month 
± 1 week 
3 month 
± 1 week 
 
6 month  
± 1 week 
 
Hematologyc 
X 
 
 
 
X (optional) 
X 
X 
Clinical chemistryd 
X 
 
 
 
X (optional) 
X 
X 
Viral serologye 
X 
 
 
 
 
X 
X 
FVIII Antigen 
X 
 
 
 
 
 
 
FVIII Activity 
X 
 
 
 
X (optional) 
 
 
Incremental Recovery (IR)f 
 
X 
 
X (optional) 
 
X 
X 
FVIII Inhibitorg 
X 
X 
X 
X 
X 
X 
X 
a 
Unscheduled visits could be performed for any reason (bleed management, safety event, etc.) as per Investigators’ discretion 
b 
Study Termination Visit will be performed only if subject is discontinuing the study or withdrawing from the study without completing the End of 
Treatment Visit. 
c  Hematology assessments include: hemoglobin, hematocrit, red blood cell count, and white blood cell count with differential (ie, basophils, eosinophils, 
lymphocytes, monocytes, neutrophils), mean corpuscular volume (MCV), mean corpuscular hemoglobin concentration (MCHC), and platelet count. 
d  Clinical chemistry assessments include: sodium, potassium, chloride, bicarbonate, total protein, albumin, alanine aminotransferase (ALT), aspartate 
aminotransferase (AST), total bilirubin, alkaline phosphatase, blood urea nitrogen (BUN), creatinine, and glucose. 
e 
Viral serology includes: HIV-1Ab, HIV-2 Ab, HBcAb, HBsAb, HBsAg, and HCVAb. Any HIV or HCV positive sample will be tested by PCR for viral 
titer, HIV positive subjects will have CD4 counts monitored every 3 months during the course of the study. 
f 
For assessment of IR: samples will be taken within 0.5 h before the start of the infusion, and at 15-30 minutes after the infusion. Prior to the pre-infusion 
blood draw for IR determination, subjects should have a washout period from previous plasma-derived and/or recombinant FVIII concentrate(s) treatment.  
The washout period will depend on the type of product the subject receives, ie, at least 48 hours for products with standard half-life and 84-96 hours for 
extended half-life products. 
g 
If an inhibitory titer ≥ 0.6 BU by Nijmegen, the test will be confirmed in the central laboratory within 2 weeks of study site notification. 
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2. INTRODUCTION 
2.1 Indication and Current Treatment Options  
FVIII is the blood clotting factor deficient or absent in individuals with hemophilia A. Hemophilia 
A is an X-linked chromosomal recessive disorder that results from defective or deficient plasma 
FVIII and consequently insufficient coagulant activity. Approximately 1 in 5,000 live male births 
worldwide has hemophilia A, resulting in over 400,000 affected individuals (Bolton-Maggs and 
Pasi, 2003, Soucie et al., 1998). Disease severity is dictated by plasma FVIII levels with 
approximately 60% of patients having severe disease, defined by FVIII levels < 1% of normal, and 
the remaining patients have moderate (FVIII levels 1-5%) or mild disease (FVIII levels 5-40%). 
Patients with severe disease are at risk of spontaneous bleeding into joints, muscles, and internal 
organs as well as trauma-induced bleeding following injury and surgery. Repeated bleeding into 
joints, which may occur as frequently as 20 to 30 times per year, is a major cause of morbidity and 
leads to hemophilic arthropathy (Lee, 2007). Bleeding episodes in young children also contribute 
to school absenteeism, interfere with physical function, and prevent them from participating in 
normal childhood activities (Shapiro et al., 2001). 
At present, FVIII replacement is the only symptomatic therapy (in terms of bleed treatment) 
available for the treatment of hemophilia A. FVIII administration temporarily increases 
FVIII levels and has been shown to temporarily correct the bleeding tendency. FVIII can 
be administered in response to a bleeding episode or as prophylactic replacement. 
ADVATE contains recombinant coagulation factor VIII (FVIII), a glycoprotein that has an amino 
acid sequence comparable to human FVIII, and posttranslational modifications that are similar to 
those of the plasma-derived molecule. Activated FVIII acts as a cofactor for activated factor IX, 
accelerating the conversion of factor X to activated factor X. Activated factor X converts 
prothrombin to thrombin. Thrombin then converts fibrinogen into fibrin and a fibrin clot is formed. 
ADVATE is a third-generation recombinant FVIII concentrate, produced by a genetically 
engineered Chinese hamster ovary (CHO) cell line and without the addition of any human or 
animal-derived protein in the cell-culture process, purification or final formulation. This 
production process virtually eliminates the risk of pathogen transmission (see Section 2.2). 
ADVATE is indicated for use in adults and children with hemophilia A for:  
• 
Control and prevention of bleeding episodes 
• 
Perioperative management 
• 
Routine prophylaxis to prevent or reduce the frequency of bleeding episodes 
 
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2.2 Product Background and Clinical Information 
Baxalta US Inc., now part of Takeda, has developed a third-generation recombinant FVIII 
concentrate (Antihemophilic Factor [Recombinant], Plasma/Albumin-Free Method [rAHF-PFM]) 
by the name of ADVATEii, produced by a genetically engineered Chinese hamster ovary (CHO) 
cell line. The plasma/albumin-free method does not employ any exogenously added proteins of 
human or animal origin in the cell culture, purification or formulation of the final product.  Other 
than factor VIII, the only proteins present in the final container product are trace quantities of 
murine immunoglobulin G (IgG) (from the immunoaffinity purification), CHO cell protein, and 
recombinant human von Willebrand factor (VWF). This process virtually eliminates any risk of 
transmission of human blood-borne viruses or other adventitious agents that could, in theory, be 
introduced by the use of animal-derived raw materials. 
The CHO cell line employed in the production of ADVATE is derived from that used in the 
biosynthesis of RECOMBINATE, Takeda´s first-generation recombinant antihemophilic factor 
(rAHF, RECOMBINATEiii), which has been licensed since 1988. 
Comprehensive physicochemical characterization studies have shown that ADVATE is virtually 
identical to RECOMBINATE. Consistent with this observation, nonclinical studies have 
demonstrated that ADVATE is comparable to RECOMBINATE with respect to hemostatic 
efficacy and pharmacokinetic (PK) parameters, as well as acute and repeat-dose toxicity. 
Extensive experience from over 30 completed clinical studies in the ADVATE clinical 
development program has shown ADVATE to be well tolerated and efficacious for hemostatic 
control, including for perioperative management, in previously treated pediatric, adolescent and 
adult patients (PTPs) and in previously untreated pediatric patients (PUPs) with severe or 
moderately-severe hemophilia A.  
ADVATE was first approved in the United States (US) on 25 July 2003 (= international birth 
date) for treatment of hemophilia A. In India, ADVATE was licensed in July 2015. 
ADVATE is currently licensed in 71 countries worldwide (as of 31 July 2018) for the 
prevention and control of bleeding episodes and for perioperative management in patients 
with hemophilia A (congenital FVIII deficiency). ADVATE is not indicated for the treatment 
of von Willebrand’s disease. 
 
ii ADVATE is a registered trademark of Baxalta Incorporated, a wholly owned, indirect subsidiary of Takeda plc. 
iii RECOMBINATE is a registered trademark of Baxalta Incorporated, a wholly owned, indirect subsidiary of 
Takeda plc. 
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2.3 Study Rationale 
The results derived from the ADVATE clinical development program have shown ADVATE to 
be well tolerated and efficacious for hemostatic control, including for perioperative management, 
in previously treated pediatric, adolescent and adult patients (PTPs) and in previously untreated 
pediatric patients (PUPs) with severe or moderately severe hemophilia A. 
This study will collect data on ADVATE administered to previously treated patients (PTPs) with 
hemophilia A in standard clinical practice and as per Product Label in India. 
The purpose of this study is to evaluate the safety and efficacy of ADVATE when used under 
standard clinical practice in previously treated hemophilia A patients (PTPs) in India. 
2.4 Benefit/Risk Assessment  
At present, FVIII replacement is the only symptomatic therapy available for the treatment of 
hemophilia A. ADVATE has structural and functional characteristics similar to those of 
endogenous FVIII. The development of a production process that virtually eliminates the risk of 
pathogen transmission represents a significant technical advance for hemophilia A patients who 
rely on chronic FVIII replacement therapy for their health and well-being, as it reduces the 
potential safety concerns associated with the use of FVIII concentrates. 
Data from ADVATE studies demonstrated that the annualized bleeding rates (ABRs) could be 
reduced to as low as one event with prophylactic treatment. In PTPs, most bleeding episodes can 
be managed with a single infusion. The PK-driven prophylactic regimens should be more 
effective in maintaining FVIII trough levels above a threshold for bleeding and may reduce the 
number of required weekly infusions, which may in turn, improve treatment adherence. 
Furthermore, the PK-driven dosing regimen based on patient's clinical response, offers some 
patients the option of fewer infusions over one year of treatment than the standard prophylaxis 
regimen. Thus, ADVATE PK-driven regimens have the potential to be more cost effective and 
thereby may expand access to prophylactic therapy. The efficacy of ADVATE for ITI has been 
demonstrated in subjects with inhibitors to FVIII. Data show that ADVATE has been used to 
induce immune tolerance. In patients where immune tolerance was achieved, the bleedings could 
be prevented or controlled with ADVATE again, and the patient could continue prophylactic 
treatment with ADVATE as maintenance therapy. 
The available safety data confirm that ADVATE is safe and well-tolerated in the treatment of 
moderately severe to severe hemophilia A. Review of spontaneous post-marketing AE reporting 
sources did not result in the detection of previously unrecognized risks or new safety concerns. 
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Potential risks are listed in the Package Insert, Section 4.4 Specials warnings and precautions for 
use (see Appendix 4.1). 
2.5 Compliance Statement 
This study will be conducted in accordance with this protocol, the International Council for 
Harmonisation Guideline for Good Clinical Practice E6 (ICH GCP, 1996; E6 R2, 2017), Title 21 
of the US Code of Federal Regulations (US CFR), the EU Directives (2001/20/EC; 2005/28/EC), 
and applicable national and local regulatory requirements. 
The responsibilities of the study sponsor and investigator(s) are described fully in Appendix 1. 
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3. OBJECTIVES AND ENDPOINTS 
3.1 Study Objectives 
3.1.1 Primary Objective 
The primary objective of this study is to assess the safety of ADVATE based on serious adverse 
events (SAEs) (including FVIII inhibitors). 
3.1.2 Secondary Objectives 
• 
To assess the safety of ADVATE based on adverse events (AEs) and changes in laboratory 
parameters 
• 
To assess the efficacy of prophylactic treatment with ADVATE 
• 
To assess the efficacy of on-demand treatment with ADVATE in the control of bleeding 
episodes 
 
3.2 Study Endpoints 
See Table 3. Each endpoint is mapped to the objective it supports. 
Table 3. Objectives and Endpoints 
Objective 
Endpoint(s) 
Primary 
 
• To assess the safety of ADVATE 
based on SAEs (including FVIII 
inhibitors) 
• Incidence of SAEs (including FVIII inhibitor formation) that are at 
least possibly related to ADVATE 
Secondary 
 
• To assess the safety of ADVATE 
based on AEs and changes in 
laboratory parameters 
• Incidence of non-serious AEs that are at least possibly related to 
ADVATE 
• Clinically significant changes in clinical laboratory parameters 
(hematology and clinical chemistry) 
• To assess the efficacy of 
prophylactic treatment with 
ADVATE 
• Annualized bleeding rate (ABR) with prophylactic use of ADVATE 
• Total number of infusions and the average number of infusions per 
week per month during prophylactic treatment 
• Total and average body mass adjusted consumption of ADVATE 
per week per month during prophylactic treatment 
• To assess the efficacy of bleed 
treatment with ADVATE  
• Overall hemostatic efficacy rating for treatment of bleeding 
episodes 
• Number of ADVATE infusions required to achieve bleed resolution 
• Body mass adjusted consumption of ADVATE per bleeding episode 
Abbreviations: ABR = annualized bleeding rate; AE = adverse event; FVIII = Factor VIII;  
SAE = serious adverse event 
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4. STUDY DESIGN 
4.1 Overall Design  
This is a Phase 4, multicenter, prospective, interventional, post-marketing study in previously 
treated hemophilia A patients (PTPs) in India receiving ADVATE under standard clinical practice.  
All enrolled subjects who have met the inclusion and exclusion criteria will be treated with 
ADVATE according to a regimen determined by the treating physician and in accordance with the 
national product label. The period of observation for each subject will be 6 months. For all subjects 
(regardless of prophylactic or on-demand treatment), the starting point of the observation will be 
an infusion of ADVATE at baseline (dose: 50±5 IU/kg) to determine incremental recovery (IR). 
See study design flowchart in Figure 1. 
According to the WFH Report on the Annual Global Survey 2017 (World Federation of 
Hemophilia, 2018) there were a total of 15,920 cases of hemophilia A in India in 2017. Due to the 
low prevalence of hemophilia A and the difficulty in switching patients from their current therapy, 
the planned sample size is 50 subjects. 
4.2 Scientific Rationale for Study Design 
This phase 4 study is designed to evaluate the safety and efficacy of ADVATE when used under 
standard clinical practice (ie, per Product Label) in previously treated hemophilia A patients 
(PTPs) in India. 
4.3 Justification for Dose 
Subjects will be treated according to a regimen determined by the treating physician and in 
accordance with the national product label. Guidance on dosing for prophylactic and on-demand 
treatment can be found in the ADVATE Package Insert for India (see Appendix 4.1). 
For the ADVATE infusion to determine IR, a dose of 50±5 IU/kg of ADVATE shall be given, as 
in previous ADVATE clinical studies. 
4.4 Duration of Subject Participation and Study Completion Definition 
Any subject who provides informed consent (ie, signs and dates the informed consent form and 
assent form, if applicable) is considered enrolled in the study (see Section 8.1 and Appendix 1.5). 
The subject’s maximum duration of participation is expected to be approximately 7-8 months. 
The period of observation for each subject will be 6 months; another 10 to 15 days are 
anticipated for the study completion visit (“End-of-Treatment Visit”). The study will be 
completed in approximately 2 years´ time.  
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The Study Completion Date is defined as the date on which the last subject in the study 
completes the final protocol-defined assessment(s). This includes the follow-up visit or contact, 
whichever is later (refer to Section 8.3.3 for the defined follow-up period for this protocol). 
4.5 Sites and Regions 
The study will be a multicenter study in India. 
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5. STUDY POPULATION 
Each subject must participate in the informed consent process and provide written informed 
consent/assent before any procedures specified in the protocol are performed. 
5.1 Inclusion Criteria 
The subject will not be considered eligible for the study without meeting all of the criteria below. 
1. The subject or legally authorized representative (in case of study participants <18 years of 
age) gave written informed consent to participate in the study. 
2. Subject of any age with hemophilia A.  
3. Subject is defined as a previously treated patient (PTP): 
• Subject aged ≥ 6 years that has been previously treated with plasma-derived and/or 
recombinant FVIII concentrate(s) for a minimum of 150 EDs. 
• Subject aged < 6 years that has been previously treated with plasma-derived and/or 
recombinant FVIII concentrate(s) for a minimum of 50 EDs. 
4. Subject has negative history of FVIII inhibitors and negative inhibitor at screening defined 
as less than 0.6 Bethesda units (BU)/mL (Nijmegen-modified Bethesda assay). 
5. Subject is human immunodeficiency virus negative (HIV-); or HIV+ with stable disease 
and CD4+ count ≥ 200 cells/mm3, as confirmed by central laboratory at screening. 
6. Subject is hepatitis C virus negative (HCV-) by antibody or PCR testing (if positive, 
antibody titer will be confirmed by PCR), as confirmed by central laboratory at screening; 
or HCV+ with chronic stable hepatitis. 
7. The subject is willing and able to comply with the requirements of the protocol. 
 
5.2 Exclusion Criteria 
The subject will be excluded from the study if any of the following exclusion criteria are met.  
1. Subject has known hypersensitivity to mouse or hamster proteins or to any of the 
excipients of FVIII concentrates. 
2. Subject has been diagnosed with bleeding disorder(s) other than congenital hemophilia A, 
such as acquired hemophilia A, von Willebrand´s disease (VWD) or thrombocytopenia 
(platelet count<100,000/mL). 
3. Subject has received treatment for hemophilia A with non-FVIII products/concentrates 
(eg, emicizumab [Hemlibra®]) in the 6 months prior to screening. 
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4. Subject has severe chronic hepatic dysfunction [eg, ≥ 5 times upper limit of normal alanine 
aminotransferase (ALT), aspartate aminotransferase (AST) or INR > 1.5 as confirmed by 
central laboratory at screening]. 
5. Subject has planned, or is likely to have, surgery during the study period. 
6. Subject has a clinically significant medical, psychiatric, or cognitive illness, or recreational 
drug/alcohol use that, in the opinion of the investigator, would affect subject’s safety or 
compliance. 
7. Subject is currently receiving or is scheduled to receive during the course of the study, an 
immunomodulating drug (eg, corticosteroid agents at a dose equivalent to hydrocortisone 
greater than 10 mg/day, or α-interferon) other than antiretroviral chemotherapy. 
8. Subject has participated in another clinical study involving an investigational product (IP) 
or investigational device within 30 days prior to enrollment or is scheduled to participate in 
another clinical study involving an IP or investigational device during the course of this 
study. 
9. Subject is a family member or employee of the investigator. 
 
5.3 Restrictions  
No dietary or activity restrictions are associated with this study. 
5.4 Reproductive Potential 
5.4.1 Female Contraception 
Not applicable for this post-marketing study. 
5.4.2 Male Contraception 
Not applicable for this post-marketing study. 
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6.  STUDY INTERVENTION 
6.1 Investigational Product 
6.1.1 Identity of Investigational Product 
ADVATE is formulated as a sterile, nonpyrogenic, lyophilized powder or friable solid of 
concentrated FVIII of white to off-white color and is provided in single-dose vials. Each vial of 
ADVATE is labeled with the antihemophilic factor (AHF) activity expressed in international units 
(IU) per vial.  
The ADVATE powder vial is provided together with the diluent vial (containing Sterile Water for 
Injections [SWFI]) and a needleless transfer device for reconstitution (BAXJECT II). 
ADVATE has a shelf life of 2 years when stored unopened under refrigeration (ie, 2°C- 8°C). 
Alternatively, ADVATE may be stored at room temperature (up to 25°C) for a period up to 
6 months, not to exceed the expiration date. Freezing should be avoided to prevent damage to the 
diluent vial. 
ADVATE will be provided by the sponsor and will be labeled as investigational product (IP). 
6.1.2 Blinding the Treatment Assignment 
Not applicable. 
6.2 Administration of Investigational Product 
ADVATE is to be administered intravenously after reconstitution. For reconstitution instructions, 
please refer to the ADVATE Package Insert for India (see Appendix 4.1). 
The prepared solution should be inspected for particulate matter and discoloration prior to 
administration. The solution should be clear and colorless and free from foreign particles. If not, 
do not use the solution and notify the sponsor immediately. 
ADVATE should be administered by bolus injection over a period of ≤5 minutes. The rate 
of administration should be at a rate that ensures the comfort of the patient, up to a maximum 
of 10 ml/min. ADVATE should be administered at room temperature within 3 hours of 
reconstitution. Plastic syringes must be used with this product, since proteins such as ADVATE 
tend to stick to the surface of glass syringes. 
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6.2.1 Allocation of Subjects to Treatment  
This is an open-label, uncontrolled, single-group, post-marketing study. Subjects will receive 
either prophylactic or on-demand treatment. The actual treatment given to individual subjects 
will be according to a regimen determined by the treating physician and in accordance with 
standard clinical practice and the national product label. 
Subject numbers are assigned to all subjects as they consent to take part in the study. Within each 
site (numbered uniquely within a protocol), the subject number is assigned to subjects according 
to the sequence of presentation for study participation.  
6.2.2 Dosing 
The dosage and duration of treatment depend on the severity of FVIII deficiency, the location 
and extent of the bleeding, and the patient´s clinical condition. 
Dosing details are provided in the ADVATE Product Label for India.  
6.2.3 Unblinding the Treatment Assignment 
Not applicable. 
6.2.4 Dose Modification 
Not applicable. 
6.3 Labeling, Packaging, Storage, and Handling of Investigational Product 
6.3.1 Labeling 
Each vial will be labeled with the actual potency in International Units and a Product Label. 
The Product Label will meet country-specific regulatory label requirements. 
6.3.2 Storage 
The investigator has overall responsibility for ensuring that investigational product is stored in a 
secure, limited-access location. Limited responsibility may be delegated to the pharmacy or 
member of the study team, but this delegation must be documented. Investigational products are 
distributed by the pharmacy or nominated member of the study team. The pharmacist/nominated 
team member will enter the unique subject identifier on the investigational product bottle/carton 
labels as they are distributed. 
Investigational product must be stored in accordance with labeled storage conditions. Details 
are provided in Section 6.1.1. Temperature monitoring is required at the storage location to ensure 
that the investigational product is maintained within an established temperature range.  
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The investigator is responsible for ensuring that the temperature is monitored throughout the 
duration of the study and that records are maintained; the temperature should be monitored 
continuously by using either an in-house system, a mechanical recording device such as a 
calibrated chart recorder, or by manual means, such that both minimum and maximum 
thermometric values over a specific time period can be recorded and retrieved as required. Such a 
device (ie, certified min/max thermometer) would require manual resetting upon each recording. 
The sponsor must be notified immediately upon discovery of any excursion from the established 
range. Temperature excursions will require site investigation as to cause and remediation. The 
sponsor will determine the ultimate impact of excursions on the investigational product and will 
provide supportive documentation as necessary. Under no circumstances should the product be 
dispensed to subjects until the impact has been determined and the product is deemed appropriate 
for use by the sponsor. 
The sponsor should be notified immediately if there are any changes to the storage area of the 
investigational product that could affect the integrity of the product(s), eg, fumigation of a storage 
room. 
6.4 Drug Accountability 
Investigators will be provided with sufficient amounts of the investigational product to carry out 
this protocol for the agreed number of subjects. The investigator or designee will acknowledge 
receipt of the investigational product, documenting shipment content and condition. Accurate 
records of all investigational product dispensed, used, returned, and/or destroyed must be 
maintained as detailed further in this section. 
The investigator has overall responsibility for administering/dispensing investigational product. 
Where permissible, tasks may be delegated to a qualified designee (eg, a pharmacist) who is 
adequately trained in the protocol and who works under the direct supervision of the investigator. 
This delegation must be documented in the applicable study delegation of authority form. 
The investigator or his/her designee (as documented by the investigator in the applicable study 
delegation of authority form) will administer/dispense the investigational product only to subjects 
included in this study following the procedures set out in the study protocol. Each subject will be 
given 
only 
the 
investigational 
product 
carrying 
his/her 
treatment 
assignment. 
All administered/dispensed medication will be documented in the subject’s source and/or other 
investigational product record. The investigator is responsible for ensuring the retrieval of all study 
supplies from subjects. The investigator must request that subjects keep the empty investigational 
product packaging after use and return it to the site for drug accountability purposes. 
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No investigational product stock or returned inventory from a Takeda-sponsored study may be 
removed from the site where originally shipped without prior knowledge and consent by the 
sponsor. If such transfer is authorized by the sponsor, all applicable local, state, and national laws 
must be adhered to for the transfer. 
The sponsor or its representatives must be permitted access to review the supplies storage and 
distribution procedures and records. 
At the end of the study, or as instructed by the sponsor, all unused stock, subject-returned 
investigational product, and empty/used investigational product packaging are to be sent to a 
nominated contractor on behalf of the sponsor. Investigational product being returned to the 
sponsor’s designated contractors must be counted and verified by clinical site personnel and the 
sponsor (or designated CRO). For unused supplies where the original supplied tamper-evident 
feature is verified as intact, the tamper-evident feature must not be broken and the labeled amount 
is to be documented in lieu of counting. Shipment return forms, when used, must be signed prior 
to shipment from the site. Validated electronic return systems (ie, IRT) do not require a shipment 
form. Returned investigational product must be packed in a tamper-evident manner to ensure 
product integrity. Contact the sponsor for authorization to return any investigational product prior 
to shipment. Shipment of all returned investigational product must comply with local, state, and 
national laws. 
Based on entries in the site drug accountability forms, it must be possible to reconcile 
investigational products delivered with those used and returned. All investigational products must 
be accounted for and all discrepancies investigated and documented to the sponsor’s satisfaction. 
6.5 Subject Compliance 
Subjects must be instructed to bring unused investigational product and empty/used investigational 
product packaging to every visit. Drug accountability must be assessed at the container/packaging 
level for unused investigational product that is contained within the original tamper-evident sealed 
container (eg, bottles, trays, vials) or at the individual count level for opened containers/packaging. 
The pharmacist/nominated person will record details on the drug accountability form. 
All study procedures are to be performed under the direct supervision of the investigator/a licensed 
healthcare professional at the study site, and thus, no separate procedures will be used to monitor 
subject compliance. 
6.6 Prior and Concomitant Therapy 
All non-study treatment received within 3 months prior to the screening visit and through the final 
study contact must be recorded in the subject’s source document.  
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The physician is expected to follow standard clinical practice and all kinds of medications and/or 
non-drug therapies are allowed.  
If any subject develops FVIII inhibitors during the study, they will be withdrawn from the study 
and treated as per standard of care (SoC) at the discretion of the Investigator (Note: ADVATE will 
not be used for ITI). 
6.6.1 Prior Treatment 
Prior treatment includes all treatment received within 6 months from the date of first dose of 
investigational product. Prior treatment information must be recorded in the subject’s source 
document. In addition, the history of any hemophilia product usage for 6 months prior to screening 
must be recorded in the medical history. Please note that the use of non-FVIII 
products/concentrates (eg, Hemlibra) in the 6 months prior to screening represents an exclusion 
criterion (see Section 5.2). 
6.6.2 Concomitant Treatment  
All medications taken and non-drug therapies received within 3 months before providing informed 
consent until completion/termination will be recorded on the concomitant medications and non-
drug therapies CRFs. 
6.6.3 Permitted Treatment 
The physician is expected to follow standard clinical practice and all kinds of medications and/or 
non-drug therapies are allowed.  
The following medications and non-drug therapies are permitted before study entry and during the 
course of the study: 
• 
Medications: 
 
Hemostatic agents, such as tranexamic acid, are permitted, as indicated by the subject’s 
treating physician, to treat mucosal bleeding during the study or during a surgical or 
other invasive procedure (Please note that subjects will be withdrawn from the study 
if they need emergency surgery during the study.) 
 
Any medications deemed necessary by the subject’s physician to treat or prevent any 
medical condition 
 
Any over-the-counter medication used by the subject to treat symptoms or signs 
 
Supplemental vitamins, minerals 
 
Immunization: 
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o 
The concurrent administration of a vaccine and ADVATE at site visits should be 
avoided. 
o 
If possible, intramuscular vaccination should be replaced by subcutaneous 
administration. 
o 
Vaccinations 1 month prior to and during the study should be recorded as 
concomitant medications 
• 
Non-drug therapies: 
 
Any non-drug therapy (eg, physiotherapy) deemed necessary by the subject’s 
physician to treat or prevent any medical condition 
 
Note: If any subject develops FVIII inhibitors during the study, they will be withdrawn from the 
study and treated as per standard of care (SoC) at the discretion of the Investigator (Note: 
ADVATE will not be used for ITI). 
6.6.4 Prohibited Treatment 
• 
The use of a FVIII concentrate other than ADVATE (eg, any other plasma derived or 
recombinant FVIII product) will disqualify the subject from further participation in the 
study. 
• 
Immunomodulating drugs are also not allowed as concomitant medication (see also 
exclusion criteria, Section 5.2). 
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7. DISCONTINUATION OF STUDY INTERVENTION AND SUBJECT 
DISCONTINUATION/WITHDRAWAL 
7.1 Discontinuation of Study Treatment 
Any subject may voluntarily withdraw (ie, reduce the degree of participation in the study) consent 
for continued participation and data collection. 
If investigational product is discontinued, regardless of the reason, the evaluations listed for the 
Study Termination Visit will be performed as completely as possible. The assessments to be 
performed at the Study Termination Visit are described in Section 1.3 (Table 1, Table 2). 
Comments (spontaneous or elicited) or complaints made by the subject must be recorded in the 
source documents. The reason for discontinuation, date of discontinuation of the investigational 
product, and the total amount of investigational product administered must be recorded in the 
source documents. 
7.2 Reasons for Discontinuation  
The reason for discontinuation must be determined by the investigator and recorded in the 
subject’s source document. If a subject is discontinued for more than 1 reason, each reason 
should be documented in the source and the most clinically relevant reason should be indicated. 
Reasons for discontinuation include, but are not limited to: 
• 
Adverse event 
• 
Protocol deviation 
• 
Withdrawal by subject 
• 
Lost to follow-up 
• 
Lack of efficacy 
• 
Use of a FVIII concentrate other than ADVATE (see also Section 6.6.4 and 
Section 8.4.2.1) 
• 
Development of FVIII inhibitors 
• 
Other (if “Other” is selected, the investigator must specify on the CRF) 
 
Additionally, the investigator and sponsor have the discretion to discontinue any subject from the 
study if, in their judgment, continued participation would pose an unacceptable risk for the 
subject.  
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Note: If any subject develops FVIII inhibitors during the study, they will be withdrawn from the 
study and treated as per standard of care (SoC) at the discretion of the investigator (Note: 
ADVATE will not be used for ITI.) 
Note: Subjects will also be withdrawn from the study if they need emergency surgery during the 
study. 
7.3 Withdrawal from the Study 
A subject may withdraw from the study at any time and for any reason without prejudice to 
his/her future medical care by the physician or at the institution, or may be withdrawn at any 
time at the discretion of the investigator or sponsor (eg, in the interest of subject safety). The 
investigator is encouraged to discuss withdrawal of a subject with the medical monitor when 
possible. 
7.4 Subjects “Lost to Follow-up” Prior to the Last Scheduled Visit 
A minimum of 3 documented attempts must be made to contact any subject who is lost to 
follow-up at any time point prior to the last scheduled contact (office visit or telephone contact). 
At least 1 of these documented attempts must include a written communication sent to the 
subject’s last known address via courier or mail (with an acknowledgement of receipt request) 
asking that the subject return to the site for final safety evaluations and return any unused 
investigational product. 
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8. STUDY ASSESSMENTS AND PROCEDURES 
8.1 Informed Consent and Enrollment 
Investigators will choose patients for participation considering the study eligibility criteria. 
The investigator will exercise no selectivity so that no bias is introduced from this source. 
Prior to performing any trial assessments that are not part of routine medical care for the subject, 
all patients and/or their legally authorized representative must sign an informed consent form 
before entering into the study according to applicable national and local regulatory requirements 
and ICH GCP. An assent form may be provided and should be signed by patients less than 
18 years of age. Any patient who provides informed consent (ie, signs and dates the informed 
consent form and assent form, if applicable) is considered enrolled in the study. 
More detailed information on the informed consent procedure can be found in Appendix 1.5. 
8.2 Subject Identification Code 
The following series of numbers will comprise the SIC: protocol identifier (eg, TAK-761-4009) 
to be provided by the sponsor, 2- or 3-digit number study site number (eg, 02) to be provided by 
the sponsor, and 3-digit subject number (eg, 003) reflecting the order of providing informed 
consent. For example, the third subject who signed an informed consent form at study site 02 
will be identified as Subject TAK-761-4009-02003. All study documents (eg, CRFs, clinical 
documentation, sample containers, drug accountability logs, etc.) will be identified with the SIC. 
Additionally, a uniquely coded SIC(s) is permitted as long as it does not contain a combination 
of information that allows identification of a subject (eg, collection of a subject’s initials and 
birth date would not be permitted), in compliance with laws governing data privacy. 
8.3 Study Periods 
The overall study periods are shown in Figure 1. Refer to Table 1 for the schedule of study 
activities and to Table 2 for an overview of the clinical laboratory assessments to be performed at 
each study visit, including screening. Study assessments are detailed in Section 8.4. 
8.3.1 Screening Period 
8.3.1.1 Screening Visit 
The screening visit will take place within 45 days prior to the Baseline Visit on Day 0 
(see Table 1 and Table 2).  
The study site is responsible for maintaining a screening log that includes all subjects who 
provided informed consent. The log also will serve to document the reason for screening failure. 
All screening data will be collected and reported in CRFs, regardless of screening outcome. 
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A screen failure is a subject who has given informed consent and failed to meet the inclusion 
and/or met at least 1 of the exclusion criteria and has not been administered investigational 
product(s). Subjects who are considered as screen failures can be rescreened at a later date if 
there is reason to believe that they may then meet all eligibility criteria. 
8.3.1.2 Baseline Visit (Day 0) 
Refer to Table 1 and Table 2 for the procedures and assessments to be performed at the Baseline 
Visit. 
8.3.2 Treatment Period  
The treatment period will be 6 months, starting with the Baseline Visit (Day 0) and ending with 
the End-of-Treatment Visit (Month 6 ± 1 week). The starting point of the treatment/observation 
period will be an infusion of ADVATE at the Baseline Visit to determine IR. 
8.3.2.1 Visit 1 and Visit 2   
Two scheduled study visits are to be performed during the treatment period: Visit 1 at Month 1 
(± 1 week) and Visit 2 at Month 3 (± 1 week). Additional unscheduled visits are also possible. 
For the individual assessments to be performed at each study visit, see Table 1 and Table 2. 
In addition, ADVATE will be dispensed to the subjects at the study visits (Baseline, Visit 1, 
Visit 2, unscheduled visits) to provide sufficient treatment until the next scheduled visit, or as 
appropriate (see Table 1). 
8.3.2.2 Final Visit (End-of-Treatment Visit / Study Termination Visit) 
After subjects have completed 6 months of treatment on the study, the End-of-Treatment Visit 
will take place. Refer to Table 1 and Table 2 for the individual assessments and procedures to be 
performed at this visit.  
If subjects discontinue the study early or withdraw from the study, a Study Termination Visit 
will be performed instead of the End-of-Treatment Visit. The assessments and procedures for the 
Termination Visit will be the same as for the End-of-Treatment Visit. 
8.3.3 Follow-up Period 
There is no follow-up period. 
8.3.4 Additional Care of Subjects after the Study 
No aftercare is planned for this study. 
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8.4 Study Assessments  
8.4.1 Demographic and Other Baseline Characteristics 
Subject demographic information including gender, age, and race will be collected prior to the 
subject receiving the first dose of investigational product.  
8.4.1.1 Height and Weight 
Height and weight will be measured and recorded in the subject’s source documents.  
8.4.1.2 Medical and Medication History 
Medical and medication history will be collected and recorded in the subject’s source documents. 
8.4.2 Efficacy 
8.4.2.1 Effectiveness of ADVATE as On-demand and Prophylactic Treatment 
In all cases, the treatment with ADVATE will be at the discretion of the investigator and will 
consist of either a prophylactic or on-demand treatment as per the ADVATE Product Label for 
India. The following information will be recorded by the subject, the subject’s legal 
representative (for home treatment) or by authorized, qualified personnel at the participating site 
(for hospital-based treatment in case of a bleeding episode): 
• 
Location of bleed, ie, joint, soft tissue, muscle, body cavity, intracranial, other 
• 
Type of bleed, ie, spontaneous, injury, unknown 
• 
Severity of bleed, ie, minor, moderate, major, life/limb threatening 
• 
Date and time of onset of bleed 
• 
Date and time of each infusion of ADVATE required to achieve adequate hemostasis 
• 
Date and time of resolution of bleeding episode 
• 
Type and number of analgesics required  
• 
Overall effectiveness assessment for on-demand or prophylactic treatment as described in 
Section 8.4.2.1.1. 
 
If a bleed occurs following resolution of the bleed, it will be considered a “new” bleed and will 
be recorded accordingly. 
Subjects will resume their prophylactic treatment regimen the next scheduled day after the last 
therapeutic infusion for the treatment of a bleeding episode. 
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Details pertaining to all home treatments for each bleed, including response to treatment, will be 
recorded by study subjects or the subject’s legal representative in subject diaries provided by the 
study sponsor. At each study visit the investigator will review together with the subject the 
response to treatment and evaluate the hemostatic efficacy rating. Any inconsistency between the 
efficacy rating and the number of infusions required to treat a bleeding episode, or a response to 
treatment rated as “none” must be immediately clarified. If 2 or more responses to treatment are 
rated with “fair”, the investigator may re-evaluate the dosing regimen, and the time from bleeding 
onset to start of treatment. In case more than one infusion was given to treat a bleeding episode, 
but the treatment was rated with “excellent”, information should be provided about the severity of 
the bleeding episode and/or whether additional infusions were given to maintain hemostasis. If 
infusions were given to maintain hemostasis after resolution of bleed, this should be recorded 
accordingly in the CRF. It may become necessary to re-discuss the rating with the subject to ensure 
that the Rating Scale is fully understood. In case of bleeding episodes requiring only one infusion 
but the response to treatment is rated with “fair”, this should also be evaluated. 
Note: The investigator must confirm all the efficacy ratings entered in the subject diary. If the 
investigator identifies any inconsistency/error in the efficacy rating, the investigator will make 
his/her own assessment in conjunction with the subject (or the subject’s legal representative) and 
enter it into the CRF. In cases where there are discrepancies between assessments made by subjects 
(or the subject’s legal representative) and the investigator, assessment made by the investigator 
shall supersede and be considered the final assessment. 
If, at any time during the study a subject’s bleeding episode does not adequately respond to 
ADVATE therapy, he/she will be evaluated for the presence of inhibitory or total binding 
antibodies to FVIII and clinically managed at the discretion of the investigator. In addition, AEs 
and the details of concomitant medication use coincident with the treatment of all acute bleeds will 
be recorded. Note that bleeding episodes are not to be reported as AEs (Appendix 3.1 Adverse 
Event Definition [subheading: symptoms of the disease under study]). 
Any non-study FVIII therapy or hemostatic product use administered for a bleeding event will be 
recorded on the appropriate section of the subject’s diary and the CRF. The use of a FVIII 
concentrate other than ADVATE will disqualify the subject from further participation in the study. 
8.4.2.1.1 Assessment of Effectiveness 
Total number (%) of treated bleeds and their corresponding hemostatic effectiveness ratings using 
an “excellent-to-none” 4-point Likert scale by the subjects/care-giver (subjects <12 years: care-
giver, subjects ≥ 12 years: self-assessment) for treatments given at home, or by the investigator for 
treatments given in the hospital/clinic. 
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Table 4. Overall Effectiveness Assessment for Bleed Treatment 
Excellent 
Full relief of pain and cessation of objective signs of bleeding (e.g., swelling, tenderness, and 
decreased range of motion in the case of musculoskeletal hemorrhage) within approximately 
6 hours to 12 hours and after 1 or 2 infusions. No additional infusion is required for the control 
of bleeding. Any additional infusion for treatment of bleeding will preclude this rating. 
Administration of further infusions to maintain hemostasis would not affect this scoring. 
Good 
Definite pain relief and/or improvement in signs of bleeding within approximately 6 hours to 
24 hours requiring more than 2 infusions for complete resolution. Administration of further 
infusions to maintain hemostasis would not affect this scoring. 
Moderate 
Probable and/or slight relief of pain and slight improvement in signs of bleeding within 
approximately 6 hours to 24 hours. Requires multiple infusions for complete resolution. 
None iv 
No improvement of signs or symptoms or conditions worsen. 
 
Table 5. Overall Effectiveness Assessment for Prophylactic Treatment 
Excellent 
Definitely low bleeding rate with improvement in daily activities and quality of life.  
Very satisfied with the treatment and worth being continued 
Good 
Relatively low bleeding rate with some improvement in daily activities and quality of life. 
Satisfied with the treatment and worth being continued 
Moderate 
Relative increase in breakthrough bleeding episodes with only partial benefit in terms of activity 
level and quality of life. Partially satisfied with the treatment. Not sure if it is worth continuing 
treatment 
Noneiv 
Frequent breakthrough bleeding episodes interfering with activity level and quality of life.  
Not satisfied with the treatment. 
 
8.4.2.2 Determination of Incremental Recovery 
The assessment of FVIII levels to determine IR will be mandatory at the Baseline Visit and at the 
End of Treatment Visit / Study Termination Visit (see Table 2). For a more detailed description 
of the IR assessment, see Appendix 2.5. 
8.4.2.3 Blood Sampling for Determination of Factor VIII Level 
See Appendix 2.4. 
 
iv If checked, the investigator should determine whether it is considered as “lack of effect” and, if yes, it should be 
considered as an AE. 
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8.4.3 Safety 
8.4.3.1 Physical Examination 
At screening and all subsequent study visits (as shown in Section 1.3, Table 1), a physical 
examination will be performed on the following body systems: general appearance, head and 
neck, eyes and ears, nose and throat, chest, lungs, heart, abdomen, extremities and joints, lymph 
nodes, skin, and neurological. At screening, if an abnormal condition is detected, the condition 
will be described on the medical history CRF. At study visits, if a new abnormal or worsened 
abnormal preexisting condition is detected, the condition will be described on the AE CRF. If the 
abnormal value was not deemed an AE because it was due to an error, due to a preexisting 
disease (described in Appendix 3.1), not clinically significant, a symptom of a new/worsened 
condition already recorded as an AE, or due to another issue that will be specified, the 
investigator will record the justification on the source record. 
8.4.3.2 Adverse Events 
At each study visit, subjects will be questioned in a general way to ascertain if AEs have 
occurred since the previous visit (eg, “Have you had any health problems since your last visit?”). 
Adverse events are collected from the time informed consent is signed.v Refer to Appendix 3 for 
AE definitions, assessment, collection time frame, and reporting procedures.  
8.4.3.3 Vital Signs 
Vital signs will include body temperature (°C), respiratory rate (breaths/min), pulse rate 
(beats/min), and systolic and diastolic blood pressure (mmHg). Blood pressure will be measured 
when subjects are in the supine position. 
Vitals signs will be measured at all study visits (see Table 1) and will be recorded on the CRF. 
Vital signs should always be assessed before any blood sampling is done at a particular 
timepoint. 
The investigator will assess whether a change from baseline in vital signs may be deemed 
clinically significant and whether the change should be considered and recorded as an AE. 
8.4.3.4 Clinical Laboratory Tests 
All clinical laboratory tests will be performed according to the laboratory’s standard procedures. 
Reference ranges will be supplied by the laboratory and used to assess the results for clinical 
significance and out-of-range changes which may be associated with, or constitute, an AE. 
 
v 
Please note that AEs are only considered treatment-emergent AEs (TEAEs) if they emerge or manifest at or after 
initiation of treatment with IP.  
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The investigator should assess out-of-range clinical laboratory values for clinical significance, 
indicating if the value(s) is/are not clinically significant or clinically significant. Abnormal clinical 
laboratory values, which are unexpected or not explained by the subject’s clinical condition, may, 
at the discretion of the investigator or sponsor, be repeated as soon as possible until confirmed, 
explained, or resolved. 
The following clinical laboratory assessments will be performed (see also Table 2): 
• 
Hematology assessments: hemoglobin, hematocrit, red blood cell count, and white blood 
cell count with differential (ie, basophils, eosinophils, lymphocytes, monocytes, 
neutrophils), mean corpuscular volume (MCV), mean corpuscular hemoglobin 
concentration (MCHC), and platelet count 
• 
Clinical chemistry assessments: sodium, potassium, chloride, bicarbonate, total protein, 
albumin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), total 
bilirubin, alkaline phosphatase, blood urea nitrogen (BUN), creatinine, and glucose 
• 
Viral serology: HIV-1Ab, HIV-2 Ab, HBcAb, HBsAb, HBsAg, and HCVAb.  
Any HIV or HCV positive sample will be tested by PCR for viral titer, HIV positive 
subjects will have CD4 counts monitored every 3 months during the course of the study. 
• 
FVIII antigen 
• 
FVIII activity 
• 
Incremental recovery 
• 
FVIII inhibitor 
 
More detailed descriptions of the clinical laboratory tests to be performed are provided in 
Appendix 2. 
8.4.3.5 Clinical Pharmacology  
Incremental recovery will be determined at baseline and at study completion (see Table 2 and 
Appendix 2.5). 
8.4.4 Volume of Blood to Be Drawn from Each Subject 
The volume of blood to be drawn from each subject for laboratory assessments will be specified 
in the laboratory manual.  
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8.4.5 Backup Samples and Biobanking 
Backup samples taken and stored short-term may be used for example for re-testing, follow-up of 
an AE(s) or other test results, and/or assay development.  After study testing is completed, the 
remaining samples may be stored in a coded form for no more than 2 years after the final study 
report has been completed and then the samples will subsequently be destroyed. 
For subjects < 6 years of age, back-up samples are optional; for subjects < 12 years of age,  
back-up samples for serum are optional.  
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9. STATISTICAL CONSIDERATIONS 
9.1 Statistical Analysis Process 
The study will be analyzed by the sponsor or its agent.  
The SAP will provide the statistical methods and definitions for the analysis of the efficacy and 
safety data, as well as describe the approaches to be taken for summarizing other study information 
such as subject disposition, demographics and baseline characteristics, investigational product 
exposure, and prior and concomitant medications. The SAP will also include a description of how 
missing, unused and spurious data will be addressed. 
To preserve the integrity of the statistical analysis and study conclusions, the SAP will be finalized 
prior to database lock. 
All statistical analyses will be performed using SAS 9.4 or later (SAS Institute, Cary, NC 27513).  
The statistical analysis for this study will be descriptive in nature. Descriptive statistics will include 
specifically, but not exclusively, arithmetic mean, standard deviation, medians, quartiles and 
interquartile range, minimum, maximum, proportions, frequency counts, and 95% confidence 
intervals of point estimates.  
9.2 Planned Interim Analysis, Adaptive Design, and Data Monitoring Committee 
No interim analysis, adaptive design, or data monitoring committee (DMC) is planned for this 
study. 
9.3 Sample Size and Power Considerations 
According to the WFH Report on the Annual Global Survey 2017 (World Federation of 
Hemophilia, 2018) there were a total of 15,920 cases of hemophilia A in India in 2017. Due to 
the low prevalence of hemophilia A and the difficulty in switching patients from their current 
therapy, the planned sample size is 50 subjects. 
9.4 Statistical Analysis Set(s) 
9.4.1 Effectiveness Full Analysis Set (EFAS) 
The EFAS will be comprised of all subjects for whom all inclusion and none of the exclusion 
criteria are met. This dataset will be used for the efficacy analyses. 
9.4.2 Safety Analysis Set (SAS) 
All subjects having received ADVATE at any time during the study will be included in the SAS. 
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9.5 Efficacy Analyses 
9.5.1 Primary Efficacy Endpoint 
Not applicable. There is no primary efficacy endpoint. 
9.5.2 Secondary Efficacy Endpoints 
The annualized bleeding rate (ABR) during the prophylactic treatment will be assumed to have 
a negative binomial distribution, and the mean ABR (95% CI) will be estimated using a 
generalized linear model (GLM). The total ABR and ABR by bleed cause/ site, i.e. joint,  
non-joint, target joints, spontaneous, traumatic, will be summarized descriptively as well. 
Summary statistics for the total number of infusions, as well as the average number of 
prophylactic infusions per week and per month of prophylaxis will be provided. Similarly, the 
total body mass adjusted consumption and the average consumption of ADVATE per week and 
per month during prophylactic treatment will be provided. 
For the overall hemostatic efficacy rating at resolution of bleed, for the number of infusions of 
ADVATE to control a bleeding episode, as well as for the body mass adjusted consumption of 
ADVATE per bleeding event, summary statistics will be presented. These tables will be also 
presented by bleeding site, cause and severity. 
9.5.3 Multiplicity Adjustment 
As the analyses will be descriptive in nature, no adjustments for multiplicity will be applied. 
9.6 Safety Analyses 
Frequency counts and percentages for possibly or probably related SAEs (including FVIII 
inhibitor formation) as well as for subjects with possibly or probably related SAEs (including 
FVIII inhibitor formation) that occurred during or after first ADVATE infusion will be 
summarized. The incidence of FVIII inhibitor development will also be summarized by high-titer 
(>5 BU) and low-titer (0.6-5 BU). 
All AEs will be cross-tabulated for relatedness, seriousness, and severity. AEs will be 
categorized according to the MedDRA dictionary and summarized by system organ class and 
preferred term. A listing of all AEs will be presented by subject identifier, age, sex, preferred 
term and reported term of the AE, duration, severity, seriousness, action taken, outcome, 
causality assessment by investigator, onset date, stop date and medication or non-drug therapy to 
treat the AE.  
Shift tables will be presented for the results of clinical laboratory data.  
9.7 Other Analyses 
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No other analyses are planned at this time. 
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10. SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
Appendix 1 
REGULATORY, ETHICAL, AND STUDY OVERSIGHT 
CONSIDERATIONS 
Appendix 1.1 
Regulatory and Ethical Considerations 
This study is conducted in accordance with current applicable regulations including ICH E6, EU 
Directive 2001/20/EC, and all updates, as well as local ethical and legal requirements.  
Compliance with these regulations and guidelines also constitutes compliance with the ethical 
principles described in the Declaration of Helsinki. 
The name and address of each third-party vendor (eg, CRO) used in this study will be maintained 
in the investigator’s and sponsor’s files, as appropriate. 
Appendix 1.2 
Sponsor’s Responsibilities 
Good Clinical Practice Compliance 
The study sponsor and any third party to whom aspects of the study management or monitoring 
have been delegated will undertake their assigned roles for this study in compliance with all 
applicable industry regulations, current ICH GCP Guidelines, as well as all applicable national 
and local laws and regulations. 
Visits to sites are conducted by representatives of the study sponsor and/or the company 
organizing/managing the research on behalf of the sponsor to inspect study data, subjects’ 
medical records, and CRFs in accordance with current GCP and the respective local and 
(inter)national government regulations and guidelines. Records and data may additionally be 
reviewed by auditors or by regulatory authorities. 
The sponsor ensures that local regulatory authority requirements are met before the start of the 
study. The sponsor (or a nominated designee) is responsible for the preparation, submission, and 
confirmation of receipt of any regulatory authority approvals required prior to release of 
investigational product for shipment to the site. 
Indemnity/Liability and Insurance 
The sponsor of this research adheres to the recommendations of the Association of British 
Pharmaceutical Industry Guidelines. If appropriate, a copy of the indemnity document is 
supplied to the investigator before study initiation, per local country guidelines. 
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The sponsor ensures that suitable clinical study insurance coverage is in place prior to the start of 
the study. An insurance certificate is supplied to the investigator as necessary. 
Public Posting of Study Information 
The sponsor is responsible for posting appropriate study information on applicable websites. 
Information included in clinical study registries may include participating investigators’ names 
and contact information.  
The timing for study registration and results summary posting must be in accordance with 
applicable local and national requirements. 
Submission of Summary of Clinical Study Report to Competent Authorities of Member 
States Concerned and Ethics Committees 
The sponsor will provide a summary of the clinical study report to the competent authority of the 
member state(s) concerned as required by regulatory requirement(s) and to comply with the 
Community guideline on GCP. This requirement will be fulfilled within 6 months of study 
completion date for pediatric studies and within 1 year for non-pediatric studies as per guidance. 
Study Suspension, Termination, and Completion 
The sponsor may suspend or terminate the study, or part of the study, at any time for any reason. 
If the study is suspended or terminated, the sponsor will ensure that applicable sites, regulatory 
agencies and IRBs/ECs are notified as appropriate. Additionally, the discontinuation of a 
registered clinical study which has been posted to a designated public website will be updated 
accordingly. 
Appendix 1.3 
Investigator’s Responsibilities 
Good Clinical Practice Compliance 
The investigator must undertake to perform the study in accordance with ICH GCP Guideline E6 
(1996) and E6 R2 (2017), EU Directive 2001/20/EC, and applicable regulatory requirements and 
guidelines. 
It is the investigator’s responsibility to ensure that adequate time and appropriately trained 
resources are available at the site prior to commitment to participate in this study. The 
investigator should also be able to estimate or demonstrate a potential for recruiting the required 
number of suitable subjects within the agreed recruitment period. 
The investigator will maintain a list of appropriately qualified persons to whom the investigator 
has delegated significant study-related tasks, and shall, upon request of the sponsor, provide 
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documented evidence of any licenses and certifications necessary to demonstrate such 
qualification. Curriculum vitae for investigators and sub-investigators are provided to the study 
sponsor (or designee) before starting the study. 
If a potential research subject has a primary care physician, the investigator should, with the 
subject’s consent, inform them of the subject’s participation in the study. 
A coordinating principal investigator is appointed to review the final clinical study report for 
multicenter studies. Agreement with the final clinical study report is documented by the signed 
and dated signature of the principal investigator (single-site study) or coordinating principal 
investigator (multicenter study), in compliance with Directive 2001/83/EC as amended by 
Directive 2003/63/EC and ICH Guidance E3 (1995). 
Protocol Adherence and Investigator Agreement 
The investigator and any sub-investigators must adhere to the protocol as detailed in this 
document. The investigator is responsible for enrolling only those subjects who have met 
protocol eligibility criteria. Investigators are required to sign an investigator agreement to 
confirm acceptance and willingness to comply with the study protocol. 
If the investigator suspends or terminates the study at their site, the investigator will promptly 
inform the sponsor and the IRB/EC and provide them with a detailed written explanation. The 
investigator will also return all investigational product, containers, and other study materials to 
the sponsor. Upon study completion, the investigator will provide the sponsor, IRB/EC, and 
regulatory agency with final reports and summaries as required by (inter)national regulations. 
Communication with local IRBs/ECs, to ensure accurate and timely information is provided at 
all phases during the study, may be done by the sponsor, applicable CRO, investigator, or for 
multicenter studies, the coordinating principal investigator according to national provisions and 
will be documented in the investigator agreement. 
Documentation and Retention of Records 
Case Report Forms 
Case report forms are supplied by the CRO and should be handled in accordance with 
instructions from the sponsor. 
The investigator is responsible for maintaining adequate and accurate medical records from 
which accurate information is recorded onto CRFs, which have been designed to record all 
observations and other data pertinent to the clinical investigation. Case report forms must be 
completed by the investigator or designee as stated in the site delegation log. 
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All data will have separate source documentation; no data will be recorded directly onto the 
CRF. 
The CRA/study monitor will verify the contents against the source data per the monitoring plan. 
If the data are unclear or contradictory, queries are sent for corrections or verification of data. 
All data will have separate source documentation; no data will be recorded directly onto the 
CRF. 
The CRFs should be approved by the investigator per study specifications and the sponsor’s data 
delivery requirements.  
Recording, Access, and Retention of Source Data and Study Documents 
Original source data to be reviewed during this study will include, but are not limited to: 
subject’s medical file, subject diary cards, and original clinical laboratory reports. 
All key data must be recorded in the subject’s source documents. 
The investigator must permit authorized representatives of the sponsor; the respective national, 
local, or foreign regulatory authorities; the IRB/EC; and auditors to inspect facilities and to have 
direct access to original source records relevant to this study, regardless of media. 
The CRA/study monitor (and auditors, IRB/EC or regulatory inspectors) may check the CRF 
entries against the source documents. The consent form includes a statement by which the 
subject agrees to the monitor/auditor from the sponsor or its representatives, national or local 
regulatory authorities, or the IRB/EC, having access to source data (eg, subject’s medical file, 
appointment books, original laboratory reports, X-rays etc.). 
These records must be made available within reasonable times for inspection and duplication, if 
required, by a properly authorized representative of any regulatory agency or an auditor. 
Essential documents must be maintained according to ICH GCP requirements and may not be 
destroyed without written permission from the sponsor. 
Audit/Inspection 
To ensure compliance with relevant regulations, data generated by this study must be available 
for inspection upon request by representatives of, for example, the US FDA (as well as other US 
national and local regulatory authorities), the EMA, the Medicines and Healthcare products 
Regulatory Agency, other regulatory authorities, the sponsor or its representatives, and the 
IRB/EC for each site. 
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Financial Disclosure 
The investigator is required to disclose any financial arrangement during the study and for 1 year 
after, whereby the outcome of the study could be influenced by the value of the compensation for 
conducting the study, or other payments the investigator received from the sponsor. The 
following information is collected: any significant payments from the sponsor or subsidiaries 
such as a grant to fund ongoing research, compensation in the form of equipment, retainer for 
ongoing consultation or honoraria; any proprietary interest in investigational product; any 
significant equity interest in the sponsor or subsidiaries as defined in 21 CFR 54 2(b) (1998). 
Appendix 1.4 
Data Management Considerations 
Data Collection 
The investigators’ authorized site personnel must enter the information required by the study 
CRF Completion Guidelines or similar for all data requiring transcription of the source. A study 
monitor will visit each site in accordance with the monitoring plan and review the CRF data 
against the source data for completeness and accuracy. Discrepancies between source data and 
data entered on the CRF will be addressed by qualified site personnel. When a data discrepancy 
warrants correction, the correction will be made by authorized site personnel. Data collection 
procedures will be discussed with the site at the site initiation visit and/or at the investigator’s 
meeting.  
Data Management 
Data are to be entered into a clinical database as specified in the CRO´s data management plan or 
similar. Quality control and data validation procedures are applied to ensure the validity and 
accuracy of the clinical database. 
Data are to be reviewed and checked for omissions, errors, and values requiring further 
clarification using computerized and manual procedures. Data queries requiring clarification are 
to be communicated to the site for resolution. Only authorized personnel will make corrections to 
the clinical database, and all corrections are documented in an auditable manner. 
Data Handling 
Not applicable to this study, as this study is not blinded. 
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Appendix 1.5 
Ethical Considerations 
Informed Consent 
It is the responsibility of the investigator to obtain written informed consent from all study 
subjects prior to any study-related procedures including screening assessments. An assent form 
may be provided and should be signed by subjects less than 18 years of age. All consent and 
assent documentation must be in accordance with applicable regulations and GCP. Subjects or 
their legally authorized representative(s) will be allowed sufficient time to consider participation 
in the study. Each subject or the subject’s legally authorized representative, as applicable, is 
requested to sign and date the subject informed consent form or a certified translation if 
applicable, after the subject has received and read (or been read) the written subject information 
and received an explanation of what the study involves, including but not limited to: the 
objectives, potential benefits and risk, inconveniences, and the subject’s rights and 
responsibilities. By signing the informed consent form, subjects or their legally authorized 
representative(s) agree that they will complete all evaluations required by the study, unless they 
withdraw voluntarily or are terminated from the study for any reason. A copy of the informed 
consent and assent documentation (ie, a complete set of subject information sheets and fully 
executed signature pages) must be given to the subject or the subject’s legally authorized 
representative, as applicable. This document may require translation into the local language. 
Signed consent forms must remain in each subject’s study file and must be available for 
verification at any time. 
Within the source documents, site personnel should document instruction of and understanding 
by the parent/legally authorized representative/caregiver of the safe, responsible storage and 
administration of investigational product to the study subject. 
The sponsor will provide to the investigator in written form any new information that 
significantly bears on the subjects’ risks associated with IP exposure. The informed consent will 
be updated, if necessary. This new information and/or revised informed consent form, that have 
been approved by the applicable Ethics Committee and regulatory authorities, where applicable, 
will be provided by the investigator to the subjects who consented to participate in the study. 
Institutional Review Board or Ethics Committee 
For sites outside the EU, it is the responsibility of the investigator to submit this protocol, the 
informed consent document (approved by the sponsor or their designee), relevant supporting 
information and all types of subject recruitment information to the IRB/EC for review, and all 
must be approved prior to site initiation. 
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Responsibility for coordinating with IRBs/ECs is defined in the investigator agreement. 
Investigational product supplies will not be released until the sponsor has received written 
IRB/EC approval. 
Prior to implementing changes in the study, the sponsor and the IRB/EC must approve any 
revisions of all informed consent documents and amendments to the protocol unless there is a 
subject safety issue. If required by local law, substantial amendments to the protocol must also 
be approved by the appropriate regulatory agency prior to implementation. 
For sites outside the EU, the investigator is responsible for keeping the IRB/EC apprised of the 
progress of the study and of any changes made to the protocol at least annually or more 
frequently in accordance with the requirements, policies, and procedures established by the 
IRB/EC. This can be the responsibility of the sponsor or investigator for sites within the EU; or 
for multicenter studies, the coordinating principal investigator, according to national provisions. 
The investigator must also keep the local IRB/EC informed of any serious and significant AEs as 
required by IRB/EC procedures. 
Privacy and Confidentiality 
The confidentiality of records that may be able to identify subjects will be protected in 
accordance with applicable laws, regulations, and guidelines. 
After subjects have consented to take part in the study, the sponsor and/or its representatives 
reviews their medical records and data collected during the study. These records and data may, in 
addition, be reviewed by others including the following: independent auditors who validate the 
data on behalf of the sponsor; third parties with whom the sponsor may develop, register, or 
market ADVATE; national or local regulatory authorities; and the IRB(s)/EC(s) which gave 
approval for the study to proceed. The sponsor and/or its representatives accessing the records 
and data will take all reasonable precautions in accordance with applicable laws, regulations, and 
guidelines to maintain the confidentiality of subjects’ identities. Subjects are assigned a unique 
identifying number; however, their initials and date of birth may also be collected, if permitted 
under local laws governing privacy.  
The results of studies containing subjects’ unique identifying number, relevant medical records, 
and possibly initials and dates of birth, where allowed per local law, may be transferred to, and 
used in, other countries which may not afford the same level of protection that applies within the 
countries where this study is conducted. The purpose of any such transfer would include: to 
support regulatory submissions, to conduct new data analyses to publish or present the study 
results, or to answer questions asked by regulatory or health authorities. 
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Study Results/Publication Policy 
The term “Publication” shall mean any paper, article, manuscript, report, poster, internet posting, 
presentation slides, abstract, outline, video, instructional material, presentation (in the form of a 
written summary), or other public disclosure of the study results, in printed, electronic, oral, or 
other form. The parties understand and agree that participation in the study may involve a 
commitment to publish the data from all sites participating in the study in a cooperative 
publication with other investigators prior to publication or oral presentations of the study results 
on an individual basis. The site agrees not to publish or present the site’s study results until such 
time as either the aggregate multi-site study results are published in a cooperative publication or 
for a period of one (1) year after termination or completion of the study at all participating sites, 
whichever shall first occur. After that time, the site may publish the site’s study results in 
scientific journals or present the study results at symposia or other professional meetings in 
accordance with the following provisions: 
If the study is part of a multicenter study, the first publication of the study results shall be made 
by the sponsor in conjunction with the sponsor’s presentation of a joint, multicenter publication 
of the compiled and analyzed study results. If such a multicenter publication is not submitted to a 
journal for publication by the sponsor within an 18-month period after conclusion, abandonment, 
or termination of the study at all sites, or after the sponsor confirms there shall be no multicenter 
study publication of the study results, an investigator may individually publish the study results 
from the specific site in accordance with this section. The investigator must, however, 
acknowledge in the publication the limitations of the single site data being presented. 
At least sixty (60) days prior to submitting an abstract, manuscript, or other document for 
publication, a copy of the proposed publication will be provided to the sponsor by the site for 
review.  Upon the sponsor’s request, the site agrees to remove any and all confidential 
information (expressly excluding study results) identified in the publication and to delay such 
submission or presentation for an additional sixty (60) day period in order to allow the sponsor 
time to file any patent application(s).  All publications of the study results shall appropriately 
reference the multi-site study publication, if any, or the fact that the study results are a subset of 
data resulting from a larger multi-site study. 
Takeda is committed to transparent dissemination of all scientific, technical and medical 
manuscripts generated from Takeda-supported research. Therefore, after January 1, 2018, 
Takeda will require the submission of all Takeda-supported research manuscripts to journals that 
offer public availability via Open Access (including publisher platforms/repositories and self-
archiving). Open Access refers to the free at point of entry, online availability of published 
research output with, where available, rights of re-use according to an End User License. 
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Unless otherwise required by the journal in which the publication appears, or the forum in which 
it is made, authorship will comply with the International Committee of Medical Journal Editors 
(ICMJE) Recommendation for the Conduct, Reporting, Editing and Publication of Scholarly 
Work in Medical journals. Participation as an investigator does not confer any rights to 
authorship of publications. 
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Appendix 2 
CLINICAL LABORATORY TESTS 
The following clinical laboratory assessments will be performed (see also Table 2): 
• 
Hematology assessments: hemoglobin, hematocrit, red blood cell count, and white blood 
cell count with differential (ie, basophils, eosinophils, lymphocytes, monocytes, 
neutrophils), mean corpuscular volume (MCV), mean corpuscular hemoglobin 
concentration (MCHC), and platelet count 
• 
Clinical chemistry assessments: sodium, potassium, chloride, bicarbonate, total protein, 
albumin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), total 
bilirubin, alkaline phosphatase, blood urea nitrogen (BUN), creatinine, and glucose 
• 
Viral serology: HIV-1Ab, HIV-2 Ab, HBcAb, HBsAb, HBsAg, and HCVAb.  
Any HIV or HCV positive sample will be tested by PCR for viral titer, HIV positive 
subjects will have CD4 counts monitored every 3 months during the course of the study. 
• 
FVIII antigen 
• 
FVIII activity 
• 
Incremental recovery 
• 
FVIII inhibitor 
 
Appendix 2.1 
Hematology and Clinical Chemistry 
Blood will be obtained for assessment of hematology and clinical chemistry parameters at the 
timepoints indicated in Table 2. In addition, assessments may be performed whenever clinically 
indicated. Hematology and clinical chemistry assessments will be performed on EDTA-
anticoagulated whole blood and serum, respectively, at the central laboratory.  
Appendix 2.2 
Viral Serology 
Viral serology assessments will be performed at Screening and at the End-of-Treatment / Study 
Termination Visit (see Table 2). 
The following viral serology tests will be performed: HIV-1Ab, HIV-2 Ab, HBcAb, HBsAb, 
HBsAg, and HCVAb. Any HIV or HCV positive sample will be tested by PCR for viral titer, 
HIV positive subjects will have CD4 counts monitored every 3 months during the course of the 
study. 
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Appendix 2.3 
FVIII Antigen 
FVIII antigen will be measured at the screening visit using a commercially available ELISA kit 
(Table 2). The samples will be prepared as described in Section Appendix 2.4. 
Appendix 2.4 
Blood Sampling for Determination of FVIII Activity 
At each blood sampling time point whole blood will be collected in S-Monovette® tubes 
(Sarstedt, Nümbrecht, Germany) containing 3.2% trisodium citrate, or equivalent blood drawing 
equipment (eg, Vacutainer tubes), and immediately mixed. The citrated whole blood samples 
will be capped and transported at room temperature (ie, 20-25°C) to the local clinical 
laboratory for centrifugation, processing, and storage. Monovettes must be kept in an upright 
position at all times to avoid leakage. 
For all clotting assays, citrated whole blood will be spun in a refrigerated centrifuge (2 to 8oC) 
at ≥ 2000 x gravity for approximately 20 minutes in capped tubes within 2 hours of collection. 
The plasma supernatant will be re-centrifuged at the same rate and duration to ensure removal of 
platelets and other particulate matter. 
At least three aliquots of 0.6 mL of the centrifuged, citrated plasma will be pipetted into 
appropriate storage tubes, capped, labeled, and stored in a freezer at ≤ -70°C, ideally within 
15 minutes, but no later than 30 minutes after processing. 
All citrated plasma samples will be stored and shipped to the central laboratory at ≤ -70°C for 
testing. All samples will be maintained capped to the greatest extent possible. All citrated plasma 
samples will be assayed for FVIII activity using the one-stage aPTT-based assay method. 
Appendix 2.5 
Incremental recovery (IR) 
The assessment of FVIII levels to determine IR will be mandatory at the Baseline Visit and at the 
End of Treatment Visit (at 6 months) / Study Termination Visit. IR determination is optional at 
Visit 2 (at 3 months) (see Table 2).  
Prior to the pre-infusion blood draw for IR determination, subjects should have a washout period 
from previous plasma-derived and/or recombinant FVIII concentrate(s) treatment. The washout 
period will depend on the type of product the subject receives, ie, 48-72 hours for products with 
standard half-life and 84-96 hours for extended half-life products (consistent with clinical studies 
with ADYNOVATE). 
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Subjects will be infused with a dose of 50±5 IU/kg of ADVATE. Upon completion of the 
infusion, the butterfly catheter should be flushed with at least 2 ml of saline solution. The 
procedures for blood sampling are described in Section Appendix 2.4. 
Table 6. Time Points for FVIII Activity Assessment for IR Determination 
Assessment of recovery 
 
Pre-infusion 
Infusion of ADVATE 
0-30 minutes prior to infusion 
 
 
Post-infusion 
15-30 minutes post infusion 
 
The sample for measurement of FVIII activity will be obtained from an extremity different from 
that used for the infusion of IP. 
Appendix 2.6 
FVIII Inhibitor 
If an inhibitory antibody with a titer ≥ 0.6 BU is detected, the inhibitor will be confirmed in 
the central laboratory within 2 weeks of study site notification of the original central laboratory 
result. Subjects who develop an inhibitor that changes from a low to a high titer inhibitor or from 
a high titer to a low titer upon a second evaluation should return to the study site for a third 
inhibitor test with a suggested minimum washout phase of 72 hours within 2 weeks of the second 
inhibitor assessment. Once a low (0.6 to 5 BU) or a high titer (> 5 BU) inhibitor is confirmed, 
the subject will be withdrawn from the study. Any inhibitor confirmed by the central laboratory 
must be recorded as an SAE (Section Appendix 3.1). 
All tests will be performed at a defined central laboratory. 
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Appendix 3 
ADVERSE EVENTS: DEFINITIONS AND PROCEDURES FOR 
RECORDING, EVALUATING, FOLLOW-UP, AND REPORTING 
Appendix 3.1 
Adverse Event Definitions 
An adverse event (AE) is any untoward medical occurrence in a clinical investigation subject 
administered a pharmaceutical product and that does not necessarily have a causal relationship 
with this investigational product or medicinal product. An AE can therefore be any unfavorable 
and unintended sign (including a clinically significant laboratory finding), symptom, or disease 
temporally associated with the use of a medicinal (investigational) product, whether or not 
causality is suspected (ICH Guidance E2A 1995). 
Treatment-emergent Adverse Event 
A treatment-emergent adverse event (TEAE) is defined as any event emerging or manifesting at 
or after the initiation of treatment with an investigational product or medicinal product or any 
existing event that worsens in either intensity or frequency following exposure to the 
investigational product or medicinal product. 
Serious Adverse Event 
A serious adverse event (SAE) is any untoward clinical manifestation of signs, symptoms or 
outcomes (whether considered related to investigational product or not and at any dose: 
• 
Results in death 
• 
Is life-threatening. Note: The term “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 was more severe. 
• 
Requires inpatient hospitalization or prolongation of hospitalization. Note: Hospitalizations 
that are the result of elective or previously scheduled investigations procedures or surgery 
for pre-existing conditions and have not worsened after initiation of treatment should not 
be classified as SAEs.  
• 
For example, an admission for a previously scheduled ventral hernia repair would not be 
classified as an SAE; however, complication(s) resulting from a hospitalization for an 
elective or previously scheduled surgery that meet(s) serious criteria must be reported as 
SAE(s). 
• 
Results in persistent or significant disability/incapacity 
• 
Results in a congenital abnormality/birth defect 
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• 
Is an important medical event. Note: Important medical events that may not result in death, 
be life-threatening, or require hospitalization may be considered an SAE when, based upon 
appropriate medical judgment, they may jeopardize the subject and may require medical or 
surgical intervention to prevent 1 of the outcomes listed in this definition. Examples of 
such medical events include: 
• 
 Bronchospasm associated with anaphylaxis requiring intensive treatment in an emergency 
room or at home; blood dyscrasias or convulsions that do not result in inpatient 
hospitalization; or the development of drug dependency or drug abuse. 
• 
Reviewed and confirmed seroconversion for human immunodeficiency virus (HIV), 
hepatitis A virus (HAV), hepatitis B virus (HBV), hepatitis C virus (HCV), hepatitis E 
virus (HEV), or parvovirus B19 (B19V) 
• 
Further examples of important medical events that are specific to this study include, but are 
not limited to: 
 Thromboembolism/DIC/Fibinolysis 
 FVIII inhibitor development (≥ 0.6 BU/mL) 
 
For this protocol, elective and planned surgeries, when these surgeries relate to a preexisting 
disease that has not worsened during study participation will not be considered as (S)AEs. 
Unexpected Adverse Event 
An unexpected adverse event is an AE whose nature, severity, specificity, or outcome is not 
consistent with the term, representation, or description used in the Reference Safety Information 
(RSI). “Unexpected” also refers to the AEs that are mentioned in the prescribing information 
(Product Label) as occurring with a class of drugs or as anticipated from the pharmacological 
properties of the product, but are not specifically mentioned as occurring with the particular 
product under investigation.  
The expectedness of AEs will be determined by the sponsor using the prescribing information 
(Product Label) as the RSI. This determination will include considerations such as the number of 
AEs previously observed, but not on the basis of what might be anticipated form the 
pharmacological properties of a product. 
Suspected Unexpected Serious Adverse Reaction  
A Suspected Unexpected Serious Adverse Reaction (SUSAR) is defined as any suspected 
adverse reaction to study treatment (ie, including active comparators) that is both serious and 
unexpected. 
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The event(s) must meet all of the following: 
• 
Suspected adverse reaction 
• 
Serious 
• 
Unexpected 
• 
Assessed as related to study treatment 
 
Unanticipated Adverse Device Effect  
An unanticipated adverse device effect (UADE) is any serious adverse effect on health or safety 
or any life-threatening problem or death caused by, or associated with, a device, if that effect, 
problem, or death was not previously identified in nature, severity, or degree of incidence in the 
study protocol or product labeling; or any other unanticipated serious problem associated with a 
device that relates to the rights, safety, or welfare of subjects. 
Symptoms of the Disease under Study 
Bleeding episodes are part of the underlying disease and are therefore not AEs; they will be 
assessed as part of the efficacy assessments. However, the investigator may decide that the event 
is an AE if the event also would have occurred in a normal patient under the same circumstances. 
If a bleeding episode was caused by an injury, the injury will be reported as an AE. Bleeding 
events will not be considered as AEs if they do not qualify as an SAE. All bleeding episodes 
must be entered in the bleeding event CRF. 
Preexisting conditions prior to randomization or initiation of study medication are described in 
the medical history, and those that manifest with the same severity, frequency, or duration after 
drug exposure, are not be recorded as AEs. However, when there is an increase in the severity, 
duration or frequency of a preexisting condition, the event must be described on the AE CRF. 
Clinical Laboratory and Other Safety Assessment 
A change in the value of a clinical laboratory parameter, vital sign measure, or ECG assessment 
can represent an AE if the change is clinically relevant or if, during administration of 
investigational product, a shift of a parameter is observed from a value in the normative range to 
a value that is outside the normal range and considered clinically significant, or a further waning 
of an already clinically significant value. When evaluating such changes, the extent of deviation 
from the reference range, the duration until return to the reference range, either while continuing 
administration or after the end of administration with the investigational product, and the range 
of variation of the respective parameter within its reference range, should also be considered. 
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If, at the end of the treatment phase, there are abnormal clinical laboratory (such as hematology 
panel or clinical chemistry panel), vital sign, or ECG values which were not present at the 
pretreatment evaluation observed closest to the start of study treatment, further investigations 
should be performed until the values return to within the reference range or until a plausible 
explanation (eg, concomitant disease or expected disease evolution) is found for the abnormal 
values. 
The investigator should assess, based on the above criteria and the clinical condition of the 
subject, whether a change in a clinical laboratory value, vital sign, or ECG parameter is clinically 
significant and represents an AE. 
Appendix 3.2 
Collection of Adverse Events  
All AEs/SAEs are collected from the time the informed consent document is signed until the 
final visit (End-of-Treatment / Study Termination Visit) stated in Section 8.3.2. This includes 
events occurring during the screening phase of the study, regardless of whether or not 
investigational product is administered.  
All AEs/SAEs must be followed to closure (the subject’s health has returned to his/her baseline 
status or all variables have returned to baseline), regardless of whether the subject is still 
participating in the study. Closure indicates that an outcome is reached, stabilization achieved 
(the investigator does not expect any further improvement or worsening of the event), or the 
event is otherwise explained. 
Appendix 3.3 
Assessment of Adverse Events 
Severity Categorization 
The severity of AEs must be recorded during the course of the event including the start and stop 
dates for each change in severity. An event that changes in severity is captured as a new event. 
Worsening medical conditions, signs or symptoms present prior to initiation of investigational 
product, must be recorded as new AEs. 
For example, if a subject reports mild intermittent dyspepsia prior to initiation of dosing with the 
investigational product, and the dyspepsia becomes severe and more frequent after first dose a 
new AE of severe dyspepsia (with the appropriate date of onset) should be documented in the 
source. 
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The medical assessment of severity is determined by using the following definitions: 
• 
Mild: A type of AE that is usually transient and may require only minimal treatment or 
therapeutic intervention. The event does not generally interfere with usual activities of 
daily living. 
• 
Moderate: A type of AE that is usually alleviated with specific therapeutic intervention. 
The event interferes with usual activities of daily living, causing discomfort but poses no 
significant or permanent risk of harm to the research subject. 
• 
Severe: A type of AE that interrupts usual activities of daily living, or significantly affects 
clinical status, or may require intensive therapeutic intervention. 
 
Relationship Categorization 
A physician/investigator must make the assessment of relationship to investigational product for 
each AE. The investigator should decide whether, in his or her medical judgment, there is a 
reasonable possibility that the event may have been caused by the investigational product. If 
there is no valid reason for suggesting a relationship, then the AE should be classified as “not 
related”. Otherwise, if there is any valid reason, even if undetermined or untested, for suspecting 
a possible cause-and-effect relationship between the investigational product and the occurrence 
of the AE, then the AE should be considered “related”. The causality assessment must be 
documented in the source. 
The following additional guidance may be helpful: 
Table 7. Adverse Event Relationship Categorization 
Related 
The temporal relationship between the event and the administration of the investigational 
product is compelling enough and/or follows a known or suspected response pattern to that 
product, and the event cannot be explained by the subject’s medical condition, other therapies, 
or accident. 
Not related 
The event can be readily explained by other factors such as the subject’s underlying medical 
condition, concomitant therapy, or accident and no plausible temporal or biologic relationship 
exists between the investigational product and the event. 
 
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Outcome Categorization 
The outcome of AEs must be documented in the source during the course of the study. Outcomes 
are as follows: 
• 
Fatal 
• 
Not Recovered/Not Resolved 
• 
Recovered/Resolved 
• 
Recovered/Resolved With Sequelae 
• 
Recovering/Resolving 
• 
Unknown 
 
If applicable, action taken (ie, dose increased, dose not changed, dose reduced, drug interrupted, 
drug withdrawn, not applicable, or unknown) will also be recorded on the AE CRF 
Appendix 3.4 
Safety Reporting 
Reference Safety Information 
The RSI for this study is the product package insert which the sponsor has provided under 
separate cover to all investigators (see also Appendix 4.1). 
Reporting Procedures 
All initial and follow-up SAE reports must be reported by the investigator to the Takeda Global 
Drug Safety Department and the CRO/Takeda medical monitor within 24 hours of becoming 
aware of the event. Note: The 24-hour reporting requirement for SAEs does not apply to reports 
of abuse, misuse, overdose, or medication errors (see Section Appendix 3.9) unless they result in 
an SAE. 
The investigator must complete, sign, and date the Takeda “Clinical Study Adverse Event Form 
for Serious Adverse Events (SAEs) and Non-serious AEs as Required by Protocol”, verify the 
accuracy of the information recorded on the form with the corresponding source documents 
(Note: Source documents are not to be sent unless requested), and fax or e-mail the form to the 
Takeda Global Drug Safety Department. A copy of the Takeda Clinical Study Adverse Event 
Form for Serious Adverse Events (SAEs) and Non-serious AEs as Required by Protocol (and any 
applicable follow-up reports) must also be sent to the CRO/Takeda medical monitor using the 
details specified in the emergency contact information section of the protocol. 
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Medical Device Safety Reporting 
The IP kit contains the BAXJECT II device. All serious injuries and UADEs must be reported to 
the sponsor as an SAE in the same process as described above. Serious injury (SI) is defined as: 
• 
Led to death; 
• 
Led to a serious deterioration in health of a patient, user, or others that 
• 
Results in a life-threatening illness or injury 
• 
Results in a permanent impairment/ damage of a body function or body structure 
• 
Requires in-patient hospitalization or prolongation of existing hospitalization 
• 
Results in medical or surgical intervention to prevent permanent impairment/ damage to 
body function/ structure. 
• 
Led to fetal distress, fetal death or a congenital abnormality/birth defect 
 
Appendix 3.5 
Serious Adverse Event Collection Time Frame 
All SAEs (regardless of relationship to investigational product) are collected from the time the 
subject signs the informed consent until the final visit (End-of-Treatment / Study Termination 
Visit) stated in Section 8.3.2 and must be reported to the Takeda Global Drug Safety Department 
and the CRO/Takeda medical monitor within 24 hours of the first awareness of the event. 
In addition, any SAE(s) considered “related” to the investigational product and discovered by the 
investigator at any interval after the study has completed must be reported to the Takeda Global 
Drug Safety Department within 24 hours of the reported first becoming aware of the event. 
Appendix 3.6 
Serious Adverse Event Onset and Resolution Dates 
The onset date of the SAE is defined as the date the event meets serious criteria. The resolution 
date is the date the event no longer meets serious criteria, the date the symptoms resolve, or the 
event is considered chronic. In the case of hospitalizations, the hospital admission and discharge 
dates are considered the onset and resolution dates, respectively. 
In addition, any signs or symptoms reported by the subject after signing the informed consent 
form, or leading up to the onset date of the SAE, or following the resolution date of the SAE, 
must be recorded as an AE, if appropriate. 
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Appendix 3.7 
Fatal Outcome 
Any SAE that results in the subject’s death (eg, the SAE was noted as the primary cause of 
death) must have fatal checked as an outcome with the date of death recorded as the resolution 
date. For all other events ongoing at the time of death that did not contribute to the subject’s 
death, the outcome should be considered not resolved, without a resolution date recorded. 
For any SAE that results in the subject’s death or any ongoing events at the time of death, unless 
another investigational product action was previously taken (eg, drug interrupted, reduced, 
withdrawn), the action taken with the investigational product should be recorded as “dose not 
changed” or “not applicable” (if the subject never received investigational product). The 
investigational product action of withdrawn should not be selected solely as a result of the 
subject’s death. 
Appendix 3.8 
Pregnancy  
All pregnancies are reported from the time informed consent is signed until the final visit  
(End-of-Treatment / Study Termination Visit) stated in Section 8.3.2 
Any report of pregnancy for any female study participant or the partner of a male study 
participant must be reported within 24 hours to the Takeda Global Drug Safety Department using 
the Takeda Investigational and Marketed Products Pregnancy Report Form.  
A copy of the Takeda Investigational and Marketed Products Pregnancy Report Form (and any 
applicable follow-up reports) must also be sent to the CRO/Takeda medical monitor using the 
details specified in the emergency contact information section of the protocol. The pregnant 
female study participant must be withdrawn from the study. 
Every effort should be made to gather information regarding the pregnancy outcome and 
condition of the infant. It is the responsibility of the investigator to obtain this information within 
30 calendar days after the initial notification and approximately 30 calendar days and 1 year 
post-partum. 
Pregnancy complications such as spontaneous abortion/miscarriage, elective abortion or 
congenital abnormality are considered SAEs and must be reported using the Takeda Clinical 
Study Serious Adverse Event and Non-serious AEs Required by the Protocol Form.  
In addition to the above, if the investigator determines that the pregnancy meets serious criteria, 
it must be reported as an SAE using the Takeda Clinical Study Serious Adverse Event and 
Non-serious AEs Required by the Protocol Form as well as the Takeda Investigational and 
Marketed Products Pregnancy Report Form. The test date of the first positive serum/urine β-hCG 
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test or ultrasound result will determine the pregnancy onset date. 
Appendix 3.9 
Abuse, Misuse, Overdose and Medication Error 
Abuse, misuse, overdose, or medication error (as defined below) must be reported to the sponsor 
according to the SAE reporting procedure whether or not they result in an AE/SAE as described 
in Section Appendix 3.1.  
Note: The 24-hour reporting requirement for SAEs does not apply to reports of abuse, misuse, 
overdose, or medication errors unless these result in an SAE. 
The categories below are not mutually exclusive; the event can meet more than 1 category. 
• 
Abuse – Persistent or sporadic intentional intake of investigational product when used for a 
non-medical purpose (eg, to alter one’s state of consciousness or get high) in a manner that 
may be detrimental to the individual and/or society 
• 
Misuse – Intentional use of investigational product other than as directed or indicated at 
any dose (Note: this includes a situation where the investigational product is not used as 
directed at the dose prescribed by the protocol) 
• 
Overdose – Intentional or unintentional intake of a dose of investigational product higher 
than the protocol-prescribed dose 
• 
Medication Error – An error made in prescribing, dispensing, administration, and/or use of 
an investigational product. For studies, medication errors are reportable to the sponsor only 
as defined below. 
 
Cases of subjects missing doses of the investigational product are not considered reportable as 
medication errors. 
Medication errors should be collected/reported for all products under investigation. 
The administration and/or use of an expired investigational product should be considered as a 
reportable medication error. 
All investigational product provided to pediatric subjects should be supervised by the 
parent/legally authorized representative/caregiver. 
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Appendix 3.10 Urgent Safety Measures  
An urgent safety measure is an immediate action taken, which is not defined by the protocol, in 
order to protect subjects participating in a clinical trial from immediate harm, these do not 
constitute de facto deviation from the protocol. Urgent safety measures may be taken by the 
sponsor or clinical investigator, and may include any of the following: 
• 
Immediate change in study design or study procedures 
• 
Temporary or permanent halt of a given clinical trial or trials 
• 
Any other immediate action taken in order to protect clinical trial participants from 
immediate hazard to their health and safety 
 
The investigator may implement urgent safety measures to protect study subjects from 
immediate hazard to their health or safety. The measures should implement immediately and 
does not require prior authorization from the sponsor. In the event(s) of an apparent direct hazard 
to the subject, the investigator will notify the sponsor immediately by phone and confirm 
notification to the sponsor in writing as soon as possible, and within 1 calendar day after the 
change is implemented. The sponsor will also ensure the responsible EC(s) and relevant 
competent authority(s) are notified of the urgent safety measures taken in such cases according to 
local regulations. 
Appendix 3.11 Regulatory Agency, Institutional Review Board, Ethics Committee and 
Site Reporting 
The sponsor and the local CRO are responsible for notifying the relevant regulatory authorities 
and ethics committees of related, unexpected SAEs.vi  
In addition, the sponsor is responsible for notifying active sites of all related, unexpected SAEs 
occurring during all interventional studies across the ADVATE clinical program. 
The investigator is responsible for notifying the local IRB/EC of SAEs or significant safety 
findings that occur at his or her site as required by IRB/EC procedures (see Appendix 1.5). 
 
 
vi The sponsor is responsible for notifying the relevant regulatory authorities, and the local CRO is responsible for 
notifying the ethics committees. 
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Appendix 4 
COUNTRY-SPECIFIC REQUIREMENTS 
Appendix 4.1 
Package Insert  
Please see enclosed an example of the ADVATE Package Insert for the dose strength 500 IU. 
Other dose strengths will also be used in the study. 
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Appendix 4.2 
Undertaking by the Investigator 
The following is a commitment/agreement from the investigator participating in the study and is 
based on the New Drugs and Clinical Trial Rules set forth by the Central Drugs Standard Control 
Organization in India (The Gazette of India et al., 2019): 
UNDERTAKING BY THE INVESTIGATOR 
1. Full name, address and title of the Principal Investigator (or Investigators when there is no 
Principal Investigator). 
2. Name and address of the medical college, hospital or other facility where the clinical trial 
will be conducted: Education, training & experience that qualify the Investigator for the 
clinical trial (Attach details including Medical Council registration number, or any other 
statements of qualifications) 
3. Name and address of all clinical laboratory facilities to be used in the study. 
4. Name and address of the Ethics Committee that is responsible for approval and continuing 
review of the study. 
5. Names of the other members of the research team (Co-or sub-Investigators) who will be 
assisting the Investigator in the conduct of the investigations. 
6. Protocol Title and Study number (if any) of the clinical trial to be conducted by the 
Investigator. 
7. Commitments: 
(i) I have reviewed the clinical protocol and agree that it contains all the necessary 
information to conduct the study. I will not begin the study until all necessary ethics 
committee and regulatory approvals have been obtained. 
(ii) I agree to conduct the study in accordance with the current protocol. I will not 
implement any deviation from or changes of the protocol without agreement by the 
Sponsor and prior review and documented approval or favourable opinion from the ethics 
committee of the amendment, except where necessary to eliminate an immediate hazard to 
the trial subject or when the changes involved are only logistical or administrative in 
nature. 
(iii) I agree to personally conduct or supervise the clinical trial at my site. 
(iv) I agree to inform all trial subject, that the drugs are being used for investigational 
purposes and I will ensure that the requirements relating to obtaining informed consent and 
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ethics committee review and approval specified in the New Drugs and Clinical Trials 
Rules, 2019 and Good Clinical Practices guidelines are met. 
(v) I agree to report to the Sponsor all adverse experiences that occur in the course of the 
investigation(s) in accordance with the regulatory requirements and Good Clinical 
Practices guidelines. 
(vi) I have read and understood the information in the Investigator's brochure, including the 
potential risks and side effects of the drug. 
(vii) I agree to ensure that all associates, colleagues and employees assisting in the conduct 
of the study are suitably qualified and experienced and they have been informed about their 
obligations in meeting their commitments in the trial. 
(viii) I agree to maintain adequate and accurate records and to make those records available 
for audit or inspection by the Sponsor, ethics committee, Central Licencing Authority or 
their authorised representatives, in accordance with regulatory provisions and the Good 
Clinical Practices guidelines. I will fully cooperate with any study related audit conducted 
by regulatory officials or authorised representatives of the Sponsor. 
(ix) I agree to promptly report to the ethics committee all changes in the clinical trial 
activities and all unanticipated problems involving risks to human subjects or others. 
(x) I agree to inform all serious adverse events to the Central Licencing Authority, sponsor 
as well as the ethics committee within twenty-four hours of their occurrence. In case, of 
failure to do so, I shall furnish the reason for the delay to the satisfaction of the Central 
Licencing Authority along with the report of the serious adverse event. 
(xi) The report of the serious adverse event, after due analysis, shall also be forwarded by 
me to the Central Licencing Authority, the Chairperson of the ethics committee and the 
Head of the institution where the trial has been conducted within fourteen days in 
accordance with the regulatory requirements. 
(xii) I will maintain confidentiality of the identification of all participating subjects and 
assure security and confidentiality of study data. 
(xiii) I agree to comply with all other requirements, guidelines and statutory obligations as 
applicable to clinical Investigators participating in clinical trials. 
8. Signature of Investigator with date. 
 
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Appendix 5 
ABBREVIATIONS  
Abbreviation 
Definition 
Ab 
antibody 
AE  
adverse event 
AHF 
antihemophilic factor 
ALT 
alanine aminotransferase (synonymous with SGPT) 
aPTT 
activated partial thromboplastin time 
AST 
aspartate aminotransferase (synonymous with SGOT) 
AUC 
area under the curve 
AUC0-∞ 
area under the curve from time 0 to infinity 
AUC0-tlast 
area under the curve from time 0 to the time of last concentration measured 
AUMC 
area under the moment curve 
BI 
bolus infusion 
BUN 
blood urea nitrogen 
CFR 
Code of Federal Regulations 
CHO 
Chinese hamster ovary 
CI 
confidence interval 
Cmax 
maximum concentration 
CRF 
case report form 
CRO 
contract research organization 
DMC 
data monitoring committee 
EC 
ethics committee 
ECG 
electrocardiogram 
eCRF 
electronic case report form  
ED 
exposure day 
EDC 
electronic data capture/collection 
EFAS 
effectiveness full analysis set 
ELISA 
enzyme-linked immunosorbent assay 
EMA 
European Medicines Agency 
EU 
European Union 
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Abbreviation 
Definition 
EUDRA 
European Union Drug Regulatory Authorities 
EUDRACT 
European Union clinical trials database 
FVIII 
factor VIII 
FDA 
Food and Drug Administration  
GCP 
Good Clinical Practice 
GLM 
generalized linear model 
h 
hour(s) 
ICF 
informed consent form 
ICH 
International Council for Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 
IgG 
Immunoglobulin G 
INR 
international normalized ratio 
IP 
investigational product 
IR 
incremental recovery 
IRB 
institutional review board 
ISTH 
International Society for Thrombosis and Haemostasis 
IU 
international unit(s) 
IV 
intravenous(ly)  
MedDRA 
Medical Dictionary for Regulatory Activities 
mmHg 
millimeter(s) of mercury  
NA 
not applicable 
PCR 
polymerase chain reaction 
PFM 
plasma/albumin free method 
PK 
pharmacokinetic(s) 
PTP 
previously treated patient 
PUP 
previously untreated patient 
rAHF 
antihemophilic factor (recombinant) 
rAHF-PFM 
Antihemophilic Factor (Recombinant) - Plasma/Albumin Free Method 
rFVIII 
recombinant FVIII 
SAE 
serious adverse event  
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Abbreviation 
Definition 
SAP 
statistical analysis plan 
SAS 
safety analysis set 
SAS 
statistical analysis system 
SC 
subcutaneous(ly) 
SmPC 
Summary of Product Characteristics 
SOC 
system organ class 
SoC 
standard of care 
SOP 
standard operating procedure 
SUSAR 
suspected unexpected serious adverse reaction 
SWFI 
sterile water for injections 
t1/2 
half-life 
TBD 
to be determined 
Tmax 
time to maximum concentration 
US 
United States 
VWD 
von Willebrand´s disease 
VWF 
von Willebrand factor 
WHO 
World Health Organization 
 
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11. REFERENCES 
Bolton-Maggs, P. H. & Pasi, K. J. 2003. Haemophilias A and B. Lancet, 361, 1801-1809. 
Lee, C. A. 2007. Prevention of haemophilic synovitis: prophylaxis. Haemophilia, 13 Suppl 3, 20-
25. 
Shapiro, A. D., Donfield, S. M., Lynn, H. S., Cool, V. A., Stehbens, J. A., Hunsberger, S. L., 
Tonetta, S. & Gomperts, E. D. 2001. Defining the impact of hemophilia:  The academic 
achievement in children with hemophilia study. Pediatrics, 108, E105. 
Soucie, J. M., Evatt, B., Jackson, D. & Investigators, H. S. S. P. 1998. Occurrence of hemophilia 
in the United States. The Hemophilia Surveillance System Project Investigators. Am J 
Hematol, 59, 288-294. 
The Gazette of India, New Dehli & Ministry of Health and Family Welfare 2019. Notification 
19th March. G.S.R. 227(E), Third Schedule, Table 4 (p. 217-218).Web Link: 
https://cdsco.gov.in/opencms/opencms/system/modules/CDSCO.WEB/elements/downloa
d_file_division.jsp?num_id=NDI2MQ== 
World Federation of Hemophilia 2018. Report on the Annual Global Survey 2017. Montreal, 
Quebec, Canada.Web Link: http://www1.wfh.org/publication/files/pdf-1429.pdf 
 
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