A Phase 3, Prospective, Multicenter, Open-label Study of Efficacy, Safety, and Pharmacokinetics of PEGylated Recombinant Factor VIII (ADYNOVATE) Administered for Prophylaxis and Treatment of Bleeding in Chinese Previously Treated Patients With Severe Hemophilia A (FVIII <1%)
Phase: PHASE3
Conditions: Hemophilia A
Sponsor: Takeda



TAKEDA PHARMACEUTICALS
Protocol:
TAK-660-3001
Title:
A Phase 3, Prospective, Multicenter, Open-label Study of Efficacy, 
Safety, and Pharmacokinetics of PEGylated Recombinant Factor VIII 
(ADYNOVATE) Administered for Prophylaxis and Treatment of Bleeding 
in Chinese Previously Treated Patients With Severe Hemophilia A (FVIII 
<1%)
Short Title:
China ADYNOVATE PTP Study in Hemophilia A
Study Phase:
Phase 3
Drug:
ADYNOVATE (antihemophilic factor [recombinant] PEGylated, 
rurioctocog alfa pegol)
IND Number:
Non-IND
EUDRACT 
Number:
2023-000502-26 
Sponsor:
Baxalta US Inc.*
* NOTE: Takeda Development Center Americas, Inc. with its legal registered address at
95 Hayden Avenue, Lexington, MA 02421 USA, has been authorized by Baxalta US Inc. to
conduct this Study in the People's Republic of China. Both companies are wholly owned
subsidiaries of Takeda Pharmaceutical Company Limited.
Principal / 
Coordinating 
Investigator:
, MD
Protocol History:
Date
Amendment Number
Amendment Type
Region
16 Apr 2023
Amendment 1
Non-substantial
China
21 Jun 2022
Original protocol
Not applicable
China
Confidentiality Statement
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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SUMMARY OF CHANGES FROM PREVIOUS PROTOCOL VERSION
Noteworthy changes to the protocol are captured in the table below. The primary reason for this 
amendment is to remove the Haemo-SYM questionnaire for patient-reported outcome 
assessment.
In this amendment, minor grammatical, editorial, formatting, and administrative changes not 
affecting the conduct of the study are included for clarification and administrative purposes only 
and are not described in this table.
Protocol Amendment 1
Summary of Changes Since the Last Version of the Approved Protocol
Description of Each Change and Rationale
Section(s) Affected by Change
Change
Number
Description of change(s)
Rationale for change(s)
Section
1
Removed the Haemo-SYM 
questionnaire from 
patient-reported outcome 
assessments
Failed to obtain the 
questionnaire license in 
China
Section 1.1 Synopsis
Table 1 Schedules of Activities
Table 4 Objectives and Endpoints
Section 4.1 Overall Design
Section 8.2.7.1 Patient-reported 
Outcomes
Section 9.8.1 Patient-reported 
Outcomes
Appendix 4 Scales and 
Assessments
2
Removed the exploratory 
biomarker assessments for 
joint health
Followed the 
recommendation written 
in the NMPA approval 
letter for Study 
TAK-660-3001 Clinical 
Trial Application (CTA)
Section 1.1 Synopsis
Table 1 Schedule of Activities
Section 3.1.3 Exploratory 
Objectives
Table 4 Objectives and Endpoints
previous Section 8.2.7.3 
(removed)
3
Added the study stopping 
rules
Specified the criteria of 
study stopping
Section 4.6 Study Stopping 
Rules
Section 7.2 Reasons for 
Withdrawal/Discontinuation 
from Study
4
Specified that dose 
adjustment for prophylactic 
treatment may be increased 
gradually by 10 IU/kg 
increments
Clarification
Section 6.2.2.2 Prophylactic 
Treatment (Dose Adjustment for 
Prophylactic Treatment)
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Protocol Amendment 1
Summary of Changes Since the Last Version of the Approved Protocol
Description of Each Change and Rationale
Section(s) Affected by Change
Change
Number
Description of change(s)
Rationale for change(s)
Section
5
Added the blood urea 
nitrogen (BUN) as an 
alternative test of the urea
Allow for use of an 
alternative local practice
Table 2 Clinical Laboratory 
Assessments
Section 8.2.5.4.2 Hematology and 
Clinical Chemistry
Appendix 2 Clinical Laboratory 
Tests
6
A new criterion was added 
for serious adverse event 
(SAE): severe 
hypersensitivity/allergic 
reactions to ADYNOVATE
Consistency with the 
ADYNOVATE global 
pivotal study protocols
Appendix 3.1 Adverse Event 
Definitions (Serious Adverse 
Event)
7
Amended the text 
regarding the report of 
changes in the severity of 
adverse events (AEs)
Only the highest severity 
rating will be reported
during the course of an 
AE. Reporting every 
change in the severity of 
an ongoing AE may 
cause confusion and lead 
to repeated counts of the 
same event
Appendix 3.3 Assessment of 
Adverse Events (Severity 
Categorization)
8
Modified language to 
clarify that the doses for 
the pharmacokinetic (PK) 
and incremental recovery 
(IR) assessments are 
required to use the same lot
Clarification
Section 6.2 Administration of 
Investigational Product
9
Removed Study 261202 as 
a reference for the study 
design
Correction
Section 4.2 Scientific Rationale 
for Study Design
10
Amended the description of 
PK analyses
Clarification
Section 1.1 Synopsis
Section 9.7 Pharmacokinetic 
Analyses
11
Updated the text regarding 
the commercial availability 
of extended half-life FVIII 
product
Per the up-to-date market 
status
Section 2.1 Indication and Current 
Treatment Options
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Protocol Amendment 1
Summary of Changes Since the Last Version of the Approved Protocol
Description of Each Change and Rationale
Section(s) Affected by Change
Change
Number
Description of change(s)
Rationale for change(s)
Section
12
Removed the time point 
restriction: patient-reported 
outcome (PRO) 
assessments/eDiaries 
should be completed the 
night prior to each 
specified study visit.
Completion of the PRO 
assessments/eDiaries just 
prior to each specified 
study visit is acceptable 
Section 1.1 Synopsis
Table 1 Schedule of Activities
Section 4.1 Overall Design
Section 8.2.3 Subject Electronic 
Diary
Section 8.2.7.1 Patient-reported 
Outcome
13
Removed the collection 
and analysis of the duration 
of emergency room visits
Correction
Section 1.1 Synopsis
Table 1 Schedule of Activities
Section 8.2.7.2 Healthcare 
Resource Utilization
Section 9.8.2 Healthcare Resource 
Utilization Analyses 
(Section 9 Statistical 
Considerations)
14
Changed the schedule of 
anti-CHO Ab analysis to 
only screening visit, 
Week 12, and 
completion/termination 
visit.
To reduce unnecessary 
blood draws while 
meeting safety monitoring 
requirements
Table 2 Clinical Laboratory 
Assessments
15
Modified the language 
regarding the informed 
consent for additional PK 
sampling
PK sampling item has 
been included in the ICF 
and no separate informed 
consent for PK sampling 
will be obtained
Appendix 1.5 Ethical 
Considerations (Additional 
Pharmacokinetic Sampling 
Consent Procedure)
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CONTACTS
Contacts
Certain events and study-related activities will require the investigator and/or patient to have 
appropriate contact information. The sponsor or contract research organization (CRO) will 
provide investigators with emergency medical contact information cards to be carried by each 
subject.
SAE Reporting
If a subject experiences a serious adverse event (SAE) or a non-serious adverse event (AE) 
requiring expedited reporting per the protocol, the investigator must report the event to the 
sponsor or CRO within 24 hours of becoming aware of the event on the electronic case report 
form (eCRF). If the eCRF is not available, then the event must be reported on the Takeda Safety 
Report Form and faxed or emailed to the sponsor or CRO to meet the 24-hour timeline 
requirement. The fax number and e-mail address are provided in the Form Completion 
Instructions.
Protocol and Safety-related Questions or Concerns
For protocol- or safety-related questions or concerns, a separate contact information list will be 
provided.
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PRODUCT QUALITY COMPLAINTS
Investigators are required to report investigational product (IP) quality complaints or 
non-medical complaints to Takeda within 1 business day. If requested, defective product(s) will 
be returned to the sponsor for inspection and analysis.
A product quality complaint includes any instances where there is an allegation or report relating 
to Takeda licensed or IPs, received in writing, electronically, or orally, which indicates an impact 
to a product’s strength, identity, safety, purity, or quality, or which suggests that the product did 
not meet the criteria defined in the regulatory applications, licenses, or marketing authorizations 
for the product. Examples of IP quality complaints include, but are not limited to, the following:
Unit issues

Capsule fill empty or overage

Bottle/vial fill shortage or overage

Capsule/tablet damaged/broken

Syringe/vial cracked/broken

Syringe leakage

Missing components

Product discoloration

Device malfunction
Labeling

Label missing

Leaflet or Instructions For Use 
missing 

Label illegible

Incomplete, inaccurate, or 
misleading labeling

Lot number or serial number missing
Packaging

Damaged packaging (eg, secondary, 
primary, bag/pouch)

Tampered seals

Inadequate or faulty closure

Missing components within package
Foreign 
material

Contaminated product

Particulate in bottle/vial

Particulate in packaging
Please report the product quality complaint using the Clinical Trial Material Complaint Form via 
the email address:
ctmcomplaint@takeda.com
For instructions on reporting AEs related to product complaints, see Appendix 3.4.
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TABLE OF CONTENTS
PROTOCOL SIGNATURE PAGE........................................................................................2
SUMMARY OF CHANGES FROM PREVIOUS PROTOCOL VERSION.....................3
CONTACTS .............................................................................................................................6
PRODUCT QUALITY COMPLAINTS................................................................................7
TABLE OF CONTENTS ........................................................................................................8
LIST OF IN-TEXT TABLES ...............................................................................................12
LIST OF IN-TEXT FIGURES .............................................................................................12
LIST OF APPENDICES .................................................. ....................................................12
1. PROTOCOL SUMMARY ................................................................................................13
1.1 Synopsis........................................................................................................................13
1.2 Schema .........................................................................................................................20
1.3 Schedules of Activities.................................................................................................21
2. INTRODUCTION..............................................................................................................29
2.1 Indication and Current Treatment Options.............................................................29
2.2 Product Background and Clinical Information .......................................................30
2.3 Study Rationale ...........................................................................................................34
2.4 Benefit/Risk Assessment.............................................................................................34
2.5 Compliance Statement................................................................................................35
3. OBJECTIVES AND ENDPOINTS ..................................................................................36
3.1 Study Objectives..........................................................................................................36
3.1.1 Primary Objective ................................................................................................36
3.1.2 Secondary Objectives ...........................................................................................36
3.1.3 Exploratory Objective..........................................................................................36
3.2 Study Endpoints ..........................................................................................................37
4. STUDY DESIGN................................................................................................................39
4.1 Overall Design .............................................................................................................39
4.2 Scientific Rationale for Study Design........................................................................41
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4.3 Justification for Dose ..................................................................................................41
4.4 Duration of Subject Participation and Study Completion Definition....................41
4.5 Sites and Regions.........................................................................................................41
4.6 Study Stopping Rules..................................................................................................42
5. STUDY POPULATION ....................................................................................................43
5.1 Inclusion Criteria ........................................................................................................43
5.2 Exclusion Criteria .......................................................................................................43
5.3 Restrictions ..................................................................................................................44
5.4 Reproductive Potential ...............................................................................................44
6. STUDY INTERVENTION................................................................................................45
6.1 Investigational Product...............................................................................................45
6.1.1 Identity of Investigational Product .....................................................................45
6.1.2 Blinding the Treatment Assignment...................................................................45
6.2 Administration of Investigational Product................... ...........................................45
6.2.1 Allocation of Subjects to Treatment ...................................................................46
6.2.2 Dosing .................................................................. .................................................46
6.2.2.1 Dosing for PK Characterization...................................................................46
6.2.2.2 Prophylactic Treatment.................... . ..........................................................47
6.2.2.3 On-demand Treatment of Bleeding Episodes .............................................48
6.2.2.4 Perioperative Bleeding Management...........................................................50
6.2.3 Unblinding the Treatment Assignment ..............................................................54
6.3 Labeling, Packaging, Storage, and Handling of Investigational Product..............54
6.3.1 Labeling............................ ....................................................................................54
6.3.2 Packaging ..............................................................................................................55
6.3.3 Storage...................................................................................................................55
6.4 Drug Accountability....................................................................................................56
6.5 Subject Compliance ....................................................................................................57
6.6 Concomitant, Permitted, and Prohibited Therapy..................................................57
6.6.1 Concomitant Treatment.......................................................................................57
6.6.2 Permitted Treatment............................................................................................57
6.6.3 Prohibited Treatment...........................................................................................58
7. DISCONTINUATION OF STUDY INTERVENTION AND SUBJECT 
DISCONTINUATION/WITHDRAWAL .......................................................................59
7.1 Discontinuation of Study Treatment.........................................................................59
7.2 Reasons for Withdrawal/Discontinuation from Study ............................................59
7.3 Subjects “Lost to Follow-up” Prior to the Last Scheduled Visit............................60
8. STUDY ASSESSMENTS AND PROCEDURES............................................................61
8.1 Study Periods...............................................................................................................61
8.1.1 Screening Visit ......................................................................................................61
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8.1.2 Initial Pharmacokinetic Assessment...................................................................62
8.1.3 Study Treatment Visits ........................................................................................62
8.1.3.1 Baseline Visit and Prophylaxis Visits (Weeks 2, 6, and 12) .......................62
8.1.3.2 Second Pharmacokinetic Assessment (Week 20) ........................................63
8.1.3.3 Study Completion/Termination Visit (Week 26 or ≥50 EDs) ....................63
8.1.4 Safety Follow-up...................................................................................................64
8.1.5 Additional Care of Subjects after the Study......................................................64
8.1.6 COVID-19–related Protocol Considerations .....................................................64
8.2 Study Assessments.......................................................................................................65
8.2.1 Demographic and Other Baseline Characteristics ............................................65
8.2.2 Medical and Medication History.........................................................................65
8.2.3 Subject Electronic Diary......................................................................................66
8.2.4 Efficacy..................................................................................................................67
8.2.4.1 Prophylaxis Treatment Assessments............................................................67
8.2.4.2 On-demand Treatment of Bleeding Episodes Assessments .......................68
8.2.4.3 Perioperative Bleeding Management Assessments.....................................70
8.2.5 Safety ............................................................................ ........................................72
8.2.5.1 Physical Examination ....................................................................................72
8.2.5.2 Adverse Events...............................................................................................73
8.2.5.3 Vital Signs.......................................................................................................73
8.2.5.4 Clinical Laboratory Tests..............................................................................74
8.2.5.5 Immunogenicity................................. ............................................................75
8.2.6 Pharmacokinetics .................................................................................................76
8.2.6.1 Pharmacokinetic Sampling and Evaluation................................................76
8.2.6.2 Determination of Incremental Recovery .....................................................76
8.2.6.3 Factor VIII and von Willebrand Factor Measurements............................76
8.2.7 Other Assessments................................................................................................77
8.2.7.1 Patient-reported Outcome.............................................................................77
8.2.7.2 Healthcare Resource Utilization...................................................................77
9. STATISTICAL CONSIDERATIONS .............................................................................78
9.1 Statistical Analysis Process.........................................................................................78
9.2 Planned Interim Analysis, Adaptive Design, and Data Monitoring Committee...78
9.3 Sample Size and Power Considerations....................................................................78
9.4 Statistical Analysis Sets...............................................................................................78
9.4.1 Safety Analysis Set................................................................................................78
9.4.2 Full Analysis Set ...................................................................................................78
9.4.3 Per Protocol Analysis Set.....................................................................................79
9.4.4 Pharmacokinetic Full Analysis Set .....................................................................79
9.4.5 Pharmacokinetic Analysis Set .............................................................................79
9.5 Efficacy Analyses.........................................................................................................79
9.5.1 Primary Efficacy Endpoint..................................................................................79
9.5.2 Secondary Efficacy Endpoints.............................................................................79
9.5.2.1 Bleeding Episodes and Annualized Bleeding Rate......................................79
9.5.2.2 Consumption of ADYNOVATE........................................................................79
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9.5.2.3 Overall Hemostatic Efficacy Rating and Global Hemostatic Efficacy 
Assessment ........................................................................................................80
9.5.2.4 Efficacy for Surgeries ....................................................................................80
9.5.3 Multiplicity Adjustment.......................................................................................80
9.5.4 Control of Type I Error .......................................................................................80
9.6 Safety Analyses............................................................................................................81
9.6.1 Adverse Events......................................................................................................81
9.6.2 Immunogenicity ....................................................................................................81
9.6.2.1 Factor VIII inhibitor development...............................................................81
9.6.2.2 Binding Antibodies.........................................................................................81
9.6.3 Vital Signs and Clinical Laboratory Parameters ..............................................81
9.7 Pharmacokinetic Analyses .........................................................................................82
9.8 Other Analyses ............................................................................................................82
9.8.1 Patient-reported Outcome Analysis....................................................................82
9.8.2 Healthcare Resource Utilization Analyses .........................................................82
10. REFERENCES.................................................................................................................83
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LIST OF IN-TEXT TABLES
Table 1. Schedule of Activities..............................................................................................21
Table 2. Clinical Laboratory Assessments ..........................................................................26
Table 3. Pharmacokinetic Sampling Time Points...............................................................28
Table 4. Objectives and Endpoints.......................................................................................37
Table 5. ADYNOVATE Example Dosing Frequency..............................................................47
Table 6. ADYNOVATE Treatment Guidelines for Bleeding Episodes .................................50
Table 7. Efficacy Rating Scale for Treatment of Bleeding Episodes.................................68
Table 8. Intraoperative Efficacy Assessment Scale ............................................................70
Table 9. Postoperative Efficacy Assessment Scale (Postoperative Day 1)........................70
Table 10. Perioperative Efficacy Assessment Scale (Discharge Visit) ..............................71
Table 11. Global Hemostatic Efficacy Assessment ................... . .......................................71
LIST OF IN-TEXT FIGURES
Figure 1. Study Schematic Diagram.....................................................................................20
LIST OF APPENDICES
Appendix 1 Regulatory, Ethical, and Study Oversight Considerations ...........................85
Appendix 2 Clinical Laboratory Tests.................................................................................94
Appendix 3 Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-Up, and Reporting................................................................................................96
Appendix 4 Scales and Assessments...................................................................................107
Appendix 5 Abbreviations...................................................................................................108
Appendix 6 Protocol History...............................................................................................111
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1. PROTOCOL SUMMARY
1.1 Synopsis
Protocol number: TAK-660-3001
Drug: ADYNOVATE
Title of the study: A Phase 3, Prospective, Multicenter, Open-label Study of Efficacy, Safety, and 
Pharmacokinetics of PEGylated Recombinant Factor VIII (ADYNOVATE) Administered for Prophylaxis and 
Treatment of Bleeding in Chinese Previously Treated Patients With Severe Hemophilia A (FVIII <1%)
Short title: China ADYNOVATE PTP Study in Hemophilia A
Number of subjects (total): At least 30 evaluable subjects aged 12 to 65 years 
Investigator(s): Multicenter study
Site(s) and Region(s): 
The study will be conducted at approximately 12 sites in China.
Study period (planned): 2023 to 2025
Clinical phase: 3
Objectives:
Primary: 
•
To assess the efficacy of ADYNOVATE® for prophylactic treatment in previously treated Chinese subjects 
with severe hemophilia A based on the total annualized bleeding rate (ABR)
Secondary: 
•
To assess the efficacy of ADYNOVATE for prophylactic treatment based on ABR by bleeding site and cause
•
To assess the overall hemostatic efficacy rating of ADYNOVATE for treatment of nonsurgical breakthrough 
bleeding episodes during the study period
•
To assess the efficacy of ADYNOVATE for perioperative bleeding management if minor surgery is performed 
during the study period
•
To evaluate the safety of ADYNOVATE as assessed by adverse events (AEs) and serious AEs (SAEs) as well 
as clinically significant findings in vital signs and clinical laboratory parameters
•
To evaluate the safety and the immunogenicity of ADYNOVATE based on the incidence of factor VIII (FVIII) 
inhibitory antibodies and binding antibodies to ADYNOVATE
•
To evaluate the pharmacokinetics (PK) of ADYNOVATE in Chinese subjects 
Exploratory:
•
To assess the effect of ADYNOVATE on health-related quality of life (QoL) and healthcare resource 
utilization
Rationale:
The study will evaluate the efficacy and safety of ADYNOVATE for prophylaxis and treatment of bleeding 
episodes in previously treated patients with severe hemophilia A (FVIII <1%) in the Chinese population. The 
study will also provide ADYNOVATE PK data in Chinese patients with severe hemophilia A.
Investigational product, dose, and mode of administration:
The investigational product (IP) is ADYNOVATE (antihemophilic factor [recombinant] PEGylated, rurioctocog 
alfa pegol). ADYNOVATE, following reconstitution, is injected intravenously using an appropriately sized syringe 
as a bolus infusion in ≤5 minutes (maximum infusion rate: 10 mL/min).
The doses for ADYNOVATE are as follows:
•
PK Evaluation: 45±5 international units (IU)/kg as a single-dose infusion for the initial PK assessment 
before receiving the first prophylactic dose. The second PK assessment will be performed during the 
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Week 20 (±1 week) visit following the scheduled prophylactic treatment dose. The dose for incremental 
recovery (IR) assessments is the same as that for prophylactic treatment at the scheduled visits.
•
Prophylactic Treatment: 45±5 IU/kg twice weekly. The subject will be treated for a minimum of 
50 exposure days (EDs) to ADYNOVATE or approximately 26 weeks (+2 weeks), whichever occurs last.
•
Treatment of Bleeding Episodes: ADYNOVATE at an individualized dose of 10 to 60 IU/kg.
•
Perioperative Bleeding Management: The dose and frequency will be individualized based on the 
subject’s IR to obtain the target level required for the minor surgical, dental, or other invasive procedures 
being performed. 
Methodology:
All subjects and/or legal representatives are required to provide signed informed consent prior to any study 
procedure. For screening, subjects need to undergo a minimum washout period of at least 72 to 96 hours 
following their last FVIII therapy (on-demand or prophylactic), if applicable. The study screening procedures 
(Table 1) will be performed for eligibility determination and will be completed within 30 days prior to the initial 
PK assessment (if applicable) or baseline visit. Screening procedures will include demographics, 
medical/medication history, concomitant medications, AEs, physical examination, vital signs, and clinical 
laboratory assessments (Table 2). Medical history (including immunization history) will include surgery history, 
hemophilia history, bleeding episode history, and history of FVIII usage over the last year. Target joints and 
subject’s ABR based on the previous 9 to 12 months will also be recorded. Medication history will include the 
name of the medication, dose, dosing interval, and regimen start and end date.
All enrolled subjects will receive twice-weekly prophylactic treatment with ADYNOVATE (45±5 IU/kg) over a 
period of 26 weeks (+2 weeks), or at least 50 EDs, whichever occurs last.
Pharmacokinetic evaluation is planned to be performed in at least 12 evaluable subjects. For subjects participating 
in the PK portion of the study, the initial PK assessment will be performed after a washout period of at least 72 to 
96 hours following their last FVIII therapy (if applicable) and prior to the baseline visit. The second PK assessment 
will be performed during the Week 20 (±1 week) visit of the prophylactic treatment phase. The PK samples will be 
collected at specified time points listed in Table 3 and measured for FVIII activity by a 1-stage clotting assay. For 
subjects not participating in the PK portion, the baseline visit may be initiated immediately upon eligibility 
confirmation. 
Following the baseline visit, subjects will return to the study site at the below timepoints for the efficacy and safety 
assessments:
•
Week 2 (±1 week) 
•
Week 6 (±1 week) 
•
Week 12 (±1 week) 
•
Week 20 (±1 week) (only for subjects undergoing PK assessment)
•
Study Completion/Termination Visit: Week 26 (+2 weeks) or at least 50 EDs (whichever occurs last)
All other study treatments may be administered either at a clinic/hospital/study site or at home by 
self-administration/administration by a parent/caregiver. The investigator will determine the setting of treatment 
administration. Unscheduled visits may occur between scheduled site visits as required. Assessments may be 
performed as clinically indicated at the discretion of the investigator.
Factor VIII (activity and antigen) and von Willebrand factor (VWF) antigen levels will be measured at specified 
study visits, preinfusion, in both PK and non-PK subjects. During the baseline visit, Week 6, and the study 
completion/termination visit, peak levels of FVIII activity will also be assessed at 30±10 minutes post the bolus 
infusion of ADYNOVATE for the determination of IR. The IR determination at the baseline visit will only be 
performed in subjects who have not undergone the initial PK assessment.
The subject electronic diary (eDiary) and electronic PRO (ePRO) devices will be dispensed after subject 
eligibility is confirmed and before first dose. The eDiary will be completed before each site visit and reviewed by 
the investigator during the visit. The investigator will check the eDiary for prophylactic treatment compliance, 
bleeding episodes and treatment, AEs, concomitant medications, and nondrug therapies. It is crucial that the 
investigator evaluates and discusses with the subject at each study visit whether the subject/legal representative 
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has adhered to the prescribed treatment regimen for prophylaxis, treatment of bleeding episodes (if applicable), 
and whether the subject/legal representative has correctly entered all necessary information.
The PRO assessment, using the European Quality of Life Questionnaire in 5 Dimensions 5-level version (EQ-5D-
5L), will be captured via an ePRO device. Subjects should complete the EQ-5D-5L prior to the baseline visit (or 
initial PK assessment for subjects participating in the PK portion of the study) and study completion/termination 
visit. Healthcare resource utilization will be gathered by sites via questionnaire as part of the electronic case 
report form. Upon completion of prophylactic treatment (at least 50 EDs or 26 weeks [+2 weeks], whichever 
occurs last), the study site will follow up via phone call with each subject after 3 to 5 days to determine the 
occurrence of AEs.
During the study period, subjects will also be treated for breakthrough bleeding episodes with ADYNOVATE. The 
dose and frequency of ADYNOVATE administration will be individualized based on the subject’s weight, type and 
severity of bleeding episode, and monitoring of appropriate clinical and laboratory measures per the 
investigator’s judgment.
If a subject requires minor elective or emergency surgical, dental, or other invasive procedures during the study 
after enrollment (ie, a surgery that was not planned before study enrollment), perioperative bleeding will be 
managed with ADYNOVATE. The dose and frequency of ADYNOVATE administration will be individualized based 
on the subject’s IR to obtain the FVIII target level required for the procedure being performed. Major surgeries 
are not in the scope of this study; any required major surgery will result in the withdrawal of the subject.
Primary Outcome Measure: 
Total ABR
Secondary Outcome Measures:
Efficacy:
•
Annualized bleeding rates based on bleeding site and cause
•
Number of infusions and weight-adjusted consumption of ADYNOVATE per week and month during the 
prophylactic treatment period
•
Proportion of subjects with zero bleeding episodes during the study
•
Time intervals between bleeding episodes
•
Overall hemostatic efficacy rating at bleed resolution for treatment of breakthrough bleeding episodes
•
Number of infusions and weight-adjusted consumption of ADYNOVATE per bleeding episode
•
Overall assessment of hemostatic efficacy based on the Global Hemostatic Efficacy Assessment score as 
assessed by the operating surgeon/investigator
•
Intra- and postoperative actual versus predicted blood loss after the surgery, at postoperative day 1, and at 
discharge, as assessed by the operating surgeon/investigator
•
Perioperative transfusion requirement of blood, red blood cells, platelets, and other blood products
•
Daily intra- and postoperative weight-adjusted consumption dose of ADYNOVATE
Safety:
•
Occurrence of AEs and SAEs, total incidence, by severity, and by causality
•
Occurrence of thromboembolic events and hypersensitivity reactions
•
Clinically significant changes in vital signs and clinical laboratory parameters
Immunogenicity: 
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•
Development of confirmed inhibitory antibodies (≥0.6 Bethesda units (BU)/mL using the Nijmegen 
modification of the Bethesda assay) to FVIII
•
Binding antibodies to ADYNOVATE
•
Binding antibodies to Chinese hamster ovary (CHO) proteins
Pharmacokinetics:
•
Factor VIII activity (1-stage clotting assay) in PK samples collected following single-dose and steady-state 
dose for PK assessments
•
Incremental recovery over time during prophylactic treatment at ED1, Week 6 (approximately ED10 to 
ED15), and ED50
•
Predose FVIII (activity and antigen) and VWF (antigen) at scheduled visits
•
Pharmacokinetic parameters including, not limited to, CL (clearance), V (volume of distribution), AUC 
(area under the concentration versus time curve between defined timepoints), Cmax (maximum 
concentration), Cpredose (predose concentration), and elimination phase T1/2 (half-life), following a single 
dose and steady-state dose, using noncompartmental analysis (NCA) methodology, subject to data 
availability
Exploratory Outcome Measures:
Patient-reported Outcome and Healthcare Resource Utilization Endpoints:
•
Health-related quality of life as assessed using the EQ-5D-5L
•
Healthcare resource utilization endpoints, including number and duration of hospitalizations, number of 
emergency room visits, number of acute care visits, and number of days missed from school/work
Inclusion and Exclusion Criteria:
Inclusion Criteria:
The subject will not be considered eligible for the study without meeting all of the criteria below:
1.
Subject and/or legally authorized representative must voluntarily sign a written informed consent form 
(ICF) after all relevant aspects of the study have been explained and discussed with the subject. For the 
subjects <18 years old, subjects will give assent AND their parents/legally authorized representative
should sign the ICF accordingly.
2.
Subject and/or legally authorized representative understands and is willing and able to comply with all 
requirements of the study protocol.
3.
Subject should be ethnic Chinese.
4.
Subject is 12 to 65 years of age at screening and male.
5.
Subject has severe hemophilia A (FVIII clotting activity <1%) as confirmed by the central laboratory at 
screening after a washout period of at least 72 to 96 hours.
6.
The last on-demand or prophylactic treatment received is within 3 months before screening.
7.
Subject has documented previous treatment with plasma-derived FVIII concentrates or recombinant FVIII 
for >150 EDs.
8.
Subject is human immunodeficiency virus (HIV) negative, or HIV-positive with stable disease and CD4+ 
count ≥200 cells/mm3.
9.
Subject is hepatitis C virus (HCV) negative by antibody testing (if positive, additional polymerase chain 
reaction testing will be performed to confirm), as confirmed at screening; or HCV-positive with chronic 
stable hepatitis as assessed by the investigator.
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Exclusion Criteria:
The subject will be excluded from the study if any of the following exclusion criteria are met:
1.
Subject has detectable FVIII inhibitory antibodies (≥0.6 BU/mL using the Nijmegen modification of the 
Bethesda assay) as confirmed by the central laboratory at screening. 
2.
Subject has a confirmed history of FVIII inhibitory antibodies (≥0.6 BU using the Nijmegen modification 
of the Bethesda assay or ≥0.6 BU using the Bethesda assay) at any time prior to screening. 
3.
Subject has a known hypersensitivity to ADYNOVATE or ADVATE or any of the components of the study 
drugs, such as mouse or hamster proteins, or other FVIII products.
4.
Subject has been diagnosed with an inherited or acquired hemostatic defect other than hemophilia A (eg, 
qualitative platelet defect or von Willebrand’s disease). 
5.
Subject has severe hepatic dysfunction (eg, ≥5 times the upper limit of normal [ULN] for alanine 
aminotransferase or aspartate aminotransferase, a recent or persistent international normalized ratio >1.5, 
as confirmed by the local laboratory at screening). 
6.
Subject has severe renal impairment (serum creatinine >1.5 times the ULN) as confirmed by the local 
laboratory at screening. 
7.
Subject is planned or likely to undergo major surgery during the study period.
8.
Subject has current or recent (<30 days) use of other PEGylated drugs before study participation or 
scheduled use of such drugs during study participation. 
9.
Subject has received emicizumab therapy within 6 months of screening. 
10. Subject is currently receiving, or scheduled to receive during the study, an immunomodulating drug (eg, 
systemic corticosteroid agent at a dose equivalent to hydrocortisone >10 mg/day, or α-interferon) other 
than antiretroviral chemotherapy.
11. Subject has participated in another clinical study involving the use of an IP other than ADYNOVATE or an 
investigational device within 30 days before the screening visit or is scheduled to participate in another 
clinical study involving an IP or investigational device during this study. 
12. Subject has a medical, psychiatric, or cognitive illness or recreational drug/alcohol use that, in the opinion 
of the investigator, would affect subject safety or compliance.
13. Subject, in the opinion of the investigator, is unable or unwilling to comply with the study protocol.
The maximum duration of subject participation in the study:
The subject’s duration of participation is expected to be approximately 8 months unless prematurely 
discontinued.
Statistical analysis:
Sample Size Determination:
At least 30 evaluable adult and adolescent subjects (aged 12 to 65 years) will be enrolled. The sample size was 
not based on statistical consideration. The evaluable subjects are defined as all subjects who are treated with 
Adynovate for a minimum of 50 EDs or approximately 26 weeks (+2 weeks), whichever occurs last. Subjects 
who withdraw or discontinue before study completion may be replaced.
Analysis Sets:
The safety analysis set (SA set) will comprise all subjects treated with at least 1 Adynovate dose. All safety 
analyses will be performed on the SA set.
The full analysis set (FAS) will comprise all subjects who were assigned to receive a treatment regimen of 
Adynovate. All efficacy analyses will be performed on the FAS.
The per protocol analysis set (PPAS) will comprise all subjects who were treated with the prophylaxis Adynovate 
treatment regimen and comply with their originally assigned dose for the duration of study participation. The 
PPAS will be the supportive analysis set.
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The PK full analysis set (PK FAS) will comprise all subjects who consented to PK evaluation, were treated with 
at least 1 Adynovate dose, and have at least 1 evaluable PK concentration post dose. All PK analyses will be 
performed on the PK FAS. 
The PK analysis set (PK AS), a subset of the PK FAS, will comprise all PK subjects who received at least 
1 Adynovate PK dose with a sufficient number of evaluable PK concentrations post dose for the estimation of PK 
parameters using an NCA.
Efficacy Analyses:
Primary Efficacy Outcome Measure (Total ABR):
The primary efficacy endpoint is the total ABR for all bleeding episodes that occurred during the study (after the 
first dose of the study drug). The ABR during the study is to be analyzed in the FAS. Point estimates with 95% 
confidence intervals (CIs) of ABRs will be presented.
Safety Analyses:
For this study, any untoward medical occurrence occurring from the time the ICF is signed will be considered an 
AE. A treatment-emergent AE (TEAE) is any event emerging or manifesting at or after the initiation of treatment 
with an IP or any existing event that worsens in either intensity or frequency following exposure to the IP.
Adverse events will be coded with the Medical Dictionary for Regulatory Activities. The number of events, 
incidence, and percentage of TEAEs, SAEs, treatment-related AEs, and TEAEs leading to discontinuation of the 
study will be summarized overall and by system organ class (SOC) and preferred term (PT). Treatment-emergent 
AEs will be further summarized by severity and relationship to IP. Adverse events related to IP, AEs leading to 
withdrawal, SAEs, and deaths will be similarly summarized/listed. 
Occurrence of hypersensitivity reactions and thromboembolic events will be monitored throughout the study and 
summarized by SOC and PT.
For immunogenicity analysis, the incidence of confirmed inhibitory antibodies (≥0.6 BU/mL using the Nijmegen 
modification of the Bethesda assay) to FVIII will be summarized by frequency table. The proportion of subjects, 
including a 95% CI using an exact Clopper-Pearson interval, who developed inhibitory antibodies to FVIII at any 
time during the study (after the first dose of the study drug) will be summarized. Histograms will be used to show 
the number and proportion of subjects with binding antibodies to Adynovate and binding antibodies to CHO 
proteins.
Clinical laboratory parameters and vital signs will be summarized for baseline and postbaseline scheduled visits 
(including the termination visit), as well as their changes from baseline. Number and percent of subjects with 
clinically significant abnormal results for vital signs and clinical laboratory parameters will be summarized for 
any postbaseline assessment. Shift tables will be used to assess the frequency of changes for clinically significant 
vital signs and clinical laboratory parameters (hematology and clinical chemistry) to note clinically significant 
changes, or vice versa, after first exposure to Adynovate.
Pharmacokinetics Analyses:
Pharmacokinetic parameters will be estimated for FVIII activity measured by the 1-stage clotting assay following 
an initial single dose and steady-state dose of Adynovate. Pharmacokinetic parameters, as appropriate but not 
limited to, will include CL, V, AUC, Cmax, Cpredose, and elimination phase T1/2. For PK subjects, subject to 
availability of FVIII activity, NCA methodology will be used. For all subjects, the population PK modeling and 
simulation method will be used, as appropriate, and reported separately.
Factor VIII activity (1-stage clotting assay) in PK samples collected following single-dose and steady-state dose 
for PK assessments, predose FVIII levels (activity and antigen), FVIII activity and VWF antigen will be tabulated 
and summarized descriptively. Incremental recovery over the prophylactic treatments will be calculated and 
summarized descriptively.
Other Analyses:
Patient-reported Outcome Analysis:
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Health-related quality of life results as assessed using the EQ-5D-5L will be summarized using descriptive 
statistics in accordance with the questionnaire user guide. Changes from baseline/preinfusion to study completion 
in this PRO will be estimated using the Hodges-Lehmann estimator.
Healthcare Resource Utilization Analyses:
Healthcare resource utilization endpoints, including number and duration of hospitalizations, number of 
emergency room visits, number of acute care visits, and number of days missed from school/work, will be 
summarized descriptively. Additional analyses may include mean hospitalizations per subject, mean length of 
stay, and mean days missed from school/work.
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1.3 Schedules of Activities
Table 1. Schedule of Activities
Procedures/
Assessments
Screening 
Visit a
Initial PK 
Assessment b
Study Treatment Visits
Safety 
Follow-up
Visit d
Second PK 
Assessment b
Study 
Completion/
Termination 
Visit
Within 30 
days
Preinfusion
Infusion
Postinfusion
Baseline
Visit
Week 2 
(±1 week)
Week 6 
(±1 week) 
Week 12
(±1 week)
Week 20 
(±1 week) 
Week 26 
(+2 weeks) 
or ≥50 EDs c, 
whichever 
occurs last
Preinfusion
Infusion
Postinfusion
Informed 
Consent/ Assente
X
Demographics
X
Eligibility 
Criteria
X
Medical/ 
Medication 
History f
X
Concomitant 
Medication g
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse Events g
X
X
X
X
X
X
X
X
X
X
X
X
X
Bleeding 
Episodes and 
Treatment g
X
X
X
X
X
X
X
X
X
X
X
X
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Table 1. Schedule of Activities
Procedures/
Assessments
Screening 
Visit a
Initial PK 
Assessment b
Study Treatment Visits
Safety 
Follow-up
Visit d
Second PK 
Assessment b
Study 
Completion/
Termination 
Visit
Within 30 
days
Preinfusion
Infusion
Postinfusion
Baseline
Visit
Week 2 
(±1 week)
Week 6 
(±1 week) 
Week 12
(±1 week)
Week 20 
(±1 week) 
Week 26 
(+2 weeks) 
or ≥50 EDs c, 
whichever 
occurs last
Preinfusion
Infusion
Postinfusion
Physical 
Examination h
X
X
X
X
X
X
X
X
Vital Signs i
X
X
X
X
X
X
X
X
X
X
Clinical 
Laboratory 
Assessments j
X
X
X
X
X
X
X
X
X
X
Subject eDiary k
X l
X l
X
X
X
X
X
ePRO 
Assessment m
X l
X l
X
Healthcare 
Resource 
Utilization n
X
X
X
X
X
X
IP Treatment o
X
X
X
X
X
X
X
IP Dispensation
X
X
X
X
X
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Table 1. Schedule of Activities
Procedures/
Assessments
Screening 
Visit a
Initial PK 
Assessment b
Study Treatment Visits
Safety 
Follow-up
Visit d
Second PK 
Assessment b
Study 
Completion/
Termination 
Visit
Within 30 
days
Preinfusion
Infusion
Postinfusion
Baseline
Visit
Week 2 
(±1 week)
Week 6 
(±1 week) 
Week 12
(±1 week)
Week 20 
(±1 week) 
Week 26 
(+2 weeks) 
or ≥50 EDs c, 
whichever 
occurs last
Preinfusion
Infusion
Postinfusion
Investigator 
Assessment of 
Hemostatic 
Efficacy p
X
X
X
X
X
IR Assessments q
X
X r
X
ABR=annualized bleeding rate; AE=adverse event; EC=ethics committee; eCRF=electronic case report form; ED=exposure day; eDiary=electronic diary; 
ePRO=electronic patient-reported outcome; FVIII=factor VIII; IP=investigational product; IR=incremental recovery; PK=pharmacokinetic(s); PRO=patient 
reported outcome
a The screening visit procedures, including laboratory evaluations, are to be completed within 30 days prior to the initial PK assessment procedures (if 
applicable) or baseline visit. At least 72 to 96 hours must have elapsed since the subject’s last FVIII therapy (on-demand or prophylactic), if applicable, and 
the subject must not be actively bleeding.
b For subjects participating in the PK portion of the study, the initial PK assessment will be conducted after a washout period of at least 72 to 96 hours 
following their last FVIII therapy (if applicable) and prior to baseline visit. The second PK assessment will be performed following the scheduled 
prophylactic treatment dose. The PK samplings for both the initial and second PK assessments should be taken following the time points listed in Table 3. 
The PK blood samples collected for PK assessments will be measured for FVIII activity (1-stage clotting assay). Subjects undergoing PK evaluation will 
enter the prophylactic treatment phase 96 hours (±4 hours) after the initial PK infusion.
c Exposure day calculation starts from the first PK infusion or baseline visit and completes at study completion/termination visit. 
d The study site will follow up via phone call with each subject 3 to 5 days after the last ADYNOVATE infusion for the occurrence of AEs.
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Table 1. Schedule of Activities
Procedures/
Assessments
Screening 
Visit a
Initial PK 
Assessment b
Study Treatment Visits
Safety 
Follow-up
Visit d
Second PK 
Assessment b
Study 
Completion/
Termination 
Visit
Within 30 
days
Preinfusion
Infusion
Postinfusion
Baseline
Visit
Week 2 
(±1 week)
Week 6 
(±1 week) 
Week 12
(±1 week)
Week 20 
(±1 week) 
Week 26 
(+2 weeks) 
or ≥50 EDs c, 
whichever 
occurs last
Preinfusion
Infusion
Postinfusion
e Written informed consent/assent must be obtained prior to any study-specific procedure.
f Medical history will include immunization history, surgery history, hemophilia history, bleeding episode history, and history of FVIII usage over the last 
year. Target joints and subject’s ABR based on the previous 9 to 12 months will also be recorded. Medication history will include the name of the product, 
dose, dosing interval, and regimen start and end date.
g Concomitant medications, nondrug therapies, AEs, bleeding episodes, and their treatment will be continuously monitored by the study site and reviewed and 
discussed with the subject at study visits.
h Physical examination will include, at a minimum, assessments of the general appearance, head and neck, eyes and ears, nose and throat, chest, lungs, heart, 
abdomen, extremities and joints, lymph nodes, skin, and neurological.
i Vital signs include height (only at screening), weight, body temperature, respiratory rate, pulse rate, and blood pressure taken following 15 minutes of rest. 
The time points for pre- and postinfusion measurements are: within 30 minutes before infusion start (prior to blood sample collection) and 30±15 minutes 
post infusion. Weight is measured preinfusion only.
j At all laboratory assessments, subjects must not be actively bleeding. Assessments should only be performed after a washout period of at least 72 to 96 hours 
following the last infusion of any other nonmodified FVIII concentrate and 84 to 96 hours following the last infusion of ADYNOVATE. In addition to the 
assessments shown, clinical laboratory assessments should be performed whenever clinically indicated. For more detailed information, please see Table 2.
k The eDiary will be dispensed after subject eligibility is confirmed and before first dose. eDiaries will be completed before each site visit and reviewed by the 
investigator during the visit. The investigator will check the eDiary for completeness and request missing information periodically, at a minimum at each 
subject visit, and in a timely manner. 
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Table 1. Schedule of Activities
Procedures/
Assessments
Screening 
Visit a
Initial PK 
Assessment b
Study Treatment Visits
Safety 
Follow-up
Visit d
Second PK 
Assessment b
Study 
Completion/
Termination 
Visit
Within 30 
days
Preinfusion
Infusion
Postinfusion
Baseline
Visit
Week 2 
(±1 week)
Week 6 
(±1 week) 
Week 12
(±1 week)
Week 20 
(±1 week) 
Week 26 
(+2 weeks) 
or ≥50 EDs c, 
whichever 
occurs last
Preinfusion
Infusion
Postinfusion
l For subjects participating in the PK portion of the study, the first eDiary/PRO assessment should be completed prior to the initial PK assessment. For 
subjects not undergoing PK assessment, the first eDiary/PRO assessment should be completed prior to baseline visit.
mThe PRO assessment, using the EQ-5D-5L, will be captured via an ePRO device dispensed after subject eligibility is confirmed and before the first dose. The 
EQ-5D-5L is to be completed before specified study visits and reviewed by the investigator during the visit.
n Healthcare resource utilization evaluation, including number and duration of hospitalizations, number of emergency room visits, number of acute care visits, 
and number of days missed from school/work will be gathered by the sites via questionnaire as part of the eCRF.
o ADYNOVATE is administered at the study site for all study-required visits. Whenever possible, the IP treatment at the study site shall be in accordance with 
the subject’s twice-weekly ADYNOVATE prophylactic treatment regimen. All other study treatments may be administered either at a clinic/hospital/study site 
or at home by self-administration/administration by a parent/caregiver. The investigator will determine the setting of treatment administration.
p Efficacy of ADYNOVATE treatment will be assessed using a 4-point efficacy rating scale (Table 7).
q Incremental recovery will be calculated by the investigator. Blood samples should be taken within 30 minutes before ADYNOVATE administration and 
30±10 minutes post ADYNOVATE infusion. The IR determination at baseline visit will only be performed in subjects who have not undergone the initial PK 
assessment.
r Incremental recovery over time during prophylactic treatment will be evaluated at ED1, Week 6, and ED50. If possible, the Week 6 visit should evaluate 
ED10 to ED15.
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Table 2. Clinical Laboratory Assessments
Procedures/
Assessments
Screening 
Visit a
Initial PK 
Assessment b
Study Treatment Visits
Second PK 
Assessment b
Study 
Completion/
Termination 
Visit
Within 
30 days
Preinfusion
Infusion
Postinfusion
Baseline
Visit
Week 2 
(±1 week)
Week 6 
(±1 week) 
Week 12
(±1 week)
Week 20 
(±1 week)
Week 26 
(+2 weeks) 
or ≥50 EDs c, 
whichever 
occurs last
Preinfusion
Infusion
Postinfusion
Immunology d
X
Blood Type e
X
Hematology f
X
X
X
X
Clinical Chemistry g
X
X
X
X
Immunogenicity h
X
X
X
X
X
X
FVIII Activity i
X
X j
X k
X
X k
X
X
X k
FVIII/VWF Antigen i
X
X j
X
X
X
X
X
X
Coagulation 
Functionl
X
Pharmacokinetic 
Testm
X
X
X
X
ALP=alkaline phosphatase; ALT=alanine aminotransferase; aPTT=activated partial thromboplastin time; AST=aspartate aminotransferase; BU=Bethesda 
unit(s); BUN=blood urea nitrogen; CHO=Chinese hamster ovary; eCRF=electronic case report form; ED=exposure day; FVIII=factor VIII; 
GGT=gamma-glutamyl transferase; HbcAb=hepatitis B core antibody; HbsAb=hepatitis B surface antibody; HbsAg=hepatitis B surface antigen;
HCV=hepatitis C virus; HIV=human immunodeficiency virus; INR= international normalized ratio; IR=incremental recovery; PK=pharmacokinetic(s); 
VWF=von Willebrand factor.
a The screening visit procedures, including laboratory evaluations, are to be completed within 30 days prior to the initial PK assessment procedures (if 
applicable) or baseline visit.
b For subjects participating in the PK portion of the study, the initial PK assessment will be conducted after a washout period of at least 72 to 96 hours 
following their last FVIII therapy (if applicable) and prior to baseline visit. The second PK assessment will be performed following the scheduled 
prophylactic treatment dose. The PK samplings for both initial and second PK assessments should be taken following the time points listed in Table 3. The 
PK blood samples will be measured for FVIII activity (1-stage clotting assay). 
c Exposure day calculation starts from the first PK infusion or baseline visit and completes at study completion/termination visit. 
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Table 2. Clinical Laboratory Assessments
Procedures/
Assessments
Screening 
Visit a
Initial PK 
Assessment b
Study Treatment Visits
Second PK 
Assessment b
Study 
Completion/
Termination 
Visit
Within 
30 days
Preinfusion
Infusion
Postinfusion
Baseline
Visit
Week 2 
(±1 week)
Week 6 
(±1 week) 
Week 12
(±1 week)
Week 20 
(±1 week)
Week 26 
(+2 weeks) 
or ≥50 EDs c, 
whichever 
occurs last
Preinfusion
Infusion
Postinfusion
d Immunology assessments will include HIV-1/HIV-2 antibody, HbsAg, HbsAb, HbcAb, and HCV antibodies. The HCV titer will be confirmed by 
polymerase chain reaction for all subjects reported as HCV-positive. If a subject is HIV-positive, CD4 count is measured to determine the subject’s 
eligibility.
e If historical data on blood group type are available, this may be recorded in the eCRF and blood type does not need to be determined. For subjects who do 
not have documentation of their blood type in their medical record, ABO blood type will be measured locally at screening.
f The hematology panel will consist of complete blood count: hemoglobin, hematocrit, erythrocytes (ie, red blood cell count), leukocytes (ie, white blood cell 
count) with differential (ie, basophils, eosinophils, lymphocytes, monocytes, and neutrophils), and platelet count.
g Clinical chemistry assessments will include sodium, potassium, chloride, bicarbonate, total protein, albumin, ALT, AST, GGT, bilirubin, ALP, urea/BUN, 
creatinine, glucose, cholesterol, very low-density lipoprotein, low-density lipoprotein, high-density lipoprotein, and triglycerides.
h Immunogenicity assessments will include the measurement of inhibitory antibodies to FVIII and binding antibodies to ADYNOVATE. A minimum washout of 
72 to 96 hours is required following the last infusion of any other nonmodified FVIII therapy and 84 to 96 hours following the last infusion of ADYNOVATE. 
Binding antibodies to CHO protein will be included in immunogenicity assessment only at the screening visit, Week 12, and the completion/termination 
visit.
i The blood sample for FVIII activity and FVIII/VWF antigen tests should be collected preinfusion.
j For PK subjects, preinfusion blood draws are performed within 30 minutes prior to infusion, meaning no additional blood draw is needed at the baseline visit 
for these assessments.
k For IR determination: blood samples should be taken within 30 minutes before ADYNOVATE administration and 30±10 minutes post ADYNOVATE infusion. 
The IR determination at the baseline visit will only be performed in subjects who have not undergone PK assessment.
l Coagulation function will be assessed via INR at screening and aPTT, as needed, for surgery.
mThe samples collected for PK assessments following single- and multiple-dose administrations should be taken following the time points listed in Table 3.
Note: At all laboratory assessments, subjects must not be actively bleeding. Assessments should only be performed after a washout period of at least 72 to 
96 hours following the last infusion of any other nonmodified FVIII concentrate and 84 to 96 hours following the last infusion of ADYNOVATE.
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Table 3. Pharmacokinetic Sampling Time Points
Preinfusion
Postinfusion
Within 
30 min
30 min 
(±10 min)
1 hour 
(±30 min)
2 hours 
(±30 min)
4 hours 
(±30 min)
8 hours 
(±1 hour)
12 hours 
(±1 hour)
24 hours 
(±2 hours)
48 hours 
(±4 hours)
72 hours 
(±4 hours)
96 hours
(±4 hours)
Initial PK 
Assessment
X
X
X
X
X
X
X
X
X
X
X
Second PK 
Assessment
Week 20
(±1 week)
X
X
X
X
X
X
X
X
X
X
X a
PK=pharmacokinetic
a Performance of 96-hour sampling is dependent on subject’s prophylaxis dosing schedule (ie, subject must be on a 3- to 4-day dosing regimen with 4 days until the 
next infusion at the time of the second PK assessment).
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2. INTRODUCTION
ADYNOVATE (antihemophilic factor [recombinant] PEGylated, rurioctocog alfa pegol) is an 
extended half-life (T1/2) recombinant human coagulation factor VIII (rFVIII) modified with 
polyethylene glycol (PEG). It was developed by Baxalta (a wholly owned subsidiary of Takeda 
Pharmaceutical Company Limited, referred to as “Takeda” throughout this document) and was 
first approved in the United States (US) on 13 Nov 2015. As of 12 Nov 2021, ADYNOVATE is 
approved to treat hemophilia A (congenital FVIII deficiency) in 28 countries. The indications for 
use of ADYNOVATE may vary in different countries.
The therapeutic activity of ADYNOVATE is derived from its parent drug substance, ADVATE
(antihemophilic factor [recombinant]; international nonproprietary name: octocog alfa), which 
was also developed by Baxalta and was approved in China on 16 May 2012.
This study will evaluate the efficacy and safety of ADYNOVATE for prophylaxis and treatment of 
bleeding episodes in previously treated patients (PTPs) with severe hemophilia A (factor VIII 
[FVIII] <1%) in the Chinese population. The study will also provide ADYNOVATE
pharmacokinetic (PK) data in Chinese patients with severe hemophilia A.
2.1 Indication and Current Treatment Options 
Factor VIII is a critical component of the intrinsic coagulation pathway. Hemophilia A is an 
X-linked recessive, congenital bleeding disorder caused by deficient or defective coagulation 
FVIII leading to bleeding episodes in joints and tissues. The incidence of hemophilia A is 
approximately 1/5000 in males, and based on Chinese survey data, the prevalence of hemophilia 
is 2.73/100,000 (Chinese Medical Association; Hematology Branch Thrombosis and Hemostasis 
Group 2017) The total number of Chinese patients with hemophilia A is 17,779 based on registry 
data collected between 2007 and 2019 by the Hemophilia Treatment Center Collaboration 
Network of China (HTCCNC); of those, 6,519 (49.7%) had severe hemophilia A (Song et al. 
2021).
Factor VIII concentrates (either plasma derived or recombinant) are used in hemophilia A 
patients to provide a hemostatic FVIII level sufficient to treat and prevent bleeding episodes. 
Current management of severe hemophilia A includes on-demand treatment for bleeding 
episodes and prophylaxis to prevent bleeding episodes (National Hemophilia Foundation 2007; 
National Hemophilia Foundation. 2006). The Medical and Scientific Advisory Council of the 
National Hemophilia Foundation considers prophylactic therapy with FVIII to be the optimal 
treatment for hemophilia A patients without inhibitors (National Hemophilia Foundation 2007). 
A number of clinical studies have investigated the effects of prophylactic regimens in patients 
diagnosed with severe hemophilia A (Aledort et al. 1994; Berntorp et al. 2014; Fischer et al. 
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2002; Gouw et al. 2007; Hoots and Nugent 2006; Lee 2007; Löfqvist et al. 1997; Mahlangu et al. 
2014; Manco-Johnson 2007; Manco-Johnson et al. 1994; Morado et al. 2005; Roosendaal and 
Lafeber 2007; Royal et al. 2002). These studies have demonstrated that when begun at a young 
age, prophylaxis reduces the number of bleeding episodes and prevents hemophilic arthropathy 
(Löfqvist et al. 1997), thereby decreasing the rate of disability and resulting in lower long-term 
health care costs for patients (Manco-Johnson et al. 1994; Roosendaal and Lafeber 2007). The 
discontinuation of prophylactic therapy and suboptimal adherence to the prophylactic regimen 
compromise the clinical outcome, leading to further arthropathy (Berntorp 2009; Hoots and 
Nugent 2006). In addition, the early initiation of prophylaxis may have a protective effect against 
inhibitor development, the most serious complication associated with FVIII treatment (Gouw et 
al. 2007; Morado et al. 2005).
The average T1/2 of current FVIII products is in the range of 10 to 14 hours for adults and is 
lower in children (Björkman 2003; Björkman and Berntorp 2001; Björkman et al. 2009; Manco-
Johnson et al. 2007; White et al. 1997). Thus, current prophylactic regimens require infusion of 
FVIII every other day, or every 2 to 3 days when based on each patient’s individual PK profile 
(Valentino et al. 2012). Recombinant FVIII products with an extended T1/2 may prolong the 
efficacy of replacement therapy. Recombinant FVIII concentrates or plasma-derived FVIII 
product are still the first choice for the replacement therapy of hemophilia A.
Non–factor replacement therapy differs from clotting factor replacement therapy in that it 
provides hemostasis through a different mechanism than FVIII/factor IX (FIX) replacement. 
Emicizumab was approved in China in 2018 for patients with hemophilia A who develop 
inhibitors. Emicizumab represents a much-needed alternative approach to managing FVIII 
deficiency, especially for those with inhibitors or limited ability to perform self-infusion (Langer 
et al. 2018). In China, the first rFVIII product was launched after 2000, but no extended half-life 
(EHL) FVIII product is available on the market as of February 2023.
2.2 Product Background and Clinical Information
The investigational product (IP), ADYNOVATE, is composed of full-length rFVIII protein 
identical to the albumin/plasma-free manufactured octocog alfa known as ADVATE. Polyethylene 
glycol chains are covalently bound to the protein using a stable linker. The ADYNOVATE product 
is reconstituted with sterile water for injection (SWFI) and delivered as a solution by bolus 
infusion. The same stabilizing agents (mannitol, trehalose dehydrate, histidine, and glutathione) 
are used as the parent rFVIII product (octocog alfa, ADVATE). ADYNOVATE is intended for use as 
an FVIII replacement therapy with an extended T1/2 in prophylaxis and treatment of bleeding 
events in subjects with severe hemophilia A.
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Nonclinical in vivo studies demonstrated that ADYNOVATE and ADVATE have similar safety and 
efficacy profiles. In vitro safety studies have shown that ADYNOVATE and ADVATE have similar 
effects on cytokine release and complement activation. The functional characterization of 
ADYNOVATE revealed similar characteristics of ADYNOVATE and ADVATE in terms of FIXa 
cofactor activity, time course of thrombin-mediated activation and inactivation, thrombin 
generation assay, activated protein C-mediated inactivation of FVIII and FVIIIa, binding to von 
Willebrand factor (VWF), and synthetic phospholipids. Interaction with the low-density 
lipoprotein receptor–related protein 1 was reduced by PEGylation of rFVIII. Nonclinical study 
results demonstrated that ADYNOVATE has prolonged efficacy and improved PK compared with 
ADVATE and a similar safety profile, including FVIII immunogenicity profile.
The clinical development program for ADYNOVATE follows the European Medicines Agency 
(EMA) guidance outlined in EMA/CHMP/BPWP/144533/2009 and consists of 6 completed 
studies in PTPs and 1 ongoing study in previously untreated patients (PUPs).
A first-in-human prospective, open-label, crossover, dose-escalation study to evaluate safety and 
PK parameters of single doses of ADYNOVATE compared to single doses of ADVATE was 
conducted in 19 adult PTPs with severe hemophilia A (FVIII <1%) (Study 261101). The mean 
T1/2 was 1.4- and 1.5-fold higher for ADYNOVATE compared to ADVATE in Cohorts 1 
(30 international units [IU]/kg) and 2 (60 IU/kg), respectively, demonstrating an extended T1/2
for ADYNOVATE compared to ADVATE. No subjects developed inhibitory antibodies to FVIII or 
binding antibodies to FVIII, PEG-FVIII, or PEG after a single ADYNOVATE infusion. There were 
no notable differences in the type or rate of adverse events (AEs) experienced by subjects after 
single infusions of ADVATE versus ADYNOVATE. Based on these data, ADYNOVATE was shown to 
be safe and well tolerated after single-dose administration.
Based on the results of the Phase 1 study, the pivotal, Phase 2/3, multicenter, nonrandomized 
open-label study (Study 261201) in adult and adolescent male PTPs with severe hemophilia A 
was performed to evaluate efficacy, safety, and PK parameters of ADYNOVATE and to assess 
health-related quality of life (HRQoL) in subjects using a prophylactic dosing regimen or an 
on-demand treatment regimen. The study included 138 evaluable subjects and confirmed the 
results of Study 261101, demonstrating that ADYNOVATE extends the mean T1/2 by 
approximately 1.4-fold and mean residence time (MRT) by approximately 1.5-fold as compared 
to ADVATE. Twice-weekly prophylactic infusions at the intended dose of 45±5 IU/kg 
ADYNOVATE resulted in an annualized bleeding rate (ABR) that was significantly lower than that 
observed with on-demand treatment, with a prophylaxis/on-demand ABR ratio of 0.10. 
Approximately 40% of subjects treated on prophylaxis did not experience any bleeding episodes, 
while all subjects treated on-demand experienced bleeding episodes. ADYNOVATE was 
efficacious in the treatment of bleeding episodes, with 96.1% rated “excellent” or “good” and 
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95.9% treated with 1 or 2 infusions. No FVIII inhibitory antibodies or persistent binding 
antibodies against FVIII, PEG-FVIII, PEG, or Chinese hamster ovary (CHO) proteins were 
reported, and no safety signals were identified. This study demonstrated that ADYNOVATE is safe 
and efficacious in treating bleeding episodes and in prophylaxis administered twice weekly in 
adults and adolescents ≥12 years of age with severe hemophilia A (Konkle et al. 2015).
A study in pediatric PTPs <12 years of age (Study 261202) commenced only after the data of 
20 PTPs ≥12 years of age who had been treated for ≥50 exposure days (EDs) and the PK data of 
at least 12 PTPs ≥12 years of age had become available in pivotal Study 261201, had been 
reviewed by an independent data monitoring committee, and had received a go decision. This 
Phase 3, prospective, uncontrolled, multicenter study was performed to evaluate PK, hemostatic 
efficacy, safety, immunogenicity, and HRQoL of ADYNOVATE and included 66 pediatric subjects 
who received prophylactic treatment. The study showed an extended T1/2 of ADYNOVATE also in 
children (N=31). Depending on the assay (1-stage clotting or chromogenic) and PK model 
(nonlinear mixed effects model or noncompartmental estimation approach) used, T1/2 and MRT 
were 1.3 to 1.5 times longer for ADYNOVATE than for ADVATE. Twice-weekly prophylactic 
infusions at the intended dose of 50±10 IU/kg resulted in a point estimate for the mean ABR of 
3.04 (95% confidence interval [CI]: 2.208; 4.186). Approximately 38% of subjects did not 
experience any bleeding episodes. ADYNOVATE was efficacious in the treatment of bleeding 
episodes: 90.0% had an efficacy rating of “excellent” or “good” and 91.5% were treated with 
1 or 2 infusions. No FVIII inhibitory antibodies or persistent binding antibodies against FVIII, 
PEG-FVIII, PEG, or CHO proteins influencing safety or PK parameters were reported. 
Twice-weekly administration of ADYNOVATE at a dose of 50±10 IU/kg was safe and efficacious 
for prophylaxis and control of bleeding in pediatric subjects <12 years of age with severe 
hemophilia A (Mullins et al. 2017).
A Phase 3, prospective, open-label, single-group, uncontrolled, multicenter study to evaluate the 
efficacy and safety of ADYNOVATE in male PTPs, 2 to 75 years of age, with severe hemophilia A 
who were to undergo major or minor elective or minor emergency surgical, dental, or other 
invasive procedures (Study 261204) included 22 subjects who received at least 1 dose of 
ADYNOVATE. The subjects either completed another ADYNOVATE study or were newly recruited. 
Twenty-six surgical procedures (21 major and 5 minor) were performed in 21 unique subjects. 
Of these, 24 surgeries (21 major and 3 minor) with available scores were rated “excellent” and 
therefore considered a treatment success. For major orthopedic surgeries, the median 
intraoperative blood loss was substantially less than the average volume predicted preoperatively 
by the investigator/surgeon. Actual median postoperative blood loss for major orthopedic 
surgeries was higher than the average volume predicted preoperatively but lower than the 
maximum predicted blood loss for the specific procedures. Median intra- and postoperative 
blood loss for nonorthopedic major surgeries and minor surgeries was similar to the average 
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volume predicted. None of the subjects who received ADYNOVATE for surgery required an 
additional surgical intervention. No FVIII inhibitors were detected in this study. ADYNOVATE
was safe and well tolerated for perioperative management of subjects with severe hemophilia A.
A Phase 3b, prospective, open-label, multicenter continuation study (Study 261302) was 
completed. This study evaluated long-term safety and efficacy of ADYNOVATE for prophylactic 
use and the control of bleeding episodes. The study included 216 pediatric and adult PTPs 
≤75 years of age with severe hemophilia A who received a fixed-dose prophylactic regimen or 
opted to receive a regimen based on the subject’s individual PK, tailored to maintain FVIII 
trough levels of ≥3%. Subjects from other ADYNOVATE studies and ADYNOVATE-naïve subjects 
were included in this study. Efficacy outcomes after long-term exposure demonstrated that 
ADYNOVATE was efficacious for prophylaxis in children, adolescents, and adults when 
administered using a fixed or a PK-tailored dose regimen. Efficacy was demonstrated also for the 
treatment of breakthrough bleeding episodes in these patient populations. No subject developed 
confirmed inhibitory antibodies to ADYNOVATE during the study. Safety outcomes demonstrated 
that ADYNOVATE remained safe and well tolerated during long-term administration for 
prophylaxis and treatment of bleeding episodes in children, adolescents, and adults.
Study 261303 was a Phase 3, prospective, randomized, open-label, multicenter study to compare 
the safety and efficacy of a PK-guided ADYNOVATE treatment regimen targeting 2 different 
FVIII trough levels of 1% to 3% and approximately 10% (8% to 12%) in adolescent and adult 
PTPs with severe hemophilia A (<1% FVIII). A total of 121 subjects received at least 1 infusion 
of ADYNOVATE. Among them, 57 were assigned to the 1% to 3% trough arm and 58 to the 
10% trough arm; 6 were not randomized. The study results showed that targeting a prophylactic 
FVIII trough level of 8% to 12% in patients with severe hemophilia A leads to lower bleeding 
rates than targeting a trough of 1% to 3%. The effect size for the proportion of subjects with an 
ABR of 0 during the second 6-month study period of 0.421 in the 1% to 3% trough arm versus 
0.621 in the 8% to 12% trough arm is large and relevant in a clinical scenario. Achieving a 
prophylactic trough target of 8% to 12% was shown to be as safe as targeting a lower trough of 
1% to 3%. There was only 1 case of a transient low-titer FVIII inhibitor. None of the AEs that 
occurred during or after ADYNOVATE administration led to death or to discontinuation of 
ADYNOVATE or discontinuation of the subject from the study. There were also no severe allergic 
reaction AEs.
There is 1 currently ongoing Phase 3 study (Study 261203) to evaluate safety and 
immunogenicity in PUPs <6 years of age.
Clinical evidence from these studies supported ADYNOVATE’s approval in countries worldwide 
indicated in children and adults with hemophilia A (congenital FVIII deficiency) for on-demand 
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treatment and control of bleeding episodes, perioperative management, and routine prophylaxis 
to reduce the frequency of bleeding episodes.
2.3 Study Rationale
Although the importance of adherence to prophylactic regimens for hemophilia A treatment has 
long been established, the frequency of infusions still poses a challenge to patient compliance. 
Clinical studies showed an association between poor adherence and self-reported bleeding 
episodes among adult hemophilia patients and more days of work/school missed and lower 
physical health status scores among pediatric patients (Hacker et al. 2001; Krishnan et al. 2015). 
This highlights the need for reducing the treatment burden associated with frequent prophylactic 
dosing and the potential for improved outcomes if patients are able to be more compliant with
less frequent dosing regimens.
Clinical studies in pediatric and adult PTPs with severe hemophilia A demonstrated that the T1/2
of ADYNOVATE is 1.3 to 1.5 times longer compared to nonextended T1/2 FVIII products, allowing 
an increase of the prophylactic dosing interval from every other day with conventional FVIII 
products to twice weekly (Konkle et al. 2015; Mullins et al. 2017). The PK results from 
completed clinical studies showed comparable PK parameters across different ethnicities, 
suggesting ethnic insensitivity of ADYNOVATE PK
Multicenter international clinical studies demonstrated that ADYNOVATE is well tolerated, has an 
acceptable safety profile, and is effective in the prevention and treatment of bleeding, including 
surgical hemostasis, in PTPs with severe hemophilia A. Efficacy was demonstrated across age 
groups and ethnicities, indicating that ADYNOVATE is a non–ethnically sensitive extended T1/2
rFVIII, from which children, adults, and adolescents may equally benefit. 
Based on the above, this study is designed to evaluate the efficacy and safety of ADYNOVATE for 
prophylaxis and treatment of bleeding episodes in PTPs with severe hemophilia A (FVIII <1%) 
in the Chinese population. The study will also provide ADYNOVATE PK data in Chinese patients 
with severe hemophilia A.
2.4 Benefit/Risk Assessment
The chemical modification of Takeda’s well-established rFVIII product ADVATE with PEG 
(PEGylation) resulted in an FVIII product, ADYNOVATE, that combines the safety and efficacy 
profile of ADVATE with a 1.3- to 1.5-fold increase in T1/2 for subjects <12 years age and a 1.4- to 
1.5-fold increase in T1/2 for subjects ≥12 years of age, depending on the assay and the PK 
calculation used. A twice-weekly regimen of ADYNOVATE was demonstrated to be efficacious in 
the prophylaxis of bleeding across age groups, and although administered at a longer interval 
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(twice weekly), compared favorably with data obtained with the parent product ADVATE and 
other unmodified FVIII preparations administered every other day or 3 times/week. ADYNOVATE
was also efficacious in the treatment of bleeding episodes in pediatric, adolescent, and adult 
PTPs with severe hemophilia A and in perioperative hemostasis. ADYNOVATE was well tolerated 
with a safety profile comparable to its parent molecule.
Please refer to the latest version of the ADYNOVATE investigator’s brochure (IB) for the overall 
benefit/risk assessment and the most accurate and current information regarding drug 
metabolism, PK, efficacy, and safety of ADYNOVATE.
2.5 Compliance Statement
This study will be conducted in accordance with this protocol, the International Council for 
Harmonisation (ICH) Guideline for Good Clinical Practice (GCP) E6 (ICH GCP, 1996; ICH E6 
R2, 2016), 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 efficacy of ADYNOVATE for prophylactic 
treatment in previously treated Chinese subjects with severe hemophilia A based on the total 
ABR.
3.1.2 Secondary Objectives
The secondary objectives of this study are:
•
To assess the efficacy of ADYNOVATE for prophylactic treatment based on ABR by 
bleeding site and cause
•
To assess the overall hemostatic efficacy rating of ADYNOVATE for treatment of 
nonsurgical breakthrough bleeding episodes during the study period
•
To assess the efficacy of ADYNOVATE for perioperative bleeding management if minor 
surgery is performed during the study period
•
To evaluate the safety of ADYNOVATE as assessed by AEs and serious AEs (SAEs) as well 
as clinically significant findings in vital signs and clinical laboratory parameters
•
To evaluate the safety and the immunogenicity of ADYNOVATE based on the incidence of 
FVIII inhibitory antibodies and binding antibodies to ADYNOVATE
•
To evaluate the PK of ADYNOVATE in Chinese subjects
3.1.3 Exploratory Objective
•
To assess the effect of Adynovate on health-related quality of life and healthcare resource 
utilization
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3.2 Study Endpoints
Table 4. Objectives and Endpoints
Objective
Endpoint(s)
Primary
•
To assess the efficacy of 
ADYNOVATE for prophylactic 
treatment in previously 
treated Chinese subjects with 
severe hemophilia A based 
on the total ABR
•
Total ABR
Secondary
•
To assess the efficacy of 
ADYNOVATE for prophylactic 
treatment based on ABR by 
bleeding site and cause
•
Annualized bleeding rates based on bleeding site and cause
•
Number of infusions and weight-adjusted consumption of 
ADYNOVATE per week and month during the prophylactic treatment 
period
•
Proportion of subjects with zero bleeding episodes during the study
•
Time intervals between bleeding episodes
•
To assess the overall 
hemostatic efficacy rating of 
ADYNOVATE for treatment of 
nonsurgical breakthrough 
bleeding episodes during the 
study period
•
Overall hemostatic efficacy rating at bleed resolution for treatment 
of breakthrough bleeding episodes
•
Number of infusions and weight-adjusted consumption of 
ADYNOVATE per bleeding episode
•
To assess the efficacy of 
ADYNOVATE for 
perioperative bleeding 
management if minor surgery 
is performed during the study 
period
•
Overall assessment of hemostatic efficacy based on the GHEA 
score as assessed by the operating surgeon/investigator
•
Intra- and postoperative actual versus predicted blood loss after the 
surgery, at postoperative day 1, and at discharge as assessed by the 
operating surgeon/investigator
•
Perioperative transfusion requirement of blood, red blood cells, 
platelets, and other blood products
•
Daily intra- and postoperative weight-adjusted consumption dose of 
ADYNOVATE
•
To evaluate the safety of 
ADYNOVATE as assessed by 
AEs and SAEs as well as 
clinically significant findings 
in vital signs and clinical 
laboratory parameters
•
Occurrence of AEs and SAEs, total incidence, by severity, and by 
causality
•
Occurrence of thromboembolic events and hypersensitivity 
reactions
•
Clinically significant changes in vital signs and clinical laboratory 
parameters
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Table 4. Objectives and Endpoints
Objective
Endpoint(s)
•
To evaluate the safety and 
the immunogenicity of 
ADYNOVATE based on the 
incidence of FVIII inhibitory 
antibodies and binding 
antibodies to ADYNOVATE
•
Immunogenicity: 
•
Development of confirmed inhibitory antibodies 
(≥0.6 BU/mL using the Nijmegen modification of the 
Bethesda assay) to FVIII
•
Binding antibodies to ADYNOVATE
•
Binding antibodies to CHO proteins
•
To evaluate the PK of 
ADYNOVATE in Chinese 
subjects
•
Factor VIII activity (1-stage clotting assay) in PK samples collected 
for single-dose and steady-state PK assessments
•
Incremental recovery over time during prophylactic treatment at 
ED1, Week 6 (approximately ED10 to ED15), and ED50
•
Predose FVIII (activity and antigen) and VWF (antigen) at 
scheduled visits
•
Pharmacokinetic parameters including CL, V, AUC, Cmax, Cpredose, 
and elimination phase T1/2, following a single dose and steady-state 
dosing, using NCA methodology, subject to data availability
Exploratory
•
To assess the effect of 
ADYNOVATE on health-
related quality of life and 
healthcare resource 
utilization
•
Health-related quality of life as assessed using the European Quality 
of Life Questionnaire in 5 Dimensions 5-level version (EQ-5D-5L)
•
Healthcare resource utilization endpoints, including number and 
duration of hospitalizations, number of emergency room visits, 
number of acute care visits, and number of days missed from 
school/work
ABR=annualized bleeding rate; AE=adverse event; AUC=area under the concentration versus time curve 
between defined timepoints; BU=Bethesda unit(s); CHO=Chinese hamster ovary; CL=clearance; Cmax=maximum 
concentration; Cpredose=predose concentration; ED=exposure day; FVIII=factor VIII; GHEA=Global Hemostatic 
Efficacy Assessment; NCA=noncompartmental analysis; PK=pharmacokinetic(s); PRO=patient-reported 
outcome; SAE=serious adverse event; T1/2=half-life; V=volume of distribution; VWF=von Willebrand factor
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4. STUDY DESIGN
4.1 Overall Design
This Phase 3, prospective, multicenter, open-label study will evaluate the efficacy and safety of 
ADYNOVATE for prophylaxis and treatment of bleeding episodes in PTPs with severe hemophilia 
A (FVIII <1%) in the Chinese population. The study will also provide ADYNOVATE PK data in 
Chinese patients with severe hemophilia A. The overall study flow chart is illustrated in
Figure 1.
It is planned to enroll at least 30 evaluable Chinese subjects aged 12 to 65 years. All subjects 
and/or legal representatives are required to provide signed informed consent. For screening, 
subjects need to undergo a minimum washout period of at least 72 to 96 hours following their 
last FVIII therapy (on-demand or prophylactic), if applicable. Thereafter, the study screening 
procedures (Table 1) will be performed for eligibility determination and will be completed 
within 30 days prior to the initial PK assessment (if applicable) or baseline visit. Screening 
procedures will include demographics, medical/medication history, concomitant medications, 
AEs, physical examination, vital signs, and clinical laboratory assessments (Table 2). Medical 
history (including immunization history) will include surgery history, hemophilia history, 
bleeding episode history, and history of FVIII usage over the last year. Target joints and 
subject’s ABR based on the previous 9 to 12 months will also be recorded. Medication history 
will include the name of the product, dose, dosing interval, and regimen start and end date.
All enrolled subjects will receive twice-weekly prophylactic treatment with ADYNOVATE
(45±5 IU/kg) over a period of 26 weeks (+2 weeks) or at least 50 EDs, whichever occurs last.
Pharmacokinetic evaluation is planned to be performed in at least 12 evaluable subjects. For 
subjects participating in the PK portion of the study, the initial PK assessment will be performed 
after a washout period of at least 72 to 96 hours following their last FVIII therapy (if applicable) 
and prior to the baseline visit. The second PK assessment will be performed during the Week 20 
(±1 week) visit following the scheduled prophylactic treatment dose. The PK samples will be 
collected at specified time points and measured for FVIII activity by a 1-stage clotting assay. For 
subjects not participating in the PK portion, the baseline visit will be initiated immediately upon 
eligibility confirmation.
Following the baseline visit, subjects will return to the study site for study treatment visits at the 
below timepoints for the efficacy and safety assessments:

Week 2 (±1 week)

Week 6 (±1 week)
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
Week 12 (±1 week)

Week 20 (±1 week) (only for subjects undergoing PK assessment)

Study Completion/Termination Visit: Week 26 (+2 weeks) or at least 50 EDs (whichever 
occurs last)
All other study treatments may be administered either at a clinic/hospital/study site or at home by 
self-administration/administration by a parent/caregiver. The investigator will determine the 
setting of treatment administration. Unscheduled visits may occur between scheduled site visits 
as required. Assessments may be performed as clinically indicated at the discretion of the 
investigator.
Factor VIII (activity and antigen) and VWF antigen levels will be measured at specified study 
visits, preinfusion, in both PK and non-PK subjects. During the baseline visit, Week 6 visit, and 
the study completion/termination visit, peak levels of FVIII activity will also be assessed within
30 minutes before ADYNOVATE administration and 30±10 minutes post ADYNOVATE infusion for 
the determination of incremental recovery (IR). The IR determination at the baseline visit will 
only be performed in subjects who have not undergone initial PK assessment. All PK samples 
collected in this part will be used, along with the samples collected in the PK assessments, to 
characterize PK properties in PTPs across age groups.
At each study visit, investigators will review subject electronic diaries (eDiaries) for prophylactic 
treatment compliance, bleeding episodes and treatment, AEs, concomitant medications, and 
nondrug therapies. The PRO assessment, using the EQ-5D-5L, will be captured via an electronic 
PRO (ePRO) device. Subjects should complete the EQ-5D-5L prior to baseline visit (or initial 
PK assessment for subjects participating in the PK portion of the study) and study 
completion/termination visit. Healthcare resource utilization will be gathered by sites via 
questionnaire as part of the electronic case report form (eCRF). Upon completion of prophylactic 
treatment (at least 50 EDs or 26 weeks [+2 weeks], whichever occurs last), the study site will 
follow up via phone call with each subject after 3 to 5 days to determine the occurrence of AEs.
During the study period, subjects will also be treated for breakthrough bleeding episodes with 
ADYNOVATE. The dose and frequency of ADYNOVATE administration will be individualized 
based on the subject’s weight, type and severity of bleeding episode, and monitoring of
appropriate clinical and laboratory measures per the investigator’s judgment (as described in 
Section 6.2.2.3).
If a subject requires minor elective or emergency surgical, dental, or other invasive procedures 
during the study after enrollment (ie, a surgery that was not planned before study enrollment), 
perioperative bleeding will be managed with ADYNOVATE. The dose and frequency of 
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ADYNOVATE administration will be individualized based on the subject’s IR to obtain the FVIII 
target level required for the procedure being performed (as described in Section 6.2.2.4). Major 
surgeries are not in the scope of this study; any required major surgery will result in the 
withdrawal of the subject.
The primary objective of this study is to assess the efficacy of ADYNOVATE for prophylactic 
treatment in previously treated Chinese subjects with severe hemophilia A based on the total 
ABR.
4.2 Scientific Rationale for Study Design
The design of this study is based on a previously completed multinational confirmatory study 
(Study 261201). The study design, including endpoints, study population, and 
inclusion/exclusion criteria, are all supported by the results of previous global studies in this 
program (refer to Section 2.2).
4.3 Justification for Dose
Pharmacokinetic results from global studies with ADYNOVATE showed similar results between 
the Chinese/Asian subjects and the overall study populations, suggesting ethnic insensitivity of
ADYNOVATE PK. Further, efficacy was demonstrated across age groups and ethnicities, 
indicating that ADYNOVATE is a non–ethnically sensitive EHL rFVIII from which Chinese adult 
and adolescent subjects may benefit. Thus, the doses and regimen of the current study are 
considered to be appropriate.
4.4 Duration of Subject Participation and Study Completion Definition
All enrolled subjects will receive twice-weekly prophylactic treatment with ADYNOVATE over a 
period of 26 weeks (+2 weeks) or at least 50 EDs, whichever occurs last. Each subject’s 
maximum duration of participation is expected to be approximately 8 months unless prematurely 
discontinued.
Study completion is defined as the date on which the last subject in the study completes the final 
protocol-defined assessments and includes the safety follow-up conducted via phone 3 to 5 days 
following prophylactic treatment completion (refer to Section 8.1.4 for the defined follow-up 
period for this protocol). The total study duration will be approximately 3 years.
4.5 Sites and Regions
The study will be conducted at approximately 12 sites in China.
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4.6 Study Stopping Rules
The study will be halted (enrollment and treatment temporarily suspended), or stopped 
(enrollment and treatment permanently discontinued), pending further review by sponsor, if one 
or more of the following criteria are met:
1. If 2 or more subjects develop a high responder inhibitory antibody (>5 BU), confirmed 
by 2 separate measurements within 2 weeks at the central laboratory, after ADYNOVATE
administration
2. If 2 or more subjects develop anaphylaxis caused by the exposure to ADYNOVATE
The study may be terminated if one or more of the following criteria are met:
1. The sponsor decides to terminate the study based upon its assessment of safety
2. The sponsor decides to terminate the study for administrative reasons
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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. Subject and/or legally authorized representative must voluntarily sign a written informed 
consent form (ICF) after all relevant aspects of the study have been explained and 
discussed with the subject. For the subjects <18 years old, subjects will give assent AND 
their parents/legally authorized representative should sign the ICF accordingly.
2. Subject and/or legally authorized representative understands and is willing and able to 
comply with all requirements of the study protocol.
3. Subject should be ethnic Chinese.
4. Subject is 12 to 65 years of age at screening and male.
5. Subject has severe hemophilia A (FVIII clotting activity <1%) as confirmed by the 
central laboratory at screening after a washout period of at least 72 to 96 hours.
6. The last on-demand or prophylactic treatment received is within 3 months before 
screening.
7. Subject has documented previous treatment with plasma-derived FVIII concentrates or 
recombinant FVIII for >150 EDs.
8. Subject is human immunodeficiency virus (HIV)-negative, or HIV-positive with stable 
disease and CD4+ count ≥200 cells/mm3.
9. Subject is hepatitis C virus (HCV) negative by antibody testing (if positive, additional 
polymerase chain reaction testing will be performed to confirm), as confirmed at 
screening; or HCV-positive with chronic stable hepatitis, as assessed by the investigator.
5.2 Exclusion Criteria
The subject will be excluded from the study if any of the following exclusion criteria are met:
1. Subject has detectable FVIII inhibitory antibodies (≥0.6 Bethesda units (BU)/mL using 
the Nijmegen modification of the Bethesda assay) as confirmed by the central laboratory 
at screening. 
2. Subject has a confirmed history of FVIII inhibitory antibodies (≥0.6 BU using the 
Nijmegen modification of the Bethesda assay or ≥0.6 BU using the Bethesda assay) at 
any time prior to screening. 
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3. Subject has a known hypersensitivity to ADYNOVATE or ADVATE or any of the 
components of the study drugs, such as mouse or hamster proteins, or other FVIII 
products.
4. Subject has been diagnosed with an inherited or acquired hemostatic defect other than 
hemophilia A (eg, qualitative platelet defect or von Willebrand’s disease). 
5. Subject has severe hepatic dysfunction (eg, ≥5 times the upper limit of normal [ULN] for 
alanine aminotransferase (ALT) or aspartate aminotransferase (AST), a recent or 
persistent international normalized ratio [INR] >1.5, as confirmed by the local laboratory 
at screening). 
6. Subject has severe renal impairment (serum creatinine >1.5 times the ULN) as confirmed 
by the local laboratory at screening. 
7. Subject is planned or likely to undergo major surgery during the study period.
8. Subject has current or recent (<30 days) use of other PEGylated drugs before study 
participation or scheduled use of such drugs during study participation. 
9. Subject has received emicizumab therapy within 6 months of screening. 
10. Subject is currently receiving, or scheduled to receive during the study, an 
immunomodulating drug (eg, systemic corticosteroid agent at a dose equivalent to 
hydrocortisone >10 mg/day, or α-interferon) other than antiretroviral chemotherapy.
11. Subject has participated in another clinical study involving the use of an IP other than 
ADYNOVATE or an investigational device within 30 days before the screening visit or is 
scheduled to participate in another clinical study involving an IP or investigational device 
during this study. 
12. Subject has a medical, psychiatric, or cognitive illness or recreational drug/alcohol use 
that, in the opinion of the investigator, would affect subject safety or compliance.
13. Subject, in the opinion of the investigator, is unable or unwilling to comply with the 
study protocol.
5.3 Restrictions 
Not applicable.
5.4 Reproductive Potential
Males, including males who are surgically sterile (vasectomy), with female partners of 
childbearing potential must agree to be abstinent or use a medically acceptable form of 
contraception from screening through at least 30 days or 5 elimination half-lives after the last 
dose of IP.
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6. STUDY INTERVENTION
6.1 Investigational Product
6.1.1 Identity of Investigational Product
The IP, ADYNOVATE (antihemophilic factor [recombinant] PEGylated, rurioctocog alfa pegol), is 
formulated as a sterile, highly purified protein preparation in lyophilized form for intravenous 
infusion and is provided in single-use vials, which may contain nominally 250, 500, 1000, 2000, 
and 3000 IU PEGylated rFVIII/vials, along with a vial of diluent (2 or 5 mL SWFI). It is filled in 
a colorless neutral Type I (US Pharmacopeia, European Pharmacopoeia) glass vial, sealed with a 
chlorobutyl rubber stopper with inert coating. Additional information is provided in the 
ADYNOVATE IB.
6.1.2 Blinding the Treatment Assignment
Not applicable; this is an open-label clinical study. There is no randomized allocation to study 
treatment; all subjects will receive the same prophylaxis dosing schedule of ADYNOVATE. 
6.2 Administration of Investigational Product
Following reconstitution, ADYNOVATE should be administered using plastic syringes provided by 
the sponsor since proteins such as ADYNOVATE may adhere to the surface of glass syringes. 
ADYNOVATE is injected intravenously using an appropriately sized syringe as a bolus infusion 
over a period of less than or equal to 5 minutes (maximum infusion rate, 10 mL/min). The 
reconstituted ADYNOVATE must be administered at room temperature and as soon as possible, 
but no later than 3 hours after the reconstitution.
ADYNOVATE dose calculation will be based on the stated actual potency on vials in respective 
lots.
For an individual subject, study product from only 1 lot/infusion and only vials with a nominal 
potency of 500 IU may normally be used for the PK portions of the study and the determination
of IRs. However, if due to a subject’s weight, the PK or IR infusion volume will exceed 30 mL, 
1000 IU vials should preferably be used to reduce the volume administered.
In case of infusions for PK or IR determination, the exact amount of IUs has to be administered 
(eg, 1.5 vials) and should not be rounded up or down to the nearest whole vial. In case of 
prophylactic infusions or infusions to control bleeding episodes or manage perioperative 
bleeding, the dose can be rounded up or down to the nearest whole vial (eg, 2 vials).
Subjects will return to the study sites to receive study treatment at the scheduled visits. All other 
study treatments may be administered either at a clinic/hospital/study site or at home by 
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self-administration/administration by a parent/caregiver. The investigator will determine the 
setting of treatment administration. If the subject/caregiver will self-administer ADYNOVATE, the 
investigator should ensure that the subject and/or subject’s caregiver has been adequately trained. 
Investigational product can be shipped directly from the site or local depot to the subject’s home.
For complete details on preparation, reconstitution, and administration of ADYNOVATE, please 
refer to the ADYNOVATE pharmacy manual.
6.2.1 Allocation of Subjects to Treatment 
This is an open-label clinical study. There is no randomized allocation to study treatment; all 
subjects will receive the same prophylaxis dosing schedule of ADYNOVATE.
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. 
Once a unique identifier has been assigned, that number must not be used again if, for example, a 
subject is withdrawn from the study. If a unique identifier is allocated incorrectly, the clinical 
research associate/study monitor must be notified as soon as the error is discovered. 
Investigational product packaging identification numbers will be assigned to subjects. The same 
IP packing identification number will only be assigned once.
6.2.2 Dosing
6.2.2.1 Dosing for PK Characterization
The dose to be used for PK determination is 45±5 IU/kg as a single-dose infusion for the initial 
PK assessment before the subject receives the first prophylactic dose. The second PK assessment 
will be performed during the Week 20 (±1 week) visit following the scheduled prophylactic 
treatment dose. The dose for IR assessments is the same as that for prophylactic treatment at the 
scheduled visits. Upon completion of the infusion, the butterfly catheter should be flushed with 
at least 2 mL of saline solution.
For subjects who have a bleeding episode requiring treatment with FVIII concentrates, if the 
bleed occurs after the start of the PK period, only ADYNOVATE should be used to treat the 
bleeding episode.
If a bleed occurs <7 hours after the start of the PK period and requires treatment with 
ADYNOVATE, the subject will undergo an 84- to 96-hour washout, followed by reinfusion of 
ADYNOVATE, and all PK time points will be repeated. If a bleed occurs ≥7 hours from the start of 
the PK period, then no further PK samples will be taken in that specific PK assessment period 
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and the PK assessment does not have to be repeated. Subjects will resume participation in the PK 
subgroup once they recover, per the study protocol, and are eligible to proceed to the following 
PK period as part of the PK subgroup.
See Section 8.2.6 for additional details about PK assessments.
6.2.2.2 Prophylactic Treatment
For prophylactic treatment, subjects will be treated with 45±5 IU/kg of ADYNOVATE
administered twice weekly. Subjects will be treated with prophylactic infusions for a minimum 
of 50 EDs to ADYNOVATE or approximately 26 weeks (+2 weeks), whichever occurs last.
Subjects must adhere as closely as possible to the dosing regimen. The days of the week on 
which treatment is administered may be selected by the subject and/or subject’s physician and 
should be selected to provide maximum coverage for vigorous activities. Dosing must be 
administered twice weekly (see Table 5), at 3- and 4-day intervals (Option X) or at 3.5-day 
intervals (Option Y with AM and PM dosing), and should be maintained during the study. If a 
dose is missed, it must be documented and the next dose will be taken as soon as possible. After 
this dose, the regularly scheduled regimen will be resumed. For example, in Option X, if 
twice-weekly dosing is scheduled for every Monday and Thursday and the subject misses the 
Thursday dose, they should infuse the next dose on Friday and then resume their schedule with 
subsequent dose on Monday. For Option Y, if dosing is scheduled for the morning on Monday 
and the evening dose on Thursday and the subject misses the Thursday dose, they should infuse 
the next dose on Friday morning and then resume their schedule with a subsequent dose on 
Monday morning.
Table 5. ADYNOVATE Example Dosing Frequency
Day
Mon
Tues
Wed
Thurs
Fri
Sat
Sun
Morning
X or Y
X
Evening
Y
Subjects requiring treatment for a breakthrough bleeding episode should resume prophylaxis as 
soon as the bleeding episode is resolved. They should return to the same schedule of dosing as if 
prophylactic dosing were not interrupted. For example, if the subject is typically dosed every 
Monday and Thursday and is treated for a bleeding episode on Wednesday and the bleeding 
episode is resolved on Thursday, they would resume prophylaxis on Thursday; if the bleeding 
episode is not resolved until Friday, their next prophylactic dose would be on Monday (ie, 
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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In order to ensure the required washout periods of 84 to 96 hours prior to study visits, the 
scheduled regimen may be interrupted for this period but should be resumed once the study visit 
is completed.
Dose Adjustment for Prophylactic Treatment
Based on the investigator’s clinical evaluation, the dose may be increased gradually by 10 IU/kg 
increments up to a maximum of 80 IU/kg but not exceeding plasmatic FVIII peak levels of 200% 
for subjects receiving prophylactic treatment at any time to ensure patient safety is adequately 
managed.
Subjects meeting any of the following criteria during prophylaxis may have their ADYNOVATE
dose increased up to a maximum of 80 IU/kg:
•
Two or more spontaneous (not related to trauma) bleeding episodes in the same target 
joint within any 2-month period, or
•
One or more spontaneous (not related to trauma) bleeding episodes in a nontarget joint 
within any 2-month period, or
•
Factor VIII trough level <1% and the investigator assesses the study subject is at increased 
risk of bleeding
A target joint is defined as a single joint (ankles, knees, hips, or elbows) with ≥3 spontaneous 
bleeding episodes in any consecutive 6-month period.
In order not to exceed plasmatic FVIII peak levels of 200%, the increase in frequency may be 
considered. Prior approval of the sponsor should be obtained.
In subjects with severe hemophilic arthropathy and/or target joints who continue to 
experience recurrent bleeding episodes despite adjustments to the prophylactic dose and/or 
dosing frequency, an ultrasound of the affected joint(s) should be performed to verify the 
presence of a bleed.
6.2.2.3 On-demand Treatment of Bleeding Episodes
ADYNOVATE will be used for the treatment of bleeding episodes (ie, breakthrough bleeding 
episodes during prophylaxis) according to the guidelines outlined in Table 6. These guidelines 
may be adjusted by the investigator based upon his or her clinical judgment. If a breakthrough 
bleed occurs, the subject will be advised to contact the investigator to discuss dose and bleed 
severity. 
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The dose must be individualized based on the subject’s weight, type and severity of bleeding 
episode, and monitoring of appropriate clinical and laboratory measures. The subject or their 
caregiver will rate the severity (mild, moderate, or severe) of the bleeding episode and will rate 
the overall treatment response at 24 hours (±2 hours) after initiating treatment. A 4-point efficacy 
rating scale (Table 7) will be used to assess the efficacy of ADYNOVATE treatment. Efficacy will 
be defined as a response of “good” or “excellent”. An inadequate response to ADYNOVATE
treatment is defined as a rating of “fair” or “none” 24 hours (±2 hours) after initiation of 
ADYNOVATE infusion. Since the efficacy rating is based to a large degree on cessation of pain, 
the investigator/subject shall, particularly in the case of injury-related bleeding into 1 or more 
than 1 location, take the injury-related symptoms into consideration when performing the 
efficacy rating at resolution of the bleed.
As per Table 6, multiple infusions of ADYNOVATE may be administered for the treatment of a 
bleeding episode. The overall response to all infusions combined is the rating that will be 
recorded.
It is critical that treatment of a bleed is initiated as soon as possible after occurrence of the 
bleeding episode.
When bleeding is controlled, additional infusions of ADYNOVATE to maintain hemostasis are 
permitted, if required. Infusions given to maintain hemostasis should be documented in the 
eDiary and eCRF.
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Table 6. ADYNOVATE Treatment Guidelines for Bleeding Episodes
Severity and Type of Bleeding Episode
Factor VIII 
Level Required 
(%)
Suggested Dose
Frequency of Dosing
Minor
Early hemarthrosis, mild muscle bleeding, 
or mild oral bleeding, including epistaxis
20% to 40%
10 to 20±5 IU/kg
Repeat infusions every 12 to 24 hours.
Duration: at least 1 day, until the bleeding 
episode is resolved or healing is achieved.
Moderate
Moderate bleeding into muscles, bleeding 
into the oral cavity, definite/more extensive 
hemarthroses, and known trauma
30% to 60%
15 to 30±5 IU/kg
Repeat infusions every 12 to 24 hours for 
3 days or more until the pain and acute 
disability/incapacity are resolved.
Major/life-threatening
Significant gastrointestinal bleeding, 
intracranial, intra-abdominal or intrathoracic 
bleeding, central nervous system bleeding, 
bleeding in the retropharyngeal or 
retroperitoneal spaces or iliopsoas sheath, 
fractures, head trauma
60% to 100%
30 to 60±5 IU/kg
In case of life-threatening bleeds, a dose of 
80±5 IU/kg may be considered.
Repeat infusions every 8 to 12 hours until 
the bleeding episode/threat is resolved.
The required units will be calculated according to the following formula:
body weight (kg) × desired FVIII rise (% or IU/dL) × {reciprocal of observed recovery}
Whenever possible, the subject’s most recent individual IR should be used. In its absence, an 
average recovery of 2 [IU/dL]/[IU/kg] for FVIII products should be used, and the required units 
are calculated using the following formula:
body weight (kg) × desired FVIII rise (% or IU/dL) × 0.5 dL/kg
The amount to be administered and the frequency of administration should always be oriented to 
the clinical effectiveness in the individual case.
6.2.2.4 Perioperative Bleeding Management
Subjects with known plans or who are likely to undergo surgery during the study period are not 
eligible and will be excluded from study. However, eligible subjects who are later identified to 
require surgery during the study have the option to undergo minor elective or emergency 
surgical, dental, or other invasive procedures. Major elective or emergency surgeries are not in 
the scope of this study; any required major surgery will result in withdrawal of the subject. 
Subjects may undergo more than 1 surgery or 2 parallel surgeries; however, in these cases, prior 
approval by the sponsor is required.
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Surgical procedures will be defined prospectively as major or minor by the investigator/surgeon 
and agreed with the sponsor, based on the protocol guidance and definitions and in consideration 
of each subject’s characteristics. The main characteristics of minor and major surgeries are as 
follows:
•
Minor surgeries comprise surgeries that can be safely and comfortably performed on a 
patient who has received local or topical anesthesia, without more than minimal 
preoperative medication or minimal intraoperative sedation. The likelihood of 
complications requiring hospitalization or prolonged hospitalization is remote. In addition, 
minor surgeries/interventions are expected to require clinical surveillance or hospital 
treatment ≤3 days after the surgery/intervention.
•
Major surgeries involve surgeries that require moderate or deep sedation, general 
anesthesia, or major conduction blockade for patient comfort and comprise major 
orthopedic (eg, joint replacement), major abdominal, intracranial, cardiovascular, spinal, 
and any other surgery that has a significant risk of large volume blood loss or blood loss 
into a confined anatomical space. Extractions of several teeth or extraction of the third 
molar and adeno-tonsillectomy in children are also generally considered as major. In 
addition, major surgeries/interventions are expected to require clinical surveillance or 
hospital treatment >3 days after the surgery/intervention.
If the subject requires minor elective surgery, an FVIII substitution plan will be drawn up by the 
investigator outlining the target peak and trough levels covering the minor surgical, dental, or 
other invasive procedure until expected wound healing. The FVIII substitution plan will be 
provided to the sponsor to ensure that the recommendations regarding FVIII target levels as 
outlined in the protocol are followed. The dose and frequency adjustments during intra- and 
postoperative dosing should follow the substitution plan provided by the investigator prior to 
minor surgery. Slight deviations from the predefined substitution plan are allowed based on the 
investigator’s clinical judgment and available laboratory FVIII data (must be based on regular 
FVIII activity measurements determined pre and post infusion of ADYNOVATE). Dosing should 
be guided by the dosing recommendations and continued until hemostasis.
If the subject requires major surgery, the subject will be withdrawn from the study. All EDs to 
ADYNOVATE accumulated as part of the minor surgery study will be factored into the overall 
number of EDs.
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6.2.2.4.1 Preoperative Loading Dose for Minor Surgeries
The below procedures are required for minor elective surgery and are recommended for 
emergency minor surgery.
Prior to surgery
The following items must be completed prior to surgery and available, at the latest, 2 hours 
before surgery start:
•
An accurate prediction of volume of expected blood loss intraoperatively (from 
completion of the procedure until approximately 24 hours post surgery) and for the overall 
perioperative time period (up to discharge/end of study)
•
An outline of the expected FVIII substitution plan with target peak and trough levels 
provided to the sponsor
Loading Dose and Post-infusion Laboratory Assessment
Within 60 minutes before initiating surgery, subjects will receive a loading dose of ADYNOVATE
to raise the preinfusion plasma level of FVIII. In general, for minor surgery, initial FVIII target 
levels in plasma should be 30% to 60% of the normal FVIII level.
The dose and frequency of ADYNOVATE administered will be individualized based on the 
subject’s IR to obtain the target level required for the minor surgical, dental, or other invasive 
procedure being performed. Surgeries will be performed based on FVIII activity levels 
determined at the local laboratory. An additional blood sample needs to be drawn for testing at 
the central laboratory to confirm local laboratory results. Activated partial thromboplastin time 
(aPTT) will be tested at the local laboratory.
The formula for calculating the required number of units is as follows:
Required units (IU) =
body weight (kg) × desired FVIII rise (% or IU/dL) × {reciprocal of IR} (IU/kg)/(IU/dL)
Subjects will undergo the following procedures:
Prior to initial ADYNOVATE loading dose:
•
Record AEs, concomitant medications and nondrug therapy usage
•
Physical examination, vital signs (pulse, respiratory rate, blood pressure, and body 
temperature), and weight
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•
Laboratory assessments, including:
-
Hematology (without differential but including platelets)
-
Clinical chemistry
-
Within 30 minutes before loading dose, blood draw for: FVIII activity and aPTT
Immediately followed by:
Loading dose of ADYNOVATE to raise the plasma level of FVIII to 30% to 60% for minor 
surgical, dental, or other invasive procedures. It will be administered within 60 minutes prior to 
surgery (prior to incision/intubation).
After infusion:
•
Laboratory assessment of FVIII activity and aPTT: 15±5 minutes after infusion of the 
loading dose
•
Vital signs (pulse, respiratory rate, blood pressure, and body temperature) will be recorded 
15±5 minutes after infusion
•
If aPTT is not normalized or desired FVIII level not obtained, rebolus of ADYNOVATE as 
necessary.
If the determination of the FVIII level is not feasible within a reasonable time period prior to the 
start of surgery, at least the postinfusion value of aPTT must be obtained. The FVIII level must 
be obtained within 4 hours after infusion of ADYNOVATE, and dose adjustments must be
performed as needed.
The surgery can begin only if aPTT has normalized.
Intraoperative Procedures
During the surgical procedure:
•
Record AEs, concomitant medications, and non-drug therapy usage
•
Record blood product usage, including salvaged blood, packed red blood cells (pRBCs), 
platelets, and other blood products.
•
Administer additional ADYNOVATE infusions according to the FVIII substitution plan
•
Record intraoperative blood loss and transfusion requirements
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If the subject has excessive or unexplained bleeding, perform blood draws for:
•
Factor VIII activity
•
Factor VIII inhibitory and binding antibodies
Treat by whatever means necessary until adequate hemostasis is achieved. If other FVIII 
concentrates become necessary, the subject will subsequently be withdrawn from this study.
After the surgical procedure:
•
Record the volume of blood loss during surgery and total blood product usage, including 
salvaged blood, pRBCs, platelets, and other blood products
•
Assess intraoperative hemostatic efficacy (Table 8) at the end of surgery
6.2.2.4.2 Postoperative Dose for Minor Surgeries
Subjects undergoing minor surgery can be re-dosed postoperatively with ADYNOVATE every 8 to 
24 hours. Preinfusion trough levels of FVIII should be kept at 30% to 60% of normal for the first 
24 hours, or longer as deemed necessary by the investigator. At least 1 postoperative dose should 
be given; the dose calculation should be based on the subject’s most recent IR value.
In case subjects are hospitalized for more than 24 hours, subjects will have a preinfusion and 
15-minute postinfusion FVIII level measurement assessed at a local laboratory at least once per 
day (preferably at the same time of the day), and the dose will be adjusted according to the most 
recent residual FVIII levels. The target FVIII levels should not exceed 180%. It is recommended 
to increase the frequency of dosing instead.
Once the subject is discharged from the hospital, the subject should resume prophylaxis 
treatment. They should return to the same schedule of dosing as if prophylactic dosing were not 
interrupted.
6.2.3 Unblinding the Treatment Assignment
Not applicable.
6.3 Labeling, Packaging, Storage, and Handling of Investigational Product
6.3.1 Labeling
Labels containing study information and pack identification are applied to the IP container. 
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All IP is labeled with a minimum of the following: protocol number, dosage form (including 
product name and quantity in pack), directions for use, storage conditions, expiry date, batch 
number and/or packaging reference, and the statement “For clinical trial use only.”
Space is allocated on the label so that the site representative can record a unique subject 
identifier.
Additional labels (eg, those used when dispensing marketed product) may, on a case-by-case 
basis, be applied to the IP in order to satisfy local or institutional requirements, but must not:
•
Contradict the clinical study label
•
Obscure the clinical study label
•
Identify the study subject by name
Additional labels may not be added without the sponsor’s prior full agreement.
6.3.2 Packaging
ADYNOVATE is supplied in packages comprising a single-use vial. Actual FVIII activity in IU is 
stated on the label of each ADYNOVATE carton and vial.
Changes to sponsor-supplied packaging prior to dosing may not occur without full agreement in 
advance by the sponsor.
6.3.3 Storage
The recommended storage condition for ADYNOVATE is +2°C to +8°C (see expiry date on the 
vial label). ADYNOVATE should be protected from light. The reconstituted product should ideally 
be used immediately but no longer than 3 hours after reconstitution. 
The investigator has overall responsibility for ensuring that IP 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 product must be stored in accordance with labeled storage conditions. 
Temperature monitoring is required at the storage location to ensure that the IP is maintained 
within an established temperature range. 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 
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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 IP 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 IP 
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 IP to carry out this protocol for the 
agreed number of subjects. The investigator or designee will acknowledge receipt of the IP, 
documenting shipment content and condition. Accurate records of all IP received, dispensed, 
used, returned, and/or destroyed must be maintained as detailed further in this section.
The investigator has overall responsibility for administering/dispensing IP. 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 site may use an alternative method for dispensing. If permitted by country or local 
regulations and ethics committees (ECs), the IP can be shipped from the site or the depot directly 
to the subject’s home address via courier. Subjects must be provided with instructions on how to 
receive, store, and ultimately return investigational/sponsor-supplied materials.
The investigator or his/her designee (as documented by the investigator in the applicable study 
delegation of authority form) will administer the IP only to subjects included in this study 
following the procedures set out in the study protocol. All administered medication will be 
documented in the subject’s source and/or other IP record. The investigator is responsible for 
ensuring the retrieval of all study supplies from subjects.
No IP 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.
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At the end of the study, or as instructed by the sponsor, all unused stock and empty/used IP 
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 contract research organization [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. Returned IP must be packed in a tamper-evident manner to ensure product integrity. 
Contact the sponsor for authorization to return any IP prior to shipment. Shipment of all returned 
IP must comply with local, state, and national laws.
Based on entries in the site drug accountability forms, it must be possible to reconcile IP 
delivered with those used and returned. All IP must be accounted for and all discrepancies 
investigated and documented to the sponsor’s satisfaction.
6.5 Subject Compliance
Subjects must be instructed how to have unused IP and empty/used IP packaging assessed for 
drug accountability. Drug accountability must be assessed at the container/packaging level for 
unused IP 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.
6.6 Concomitant, Permitted, and Prohibited Therapy
6.6.1 Concomitant Treatment 
Concomitant treatment refers to all treatments taken from the time informed consent is signed 
until end of the safety follow-up period. Concomitant treatment information will be recorded on 
the eCRF and in the subject’s eDiary.
6.6.2 Permitted Treatment
During the screening period (ie, between subject enrollment [signing of the ICF] up to the first 
prophylactic dose or the initial PK assessment), subjects will continue receiving their usual FVIII 
concentrate for prophylaxis and/or treatment of bleeding events. 
The following medications and nondrug therapies are permitted before study entry and during 
the course of the study:
Medications:
•
Hemostatic agents, such as tranexamic acid, as indicated by the subject’s treating 
physician, to treat mucosal bleeding during the study
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•
Any medications deemed necessary by the subject’s physician to treat or prevent any 
medical condition (with the exception of any PEGylated medication, any 
immunomodulating drug other than antiretroviral chemotherapy, any investigational drug 
or device, and any FVIII concentrate other than ADYNOVATE)
•
Any over-the-counter medication used by the subject to treat symptoms or signs of any 
medical condition
•
Supplemental vitamins and/or minerals
Nondrug therapies:
•
Any nondrug therapy (eg, physiotherapy) deemed necessary by the subject’s physician to 
treat or prevent any medical condition.
6.6.3 Prohibited Treatment
The following medications are not permitted within 30 days before study entry and during the 
course of the study:
•
Any PEGylated medication (eg, PEG-interferon)
•
Any immunomodulating drug (eg, corticosteroid agents at a dose equivalent to 
hydrocortisone >10 mg/day, or α-interferon) other than antiretroviral chemotherapy
•
Any investigational drug or device
•
Any FVIII concentrate other than ADYNOVATE following the first infusion of ADYNOVATE
A subject who has taken any of these medications will be withdrawn from further study 
participation.
Treatments not listed above that may influence study efficacy and safety results should be 
discussed with the sponsor.
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7. DISCONTINUATION OF STUDY INTERVENTION AND SUBJECT 
DISCONTINUATION/WITHDRAWAL
7.1 Discontinuation of Study Treatment
A subject is considered to have completed the study when they cease active participation because 
the subject has, or is presumed to have, completed all study procedures according to the protocol 
(with or without protocol deviations).
Every effort will be made to have discontinued subjects complete the assessments for the study 
termination visit. If the termination visit is done as an additional, unscheduled visit, the 
assessment results shall be recorded with the completion/termination visit. If a subject terminates 
participation in the study and does not return for the study termination visit, their last recorded 
assessments shall remain with their last visit in the eCRF.
In the event of subject discontinuation due to an AE or clinical and/or laboratory investigations 
that are beyond the scope of the required study, observations and assessments may be performed 
as part of the evaluation of the event. These investigations will take place under the direction of 
the investigator in consultation with the sponsor, and the details of the outcome may be reported 
to the appropriate regulatory authorities by the sponsor.
7.2 Reasons for Withdrawal/Discontinuation from Study
Any legal representative/subject may withdraw from the study at any time and for any reason 
without prejudice to their 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 
sponsor when possible. The reason for withdrawal/discontinuation will be recorded on the eCRF. 
The data collected on withdrawn subjects will be used in the analysis and included in the clinical 
study report.
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.
The reason for discontinuation must be determined by the investigator and recorded in the 
subject’s source document and the eCRF. If a subject is discontinued for more than 1 reason, 
each reason should be documented in the source and the primary (most clinically relevant) 
reason should be indicated. 
Reasons for withdrawal/discontinuation include, but are not limited to:
•
Adverse event
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-
Development of a confirmed inhibitory antibody based on a second blood draw to 
FVIII within 2 weeks of study site notification of an inhibitor determined at the 
central laboratory with an inhibitor level ≥0.6 BU/mL using the Nijmegen 
modification of the Bethesda assay.
-
The subject experiences a severe anaphylactic reaction to ADYNOVATE.
•
Protocol deviation
-
The subject requires therapy with another PEGylated product (eg, PEG-interferon).
-
The subject frequently misses more than 30% of planned prophylactic doses within 
any 3-month period.
-
The subject uses an FVIII concentrate or treatment regimen other than ADYNOVATE
or the treatment regimen prescribed.
-
The subject experiences a life-threatening bleeding episode (eg, any gastrointestinal 
hemorrhage or intracranial hemorrhage) requiring the use of another FVIII 
concentrate.
-
The subject requires a major emergency or major elective surgical procedure.
•
Withdrawal by subject
•
Lost to follow-up
•
Lack of efficacy
•
Study termination by the sponsor
-
See Section 4.6 for study stopping rules
•
Other
-
The subject/legal representative is noncompliant with study procedures, in the 
opinion of the investigator.
7.3 Subjects “Lost to Follow-up” Prior to the Last Scheduled Visit
A minimum of 3 documented attempts must be made to contact (by phone) any subject who is 
lost to follow-up at any time point prior to the last scheduled contact.
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8. STUDY ASSESSMENTS AND PROCEDURES
8.1 Study Periods
Refer to Table 1 for the schedule of study activities. Study assessments are detailed in 
Section 8.2.
The study period comprises a screening visit, initial PK assessment (for subjects participating in 
the PK portion of the study), a prophylactic treatment phase (includes the baseline, Week 2, 
Week 6, Week 12, second PK assessment [for subjects participating in the PK portion of the 
study], and study completion/termination visits), and a safety follow-up.
The prophylactic treatment phase consists of twice-weekly treatment that starts at the baseline 
visit and continues over a period of 26 weeks (+2 weeks) or at least 50 EDs (whichever occurs 
last). The treatment concludes at the study completion/termination visit.
8.1.1 Screening Visit
Written informed consent and, if appropriate, written assent must be obtained from each 
participant and/or their parent/legal guardian before any study-related procedures are performed. 
The investigational site is responsible for the consenting process. The requirements of informed 
consent are described in Appendix 1.5.
At least 72 to 96 hours must have elapsed since the subject’s last FVIII therapy (on-demand or 
prophylactic), if applicable, and the subject must not be actively bleeding. The screening visit 
procedures (Table 1) will be performed for eligibility determination and completed within 
30 days prior to the initial PK assessment (if applicable) or baseline visit. Screening procedures 
will include demographics, medical/medication history, concomitant medications, AEs, physical 
examination, vital signs, and clinical laboratory assessments (Table 2). Medical history 
(including immunization history) will include surgery history, hemophilia history, bleeding 
episode history, and history of FVIII usage over the last year. Target joints and subject’s ABR 
based on the previous 9 to 12 months will also be recorded. Medication history will include the 
name of the product, dose, dosing interval, and regimen start and end date.
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 IP. Subjects who fail 
screening due to a single laboratory test result that does not meet eligibility criteria may have that 
laboratory test repeated at the discretion of the investigator. This includes a repeat of only the 
failed assessment (retesting) rather than a repeat of all screening assessments, which is allowed 
only once within 30 days of initial screening. If this screening time frame is exceeded, then all 
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screening assessments must be repeated and the subject assigned a new subject identification 
code. Exemptions may be provided if the time frame is exceeded due to administrative reasons.
Subjects with an inadequate interval between screening and prior PEGylated drug administration 
or prior participation in a drug or device study (ie, within 30 days), may be rescreened only once 
and only when the required interval is reached. Subjects who still do not meet eligibility criteria 
may not be rescreened a second time unless a justification can be provided.
Electronic devices (eDiary and ePRO device) will be handed out after subject eligibility is 
confirmed and before the first dose. Training will be provided to the subject and/or caregiver.
Treatment of Bleeding Episodes and Prophylaxis During Screening
During the screening period (ie, between subject enrollment [signing of the ICF] up to the first 
prophylactic dose or the initial PK assessment), subjects will continue receiving their usual FVIII 
concentrate for prophylaxis and/or treatment of bleeding events. Bleeding events and treatment 
information will be reviewed by the investigator before eligibility confirmation and will be 
recorded in the eCRF.
8.1.2 Initial Pharmacokinetic Assessment
For those subjects who will undergo PK assessments, and prior to PK infusion, the following 
3 conditions must be met:
•
The subject has not received an infusion of any FVIII-containing product for at least 72 to 
96 hours prior to the PK infusion
•
The subject is not actively bleeding at the time of the infusion
•
The subject does not exhibit an FVIII inhibitor at levels ≥0.6 BU/mL, as tested at 
screening/enrollment in the central laboratory by the Nijmegen-modified Bethesda assay
Pre- and postinfusion activities and assessments will be carried out as presented in Table 1 and 
Table 2, respectively. Refer to Table 3 for PK sample collection timepoints.
8.1.3 Study Treatment Visits
8.1.3.1 Baseline Visit and Prophylaxis Visits (Weeks 2, 6, and 12)
The prophylactic treatment phase consists of twice-weekly treatment that starts at the baseline 
visit and continues over a period of 26 weeks (+2 weeks) or at least 50 EDs (whichever occurs 
last). The treatment concludes at the study completion/termination visit. Study procedures for 
assessment of efficacy and safety and review of subject eDiaries will be conducted as described 
in Table 1.
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At all visits, blood will be drawn for the assessments presented in Table 2 only after a washout 
period of 72 to 96 hours following the last infusion of any other nonmodified FVIII concentrate 
and at least 84 to 96 hours following the last infusion of ADYNOVATE. Subjects must not be 
actively bleeding during visits.
For subjects not participating in the PK portion of the study, the baseline visit will be initiated 
immediately upon eligibility confirmation. Those subjects undergoing PK evaluation will enter 
the prophylactic treatment phase 96 hours (±4 hours) after the initial PK infusion.
Treatment administration will be done at the study site for all scheduled visits. All other study 
treatments may be administered either at a clinic/hospital/study site or at home by 
self-administration/administration by a parent/caregiver. The investigator will determine the
setting of treatment administration. Unscheduled visits may occur between scheduled site visits 
as required. Assessments may be performed as clinically indicated at the discretion of the 
investigator. 
A sufficient quantity of IP will be dispensed at the prophylactic treatment study visits to cover 
the period until the next scheduled visit. 
8.1.3.2 Second Pharmacokinetic Assessment (Week 20)
A second PK assessment will be performed during the Week 20 (±1 week) visit following the 
scheduled prophylactic treatment dose. The PK samples will be collected at specified time points 
and measured for FVIII activity by a 1-stage clotting assay. 
Pre- and postinfusion activities and assessments will be carried out as presented in Table 1 and 
Table 2, respectively. Refer to Table 3 for PK sample collection timepoints.
8.1.3.3 Study Completion/Termination Visit (Week 26 or ≥50 EDs)
Treatment administration will be done at the study site for the study completion visit. Study 
procedures for assessment of efficacy and safety and review of subject eDiaries will be 
conducted as described in Table 1. Blood will be drawn for the assessments presented in Table 2
only after a washout period of at least 84 to 96 hours following the last infusion of ADYNOVATE. 
Subjects must not be actively bleeding during the visit.
In case of early discontinuation, every effort will be made to have discontinued subjects 
complete the assessments for the study completion/termination visit.
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8.1.4 Safety Follow-up
Upon completion of prophylactic treatment (at least 50 EDs or 26 weeks [+2 weeks], whichever 
occurs last), the study site will follow up via phone call with each subject after 3 to 5 days to 
determine the occurrence of AEs.
All AEs and SAEs that are not resolved at the time of this contact will be followed to closure 
(see Appendix 3.2).
8.1.5 Additional Care of Subjects after the Study
No aftercare is planned for this study.
8.1.6 COVID-19–related Protocol Considerations
On a temporary basis, in order to maintain subject safety, confidentiality, and study integrity in 
the context of healthcare delivery challenges presented by the coronavirus disease of 2019 
(COVID-19) pandemic, subjects who may be impacted should contact study sites and 
investigators to determine the best course of action. Depending on the impact, in some cases it 
may be possible to arrange for alternative solutions as permitted by local regulations. Any 
decision on procedural changes should be made on a case-by-case basis by the principal 
investigator in consultation with the sponsor, while maintaining subject safety and 
confidentiality as the priority.
Missing data, remote visits, changes to assessment approaches, and altered visit windows during 
the COVID-19 public health emergency may affect the study results. Thus, it is important to 
identify all protocol deviations and altered data collection or assessment methods. It is crucial 
that any deviations related to COVID-19 be clearly identified as such in the eCRF or tracked in 
the clinical trial management system of the participating CRO.
The following procedural changes may be considered:
•
If necessary, informed consent from a potential or current trial participant may be obtained 
via electronic informed consent capabilities or an electronic face-to-face consent interview 
when potential participants are unable to travel to the site.
•
Subjects who discontinued from screening due to COVID-19–related factors but were 
otherwise qualified to participate in the study may be rescreened if the sponsor agrees.
•
Remote checks instead of site visits (if appropriate) may be performed as a safety check 
on subject well-being.
•
Transfer to investigational sites away from risk zones to complete required visits.
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8.2 Study Assessments
8.2.1 Demographic and Other Baseline Characteristics
Subject demographic information, including sex, age, and race, will be collected at screening 
prior to the subject receiving the first dose of ADYNOVATE.
8.2.2 Medical and Medication History
Medical and medication history will be collected at screening and recorded on the eCRF.
The subject’s medical history (including immunization history) will be described and include 
surgery history, hemophilia history, bleeding episode history, and history of FVIII usage over the 
last year. 
Target joints will be documented, whereby a target joint is defined as a single joint (ankles, 
knees, hips, or elbows) with ≥3 spontaneous bleeding episodes in any consecutive 6-month 
period. The joint is no longer considered a target joint when there have been ≤2 bleeds into the 
joint within a consecutive 12month period (Blanchette et al. 2014).
The subject’s ABR based on the previous 9 to 12 months will be recorded, based on the subject’s 
own diary or recall.
Medication history will include the name of the product, dose, dosing interval, and regimen start 
and end date. All FVIII replacement therapies used within the previous 12 months will be 
documented, including:
•
Factor VIII regimen (prophylaxis or on-demand)
•
Product name (or IP name and manufacturer, if applicable)
•
Dose (for prophylaxis, if applicable, and for treatment of bleeding episodes)
•
Frequency of administration (for prophylaxis)
•
Estimate of average number of infusions for each bleeding episode
•
Usual response to treatment for bleeding episodes
•
Total number of EDs
Any prior use of the following, at any time in the past, will also be recorded:
•
Any PEGylated medication (name of drug, indication, and dates of use)
•
Fresh frozen plasma, cryoprecipitate, and/or any type of FVIII concentrate
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•
Any kind of blood transfusion, such as pRBCs, platelets, or plasma
All nonstudy treatments (including but not limited to herbal treatments, vitamins, behavioral 
treatment, nonpharmacological treatment, such as psychotherapy) received within 30 days prior 
to the screening visit and through the final study contact (including protocol-defined follow-up 
period) must be recorded on the eCRF.
8.2.3 Subject Electronic Diary
After eligibility is confirmed (and before the first dose), an eDiary will be provided to each 
subject and/or subject’s legally authorized representative to record the following information:
•
Daily infusion record of ADYNOVATE, including:
-
Date and time of infusion
-
Number of units infused
-
Number of vials used
-
Reason for infusion (eg, bleeding episode, maintain hemostasis, prophylaxis)
-
Total volume
•
Details of bleed episodes and response to treatment
•
Untoward events
•
Concomitant medications and nondrug therapies
For each bleeding episode, the following information will be recorded by the subject/subject’s 
caregiver or by authorized, qualified personnel at the study site:
•
Location of the bleed; eg, joint, soft tissue, muscle, body cavity, intracranial, other
•
Type of bleed; ie, spontaneous (ie, not related to injury/trauma), injury (definitely due to 
injury/trauma)
•
Severity of the bleed; eg, minor, moderate, major (see Table 6)
•
Date and time of onset of the bleed
•
Date and time of each infusion of ADYNOVATE required to achieve adequate hemostasis
•
Date and time of resolution of bleeding episode
•
Overall clinical efficacy rating according to the rating scale as described in Table 7 at 
24 hours (±2 hours) after initiation of treatment and at a resolution of bleed
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Subjects and/or their legally authorized representative will be trained on use of the eDiary at the 
time it is issued. The eDiary will be provided in electronic format and remain with the subject for 
the duration of the study. eDiaries will be completed before each site visit and reviewed by the 
investigator during the visit. The investigator will review the eDiary for completeness and 
request missing information periodically, at a minimum at each subject visit, and in a timely 
manner. Untoward events recorded in the eDiary will be reported as AEs according to the 
investigator’s discretion and clinical judgment.
Subject entries in the eDiary will serve as source records. During study participation, the 
investigator has access to the database holding the subject eDiary data. After study closure, the 
investigator will receive the eDiary records for their subjects, including audit trail records. The 
eDiary records will be transmitted to the CRO.
Note: It is crucial that the investigator evaluates and discusses with the subject at each study visit 
whether the subject/legal representative has adhered to the prescribed treatment regimen for 
prophylaxis, treatment of bleeding episodes (if applicable), and whether the subject/legal 
representative has correctly entered all necessary information. The investigator will review the 
eDiary for completeness and ask for missing information. Any unclear or implausible 
information should be immediately clarified with the subject at each study visit, and instructions 
related to treatment and data entry should be reinforced. If necessary, an additional remote visit 
via phone or an unscheduled on-site visit can be conducted at the investigator’s discretion.
8.2.4 Efficacy
This section details the efficacy assessments and procedures for prophylaxis treatment 
(Section 8.2.4.1), on-demand treatment of bleeding episodes (Section 8.2.4.2), and perioperative 
bleeding management (Section 8.2.4.3).
8.2.4.1 Prophylaxis Treatment Assessments
8.2.4.1.1 Annualized Bleeding Rates
The primary measure of hemostatic efficacy is the total ABR. The ABR will be assessed based 
upon each individual bleeding episode, spontaneous or traumatic, recorded in the subject’s 
eDiary and/or recorded in the physician/nurse/study site notes. A bleed is defined as subjective 
(eg, pain consistent with a joint bleed) or objective evidence of bleeding that may or may not 
require treatment with FVIII. Bleeding episodes occurring at the same anatomical location 
(eg, right knee) with the same etiology (eg, spontaneous vs. injury) within 24 hours of onset of 
the first episode will be considered a single bleeding episode. If a bleed occurs following 
resolution of the bleed, it will be considered a “new” bleed and recorded accordingly. Bleeding 
occurring at multiple locations related to the same injury (eg, knee and ankle bleeds following a 
fall) will be counted as a single bleeding episode.
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The time intervals between bleeding episodes and proportion of subjects with zero bleeding
episodes will also be determined based on the subject’s eDiary and/or recorded in the 
physician/nurse/study site notes.
8.2.4.1.2 Consumption of ADYNOVATE for Prophylaxis Treatment
The total number of ADYNOVATE infusions and the average number of ADYNOVATE infusions per 
week and per month during prophylactic treatment will be measured.
The total and average weight-adjusted consumption of ADYNOVATE per week and per month 
during prophylactic treatment will be determined based upon the amount of ADYNOVATE
infused, as recorded in the subject’s eDiary or eCRF, and the subject’s weight, as measured at 
the study site.
8.2.4.2 On-demand Treatment of Bleeding Episodes Assessments
8.2.4.2.1 Hemostatic Efficacy Rating
The subject or their caregiver will rate the severity (minor, moderate, or major) of the bleeding 
episode and will rate the overall treatment response at 24 hours (±2 hours) after the initiation of 
treatment and at the resolution of bleed using a 4-point efficacy rating scale (Table 7). Since the 
efficacy rating is based to a large degree on cessation of pain, the investigator/subject shall, in 
particular in case of injury-related bleeding into 1 or more than 1 location, consider the 
injury-related symptoms when performing the efficacy rating 24 hours (±2 hours) after initiating 
treatment and at resolution of bleed.
As per Table 7, multiple infusions of ADYNOVATE may be administered for the treatment of a 
bleeding episode. The overall response to all infusions combined is the rating that will be 
recorded at resolution of the bleed.
Table 7. Efficacy Rating Scale for Treatment of Bleeding Episodes
Excellent
Full relief of pain and cessation of objective signs of bleeding (eg, swelling, tenderness, and 
decreased range of motion in the case of musculoskeletal hemorrhage) after a single infusion. 
No additional infusion is required for the control of bleeding. Administration of further 
infusions to maintain hemostasis would not affect this scoring.
Good
Definite pain relief and/or improvement in signs of bleeding after a single infusion. Possibly 
requires more than 1 infusion for complete resolution.
Fair
Probable and/or slight relief of pain and slight improvement in signs of bleeding after a single 
infusion. Required more than 1 infusion for complete resolution.
None
No improvement or condition worsens.
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Details pertaining to all home treatments for each bleed, including response to treatment, will be 
recorded by study subjects (or their caregiver) in subject eDiaries provided by the sponsor or 
sponsor’s representative (see Section 8.2.3). At each study visit, the investigator will review 
together with the subject (or their caregiver) the response to treatment and evaluate the 
hemostatic efficacy rating. If a breakthrough bleed occurs, the subject will be advised to contact 
the investigator to discuss dose and bleed severity. It may become necessary to rediscuss the 
rating with the subject (or their caregiver) to ensure the rating scale is fully understood:
•
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 of a unique bleeding episode are rated with “fair”, the 
investigator may re-evaluate the dosing regimen and the time from bleeding onset to start 
of treatment. In case of bleeding episodes requiring only 1 infusion but response to 
treatment is rated as “fair”, the rating scale should be evaluated and discussed with the 
subject (or their caregiver).
•
In case more than 1 infusion was given to treat a bleeding episode but the treatment was 
rated as “excellent”, information should be provided about the severity of the bleeding 
episode (see Table 6) 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 on the eCRF.
Adverse events and the details of concomitant medication use coincident with the treatment of all 
acute bleeding episodes will be recorded. Note that bleeding episodes are not to be reported as 
AEs (Appendix 3).
8.2.4.2.2 Consumption of ADYNOVATE per Bleeding Episode
The number of ADYNOVATE infusions to treat each bleeding episode is determined by the 
subject, subject’s caregiver, and/or investigator and is based upon the subject’s response to 
treatment, using the efficacy rating scale in Table 7. An infusion is defined as completion of 
administration of the calculated dose of ADYNOVATE. If an infusion is interrupted, eg, due to 
vascular access issues, and must be restarted, it will be recorded as 1 infusion. If an infusion is 
terminated for any reason prior to completion of infusion and not restarted, it will be recorded as 
an infusion; reasons for interruption and volume of the infusion will be recorded.
The weight-adjusted consumption of ADYNOVATE per bleeding episode will be determined based 
upon the amount of ADYNOVATE infused to treat the bleeding episode, as recorded in the 
subject’s eDiary, and the subject’s weight, as measured at the study site.
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8.2.4.3 Perioperative Bleeding Management Assessments
8.2.4.3.1 Global Hemostatic Efficacy Assessment
The primary outcome measure for perioperative bleeding management is the Global Hemostatic 
Efficacy Assessment (GHEA) score, which is composed of 3 individual ratings (see Table 8, 
Table 9, and Table 10). Assessments are performed intraoperatively and postoperatively at 
24 hours by the surgeon and at discharge by the investigator.
•
Assessment of intraoperative hemostatic efficacy of ADYNOVATE is to be performed by 
the operating surgeon (Table 8).
Table 8. Intraoperative Efficacy Assessment Scale
Rating
Criteria
Score
Excellent
Intraoperative blood loss is less than or equal to that expected for the type of 
procedure performed in a non-hemophilic population (≤100%)
3
Good
Intraoperative blood loss is up to 50% more than expected for the type of 
procedure performed in a non-hemophilic population (101% to 150%)
2
Fair
Intraoperative blood loss is more than 50% of that expected for the type of 
procedure performed in a non-hemophilic population (>150%)
1
None
Uncontrolled hemorrhage that is the result of inadequate therapeutic response 
despite proper dosing, necessitating rescue therapy
0
•
Assessment of postoperative hemostatic efficacy of ADYNOVATE is to be performed on 
postoperative day 1 (ie, the day after surgery) by the operating surgeon (Table 9).
Table 9. Postoperative Efficacy Assessment Scale (Postoperative Day 1)
Rating
Criteria
Score
Excellent
Postoperative blood loss is less than or equal to (≤100%) that expected for 
the type of procedure performed in a non-hemophilic population
3
Good
Postoperative blood loss is up to 50% more (101% to 150%) than expected 
for the type of procedure performed in a non-hemophilic population
2
Fair
Postoperative blood loss is more than 50% (>150%) of that expected for the 
type of procedure performed in a non-hemophilic population
1
None
Significant postoperative bleeding that is the result of inadequate therapeutic 
response despite proper dosing, necessitating rescue therapy
0
•
Assessment of perioperative hemostatic efficacy of ADYNOVATE is to be performed by the 
investigator at discharge (Table 10).
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Table 10. Perioperative Efficacy Assessment Scale (Discharge Visit)
Rating
Criteria
Score
Excellent
Perioperative blood loss is less than or equal to (≤100%) that expected for 
the type of procedure performed in a non-hemophilic population
Required blood components for transfusions are less than or similar to that 
expected in non-hemophilic population
3
Good
Perioperative blood loss is up to 50% more (101% to 150%) than expected 
for the type of procedure performed in a non-hemophilic population
Required blood components for transfusions are less than or similar to that 
expected in non-hemophilic population
2
Fair
Perioperative blood loss is more than 50% of that expected for the type of 
procedure performed in a non-hemophilic population (>150%)
Required blood components transfusions are greater than that expected in 
non-hemophilic population
1
None
Significant perioperative bleeding that is the result of inadequate therapeutic 
response despite proper dosing, necessitating rescue therapy
Required blood components for transfusions are substantially greater than 
that expected in non-hemophilic population
0
The scores of each of the 3 individual ratings described in Table 8, Table 9, and Table 10 are 
added together to form a GHEA score (Table 11). Treatment success is defined as a rating of 
“excellent” and/or “good”. For a GHEA score of 7 to be rated “excellent”, no individual 
assessment score is less than 2 (ie, an individual assessment score must be 3 and the other 
2 individual assessment scores must be 2). The only other option to achieve a GHEA score of 7 
is for 2 individual assessment scores of 3 and an individual assessment score of 1. Although this 
GHEA score will not qualify for a rating of “excellent”, the GHEA score will satisfy the 
definition of “good” (with no individual assessment score less than 1).
Table 11. Global Hemostatic Efficacy Assessment
Assessment
Global Hemostatic Efficacy Assessment Score
Excellent
7 to 9 (with no category scored <2)
Good
5 to 7 (with no category scored <1)
Fair
3 to 4 (with no category scored <1)
None
0 to 2 (or at least 1 category scored 0)
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8.2.4.3.2 Actual Versus Predicted Blood Loss
The observed versus predicted operative blood loss for all procedures will be described for the 
period from initiation of the intervention to discharge.
Prior to each surgery, the surgeon/investigator will predict the estimated volume (mL) of the 
expected average and maximum blood loss for the planned surgical intervention in a 
hemostatically normal individual of the same sex, age, and stature as the study subject for 
intraoperative, postoperative, and overall perioperative time periods. Every effort should be 
made to predict the volume as precisely as possible. The estimate will be for the intraoperative 
time period from completion of the procedure until approximately 24 hours after surgery and for 
the overall perioperative time period (assessed at discharge).
The intraoperative blood loss will be measured by determining the volume of blood and fluid 
removed through suction into the collection container (waste box and/or cell saver) and the 
estimated blood loss into swabs and towels during the procedure, per the anesthesiologist’s 
record. Postoperatively, blood loss will be determined by the drainage volume collected, which 
will mainly consist of drainage fluid via vacuum or gravity drain, as applicable. In cases where 
no drain is present, blood loss will be determined by the surgeon’s clinical judgment, as 
applicable, or entered as “not available”.
8.2.4.3.3 Blood Transfusion Requirement
The volume of blood, pRBCs, platelets, and other blood products transfused to the subject to 
manage the intraoperative and postoperative bleeding until discharge will be recorded.
8.2.4.3.4 Consumption of ADYNOVATE for Perioperative Bleeding Management
The daily and total weight-adjusted consumption of ADYNOVATE for intraoperative and 
postoperative bleeding management until discharge will be determined based upon the amount of 
ADYNOVATE infused, as recorded in the subject’s eDiary or eCRF, and the subject’s weight, as 
measured at the study site.
8.2.5 Safety
8.2.5.1 Physical Examination
A physical examination will be performed by the investigator during each study visit. A 
complete physical examination will include, at a minimum, assessments of general appearance, 
head and neck, eyes and ears, nose and throat, chest, lungs, heart, abdomen, extremities and 
joints, lymph nodes, skin, and neurological.
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Abnormalities identified at the screening visit and at subsequent study visits will be recorded on
the eCRF. The investigator will assess whether a change from baseline may be deemed clinically 
significant and therefore recorded as an AE. For each abnormal physical examination finding 
deemed to be an AE (see definition in Appendix 3.1), the medical diagnosis (preferably) or 
symptom will be recorded. Additional tests and other evaluations required to establish the 
significance or etiology of the abnormal value, or to monitor the course of the AE, should be 
obtained when clinically indicated. Any abnormal value that persists should be monitored at the 
discretion of the investigator.
8.2.5.2 Adverse Events
The occurrence of AEs and SAEs will be monitored, including the total incidence, by severity, 
and by causality. 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?”). Occurrence of thromboembolic events and hypersensitivity reactions will 
particularly be monitored. Adverse events are collected from the time the ICF is signed. Refer to 
Appendix 3 for AE definitions, assessment, collection time frame, and reporting procedures. 
8.2.5.3 Vital Signs
Vital signs will include height (only at screening), weight (kg), body temperature (°C), 
respiratory rate (breaths/min), pulse rate (beats/min), and systolic and diastolic blood pressure 
(mmHg) taken following 15 minutes of rest  The time points for pre- and postinfusion 
measurements are within 30 minutes before infusion start (prior to blood sample collection) and 
30±15 minutes after infusion. Vital signs will be measured at the study visits presented in 
Table 1. Weight is measured preinfusion only.
Blood pressure should be determined by cuff and measured while subjects are in a sitting 
position (the same method, same arm, and same position should be used throughout the study).
Vital sign values are to be recorded on the eCRF. The investigator will assess whether a change 
from baseline in vital signs may be deemed clinically significant and therefore recorded as an 
AE. For each abnormal vital sign value, if the investigator deems this to be an AE (see definition 
in Appendix 3), the medical diagnosis (preferably), symptom, or sign will be recorded on the AE 
eCRF. Additional tests and other evaluations required to establish the significance or etiology of 
an abnormal value, or to monitor the course of an AE, should be obtained when clinically 
indicated. Any abnormal value that persists should be followed at the discretion of the 
investigator.
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8.2.5.4 Clinical Laboratory Tests
At all laboratory assessments, subjects must not be actively bleeding. Assessments should only 
be performed after a washout period of at least 72 to 96 hours following the last infusion of any 
other nonmodified FVIII concentrate and 84 to 96 hours following the last infusion of 
ADYNOVATE. In addition to the assessments shown, clinical laboratory assessments should be 
performed whenever clinically indicated.
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 that may be associated with, or constitute, an AE. 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.
A complete list of the clinical laboratory tests to be performed is provided in Appendix 2. The 
schedule of clinical laboratory assessments is presented in Table 2.
8.2.5.4.1 Immunology
Immunology assessments will include HIV-1/HIV-2 antibody, hepatitis B surface antigen, 
hepatitis B surface antibody, hepatitis B core antibody, and HCV antibody. The HCV titer will 
be confirmed by polymerase chain reaction for all subjects reported as HCV-positive.
If a subject is HIV-positive, CD4 count is measured using flow cytometry to determine the 
subject’s eligibility.
All immunology assessments will be performed at screening only. Testing will be conducted at a 
local laboratory as the first choice and at a central laboratory as back-up.
8.2.5.4.2 Hematology and Clinical Chemistry
Blood will be obtained for assessment of hematology and clinical chemistry parameters at the 
study visits presented in Table 2. Hematology and clinical chemistry assessments will be 
performed on anticoagulated whole blood and serum, respectively, at a local laboratory.
The hematology panel will consist of complete blood count: hemoglobin, hematocrit, 
erythrocytes (ie, red blood cell count), leukocytes (ie, white blood cell count) with differential 
(ie, basophils, eosinophils, lymphocytes, monocytes, and neutrophils), and platelet count. 
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If historical data on blood group type are available, this may be recorded in the eCRF and blood 
type does not need to be determined. For subjects who do not have documentation of their blood 
type in their medical record, ABO blood type will be measured locally at screening.
The clinical chemistry panel will consist of sodium, potassium, chloride, bicarbonate, total 
protein, albumin, ALT, AST, gamma-glutamyl transferase, bilirubin, alkaline phosphatase, 
urea/blood urea nitrogen (BUN), creatinine, glucose, cholesterol, very low-density lipoprotein, 
low-density lipoprotein, high-density lipoprotein, and triglycerides.
8.2.5.4.3 Coagulation Function
Coagulation function will be assessed at a local laboratory via INR at screening and aPTT, as 
needed, for surgery (see Section 6.2.2.4.1).
8.2.5.5 Immunogenicity
Blood samples for immunogenicity testing should only be collected after the required washout 
period and the subject is in a nonbleeding state. A minimum washout of 72 to 96 hours is 
required following the last infusion of FVIII therapy and 84 to 96 hours following the last 
infusion of ADYNOVATE.
Immunogenicity assessments will include the measurement of inhibitory antibodies to FVIII and 
binding antibodies to ADYNOVATE and CHO proteins.
•
Inhibitory antibodies to FVIII will be measured using the Nijmegen modification of the 
Bethesda assay. A sample will be defined as positive for inhibitor development with a titer 
of ≥0.6 BU/mL. Any positive titers should be confirmed with a second repeat sample 
drawn within 2 weeks of study site notification of an inhibitor-positive result.
•
Binding antibodies to ADYNOVATE will be measured via enzyme-linked immunosorbent 
assay (ELISA). A tiered approach will be used. All samples will be screened for 
anti-ADYNOVATE binding antibodies. Screen-positive samples will be tested by a 
confirmatory assay. Confirmed positive samples will be serially diluted to assess antibody 
titer.
•
Binding antibodies to CHO proteins will be measured via ELISA. A tiered approach, as 
described above for anti-ADYNOVATE binding antibody, will be used.
Factor VIII inhibitory antibodies must be determined at the central laboratory. However, in order 
to ensure the timely availability of FVIII inhibitor results, the clinical management of the subject 
may be based on results generated at the local laboratory. An additional blood sample needs to 
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be drawn for testing at the central laboratory to confirm the result determined at the local 
laboratory. Blood will be obtained for these assessments at the visits shown in Table 2.
8.2.6 Pharmacokinetics
Pharmacokinetic activities, assessments, and sampling time points are listed in Table 1, Table 2, 
and Table 3, respectively.
8.2.6.1 Pharmacokinetic Sampling and Evaluation
The PK samples for both the initial and second PK assessments should be taken following the 
sampling time points listed in Table 3. Evaluation will be performed in the clinic to ensure a 
sufficient number of PK blood samples are available for participating subjects.
For subjects participating in the PK portion of the study, the initial PK assessment will be 
conducted after a washout period of at least 72 to 96 hours following their last FVIII therapy (if 
applicable) and prior to the baseline visit. The second PK assessment will be performed during 
the Week 20 (±1 week) visit following the scheduled prophylactic treatment dose.
8.2.6.2 Determination of Incremental Recovery
During the baseline visit (ED1), Week 6 visit (approximately ED10 to ED15), and the study 
completion visit (ED50), peak levels of FVIII activity will be assessed within 30 minutes before 
ADYNOVATE administration and 30±10 minutes post ADYNOVATE infusion for determination of 
IR. The IR determination at baseline visit will only be performed in subjects who have not 
undergone the initial PK assessment.
All PK samples collected in this part will be used, along with the samples collected in the PK 
assessments, to characterize PK properties in PTPs.
8.2.6.3 Factor VIII and von Willebrand Factor Measurements
In addition to PK and IR assessments, FVIII (activity and antigen) and VWF antigen levels will 
be measured at specified study visits, preinfusion, in both PK and non-PK subjects. For PK 
subjects, preinfusion blood draws are performed within 30 minutes prior to infusion, meaning no 
additional blood draw is needed at the baseline visit for these assessments.
Plasma FVIII levels will be measured using a 1-stage clotting assay for FVIII:C activity and 
ELISA for FVIII antigen concentrations. von Willebrand factor antigen will be measured via 
ELISA.
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8.2.7 Other Assessments
8.2.7.1 Patient-reported Outcome
The PRO assessment, using the EQ-5D-5L, will be captured via an ePRO device dispensed after 
subject eligibility is confirmed and before the first dose. Subjects should complete the EQ-5D-5L
prior to study visits listed in Table 1. Investigators should review subject responses during each 
scheduled visit.
For subjects participating in the PK portion of the study, the first PRO measurement should be 
completed prior to the initial PK assessment. For subjects not undergoing PK assessment, the 
first PRO measurement should be completed prior to the baseline visit.
Further information concerning the PRO assessment included in the study is provided in 
Appendix 4.
8.2.7.2 Healthcare Resource Utilization 
Healthcare resource utilization endpoints will be gathered by the sites via questionnaire as part of 
the eCRF. This information is necessary to collect as input into a cost-effectiveness analysis that 
may be developed in the future. It assesses the following:
•
Number and duration of hospitalizations
•
Number of emergency room visits
•
Number of acute care visits
•
Number of days missed from school/work
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9. STATISTICAL CONSIDERATIONS
9.1 Statistical Analysis Process
The study will be analyzed by the sponsor and its designated agent. 
Statistical analyses will be performed using SAS® (SAS Institute, Cary, NC 27513) software 
package, Version 9.4 (or newer) on a suitably qualified environment.
The population PK analysis plan and statistical analysis plan (SAP) will be provided as separate 
documents.
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, IP 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.
9.2 Planned Interim Analysis, Adaptive Design, and Data Monitoring Committee
No interim analysis, adaptive design, or data monitoring committee is planned for this study.
9.3 Sample Size and Power Considerations
At least 30 evaluable adult and adolescent subjects (aged 12 to 65 years) will be enrolled. The 
sample size was not based on statistical consideration. The evaluable subjects are defined as all 
subjects who are treated with ADYNOVATE for a minimum of 50 EDs or approximately 26 weeks 
(+2 weeks), whichever occurs last. Subjects who withdraw or discontinue before study 
completion may be replaced.
9.4 Statistical Analysis Sets
9.4.1 Safety Analysis Set 
The safety analysis set (SA set) will comprise all subjects treated with at least 1 ADYNOVATE
dose. All safety analyses will be performed on the SA set.
9.4.2 Full Analysis Set 
The full analysis set (FAS) will comprise all subjects who were assigned to receive a treatment 
regimen of ADYNOVATE. All efficacy analyses will be performed on the FAS.
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9.4.3 Per Protocol Analysis Set 
The per protocol analysis set (PPAS) will comprise all subjects who were treated with the 
prophylaxis ADYNOVATE treatment regimen and comply with their originally assigned dose for 
the duration of study participation. The PPAS will be the supportive analysis set.
9.4.4 Pharmacokinetic Full Analysis Set 
The PK full analysis set (PK FAS) will comprise all subjects who consented to PK evaluation, 
were treated with at least 1 ADYNOVATE dose, and have at least 1 evaluable PK concentration 
post dose. All PK analyses will be performed on the PK FAS. 
9.4.5 Pharmacokinetic Analysis Set 
The PK analysis set (PK AS), a subset of the PK FAS, will comprise all PK subjects who 
received at least 1 ADYNOVATE PK dose with a sufficient number of evaluable PK concentrations 
post dose for the estimation of PK parameters using a noncompartmental analysis (NCA).
9.5 Efficacy Analyses
9.5.1 Primary Efficacy Endpoint
The primary efficacy endpoint is the total ABR for all bleeding episodes that occurred during the 
study (after the first dose of the study drug). The ABR during the study is to be analyzed in the 
FAS. Point estimates with 95% CIs of ABRs will be presented.
9.5.2 Secondary Efficacy Endpoints
9.5.2.1 Bleeding Episodes and Annualized Bleeding Rate
The ABRs will be summarized using descriptive statistics (mean, standard deviation [SD], 
median, quartiles, and ranges) by bleed site and cause.
The number and percent of subjects with zero bleeding episodes during the study period will be 
summarized.
The time intervals between any 2 consecutive bleeding episodes will be summarized using 
descriptive statistics (mean, SD, median, quartiles, and ranges). 
9.5.2.2 Consumption of ADYNOVATE
Drug consumption of ADYNOVATE will be summarized using descriptive statistics (mean, SD, 
median, quartiles, and ranges) as follows:
•
Number of prophylactic infusions per week and per month
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•
Number of prophylactic units (IU) and weight-adjusted units (IU/kg) per week and per 
month
•
Total number of infusions for prophylactic treatment during the study per subject 
•
Total number of prophylactic units (IU) and weight-adjusted units (IU/kg) during the 
study per subject
•
Number of infusions per bleeding episode
•
Number of units (IU) and weight-adjusted units (IU/kg) per bleeding episode
•
Total number of infusions used to treat bleeding per subject
•
Total number of units (IU) and weight-adjusted units (IU/kg) to treat bleeding per subject
•
Total number of EDs per subject
9.5.2.3 Overall Hemostatic Efficacy Rating and Global Hemostatic Efficacy Assessment
The overall hemostatic efficacy at resolution of each bleeding episode will be summarized by 
frequency table and by severity (mild, moderate, or severe) of bleeding.
9.5.2.4 Efficacy for Surgeries
The overall assessment of hemostatic efficacy based on the GHEA score, as assessed by the 
operating surgeon/investigator, will be summarized by frequency table for minor surgeries.
Intra- and postoperative actual versus predicted blood loss after the surgery, at postoperative 
day 1, and at discharge as assessed by the operating surgeon/investigator will be summarized 
using descriptive statistics for minor surgeries.
Number and percent of subjects who have any surgeries and require perioperative transfusion of 
blood, red blood cells, platelets, and other blood products will be summarized by frequency table 
for minor surgeries. The volume of transfusions will be summarized using descriptive statistics 
for each surgery.
Daily intra- and postoperative weight-adjusted consumption dose of ADYNOVATE will be 
summarized using descriptive statistics for minor surgeries.
9.5.3 Multiplicity Adjustment
No multiplicity adjustment is planned in this single-arm study.
9.5.4 Control of Type I Error
No Type I error control will be applied for the study.
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9.6 Safety Analyses
The analysis of the safety will be performed based on the SA set.
9.6.1 Adverse Events
For this study, any untoward medical occurrence occurring from the time the ICF is signed will 
be considered an AE. A treatment-emergent AE (TEAE) is any event emerging or manifesting at 
or after the initiation of treatment with an IP or any existing event that worsens in either intensity 
or frequency following exposure to the IP. Refer to Appendix 3 for AE definitions, assessment, 
collection time frame, and reporting procedures.
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). The number of events, incidence, and percentage of TEAEs, SAEs, 
treatment-related AEs, and TEAEs leading to discontinuation of the study will be summarized 
overall and by system organ class (SOC) and preferred term (PT)  Treatment-emergent AEs will 
be further summarized by severity and relationship to IP. Adverse events related to IP, AEs 
leading to withdrawal, SAEs, and deaths will be similarly summarized/listed.
Occurrence of hypersensitivity reactions and thromboembolic events will be monitored 
throughout the study and summarized by SOC and PT. Standardized MedDRA queries may be 
used, as applicable.
9.6.2 Immunogenicity
9.6.2.1 Factor VIII inhibitor development 
The incidence of confirmed inhibitory antibodies (≥0.6 BU/mL using the Nijmegen modification 
of the Bethesda assay) to FVIII will be summarized by frequency table. The proportion of 
subjects, including a 95% CI using an exact Clopper-Pearson interval, who developed inhibitory 
antibodies to FVIII at any time during the study (after the first dose of the study drug) will be 
summarized.
9.6.2.2 Binding Antibodies
Histograms will be used to show the number and proportion of subjects with binding antibodies 
to ADYNOVATE and binding antibodies to CHO proteins.
9.6.3 Vital Signs and Clinical Laboratory Parameters
Clinical laboratory parameters and vital signs will be summarized for baseline and postbaseline 
scheduled visits (including the termination visit), as well as their changes from baseline. Number 
and percent of subjects with clinically significant abnormal results for vital signs and clinical 
laboratory parameters will be summarized for any postbaseline assessment.
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Shift tables will be used to assess the frequency of changes for clinically significant vital signs 
and clinical laboratory parameters (hematology and clinical chemistry) to note clinically 
significant changes, or vice versa, after first exposure to ADYNOVATE.
9.7 Pharmacokinetic Analyses
Pharmacokinetic parameters will be estimated for FVIII activity measured by the 1-stage clotting 
assay following an initial single dose and steady-state dose of ADYNOVATE. Pharmacokinetic 
parameters, as appropriate but not limited to, will include CL (clearance), V (volume of 
distribution), AUC (area under the concentration versus time curve between defined timepoints), 
Cmax (maximum concentration), Cpredose (predose concentration), and elimination-phase T1/2. For 
PK subjects, subject to availability of FVIII activity, NCA methodology will be used. For all 
subjects, the population PK modeling and simulation method will be used, as appropriate, and 
reported separately.
Factor VIII activity (1-stage clotting assay) in PK samples collected following single-dose and 
steady-state dose for PK assessments, predose FVIII levels (activity and antigen), FVIII activity 
and VWF antigen will be tabulated and summarized descriptively. Incremental recovery over the 
prophylactic treatments will be calculated and summarized descriptively.
9.8 Other Analyses
9.8.1 Patient-reported Outcome Analysis
Health-related quality of life results as assessed using the EQ-5D-5L will be summarized using 
descriptive statistics in accordance with the questionnaire user guide. Changes from 
baseline/preinfusion to study completion in this PRO will be estimated using the 
Hodges-Lehmann estimator.
9.8.2 Healthcare Resource Utilization Analyses
Healthcare resource utilization endpoints, including number and duration of hospitalizations, 
number of emergency room visits, number of acute care visits, and number of days missed from 
school/work, will be summarized descriptively. Additional analyses may include mean 
hospitalizations per subject, mean length of stay, and mean days missed from school/work.
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Mahlangu, J., Powell, J. S., Ragni, M. V., Chowdary, P., Josephson, N. C., Pabinger, I., et al. 
2014. Phase 3 study of recombinant factor VIII Fc fusion protein in severe hemophilia A. 
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al. 2007. Prophylaxis versus episodic treatment to prevent joint disease in boys with 
severe hemophilia. N Engl J Med, 357(6), 535-44.
Manco-Johnson, M. J., Nuss, R., Geraghty, S., Funk, S. and Kilcoyne, R. 1994. Results of 
secondary prophylaxis in children with severe hemophilia. Am J Hematol, 47(2), 113-7.
Morado, M., Villar, A., Jiménez-Yuste, V., Quintana, M. and Hernandez-Navarro, F. 2005. 
Prophylactic treatment effects in inhibitor risk: experience in one centre. Haemophilia,
11(2), 79-83.
Mullins, E. S., Stasyshyn, O., Alvarez-Roman, M. T., Osman, D., Liesner, R., Engl, W., et al. 
2017. Extended half-life pegylated, full-length recombinant factor VIII for prophylaxis in 
children with severe haemophilia A. Haemophilia, 23(2), 238-46.
National Hemophilia Foundation 2007. Recommendation concerning prophylaxis (Regular 
administration of clotting factor concentrate to prevent bleeding). MASAC 241. 4-11-
2007.
National Hemophilia Foundation. 2006. Recommendation concerning prophylaxis (regular 
administration of clotting factor concentrate to prevent bleeding). MASAC 170. 4-22-
2006.
Roosendaal, G. and Lafeber, F. 2007. Prophylactic treatment for prevention of joint disease in 
hemophilia--cost versus benefit. N Engl J Med, 357(6), 603-5.
Royal, S., Schramm, W., Berntorp, E., Giangrande, P., Gringeri, A., Ludlam, C., et al. 2002. 
Quality-of-life differences between prophylactic and on-demand factor replacement 
therapy in European haemophilia patients. Haemophilia, 8(1), 44-50.
Song, X., Zhong, J., Xue, F., Chen, L., Li, H., Yuan, D., et al. 2021. An overview of patients 
with haemophilia A in China: Epidemiology, disease severity and treatment strategies. 
Haemophilia, 27(1), e51-e9.
Valentino, L. A., Mamonov, V., Hellmann, A., Quon, D. V., Chybicka, A., Schroth, P., et al. 
2012. A randomized comparison of two prophylaxis regimens and a paired comparison of 
on-demand and prophylaxis treatments in hemophilia A management. J. Thromb. 
Haemost, 10(3), 359-67.
White, G. C., Courter, S., Bray, G. L., Lee, M. and Gomperts, E. D. 1997. A multicenter study of 
recombinant factor VIII (Recombinate) in previously treated patients with hemophilia A  
The Recombinate Previously Treated Patient Study Group. Thromb Haemost, 77(4), 660-
7.
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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 
International Council for Harmonisation (ICH) E6 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, contract research organization [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 Good Clinical Practice (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 electronic case report forms (eCRFs) 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 (IP) 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 CRO 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 nonpediatric 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 institutional review boards (IRBs)/ethics committees (ECs) are notified as 
appropriate. Additionally, the discontinuation of a registered clinical study that has been posted 
to a designated public website will be updated accordingly
The sponsor will make an end-of-study declaration to the relevant competent authority as 
required by Article 10 (c) of Directive 2001/20/EC.
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) and applicable regulatory requirements and guidelines.
It is the investigator’s responsibility to ensure that adequate time and appropriately trained 
resources are available 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.
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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 
documented evidence of any licenses and certifications necessary to demonstrate such 
qualification. Curriculum vitae for investigators and subinvestigators 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 ICH Guidance E3 (1995). 
Protocol Adherence and Investigator Agreement
The investigator and any subinvestigators 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 IP, 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.
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Documentation and Retention of Records
The investigator will retain study documentation and data (paper and electronic forms) in 
accordance with applicable regulatory requirements and the document and data retention policy, 
as described in the clinical study agreement.
Electronic Case Report Forms
Electronic case report forms are supplied by the sponsor 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 eCRFs that have been designed to record all 
observations and other data pertinent to the clinical investigation. Electronic case report forms 
must be completed by the investigator or designee as stated in the site delegation log.
The clinical research associate (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. Alternative approaches may be used to ensure data quality, 
data integrity, and subject safety (eg, remote source data review via phone) as permitted by 
regional and local regulations. Additional details are in the monitoring plan.
The eCRFs must 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’s eDiary/electronic patient-reported outcomes device, 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 eCRF 
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, 
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appointment books, original laboratory reports, X-rays, data obtained using electronic devices 
and associated technologies [if applicable], 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 (eg, the United States 
[US] Food and Drug Administration [FDA], European Medicines Agency [EMA], United 
Kingdom Medicines and Healthcare products 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.
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 the IP; and any significant equity 
interest in the sponsor or subsidiaries as defined in 21 Code of Federal Regulations 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 
eCRF 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 eCRF data 
against the source data for completeness and accuracy. Discrepancies between source data and 
data entered on the eCRF will be addressed by qualified site personnel. When a data discrepancy 
warrants correction, the correction will be made by authorized site personnel. Data collection 
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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 sponsor’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.
Appendix 1.5 Ethical Considerations
Informed Consent
It is the responsibility of the investigator to obtain written informed consent and assent, where 
applicable, from all study subjects prior to any study-related procedures, including screening 
assessments. All consent and assent documentation must be in accordance with applicable 
regulations and GCP: 
The subject must receive 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. The investigational site is responsible for the consenting process.
After the subject has received and read (or been read) the subject information, the subject and/or 
the subject’s legally authorized representative (as applicable), is/are requested to sign and date 
the subject informed consent form or a certified translation if applicable.
A copy of the informed consent and assent documentation (ie, a complete set of subject 
information sheets and fully executed signature pages) must be provided 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 at the site 
and must be available for verification at any time.
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The principal investigator provides the sponsor with a copy of the consent form and assent form, 
where applicable, that was reviewed by the IRB/EC and received their favorable 
opinion/approval. A copy of the IRB/EC’s written favorable opinion/approval of these 
documents must be provided to the sponsor prior to the start of the study unless it is agreed to 
and documented (abiding by regulatory guidelines and national provisions) prior to study start 
that another party (ie, sponsor or coordinating principal investigator) is responsible for this 
action. Additionally, if the IRB/EC requires modification of the sample subject information and 
consent document provided by the sponsor, the documentation supporting this requirement must 
be provided to the sponsor.
Additional Pharmacokinetic Sampling Consent Procedure
Informed consent must also be obtained for patients who self-identify as Asian and agree to 
additional pharmacokinetic (PK) sampling before any additional PK samples are drawn.
Institutional Review Board or Ethics Committee
It is the responsibility of the investigator to submit this protocol, the informed consent form and 
assent form, where applicable, (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.
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.
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. The investigator must also 
keep the local IRB/EC informed of any serious and significant adverse events 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.
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After subjects have consented to take part in the study, the sponsor and/or its representatives 
review(s) 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 ADYNOVATE; national or local regulatory authorities; and the IRBs/ECs that 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 numbers, relevant medical records, 
and possibly initials and dates of birth, where allowed per local law, may be transferred to, and 
used in, other countries that 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.
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 multisite study results are published in a cooperative publication or 
for a period of 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 
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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 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 
multisite study publication, if any, or the fact that the study results are a subset of data resulting 
from a larger multisite study.
Takeda is committed to transparent dissemination of all scientific, technical, and medical
manuscripts generated from Takeda-supported research. Therefore, after 01 Jan 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 reuse according to an end user license.
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 and analyzed by a central and/or 
local laboratory:
Clinical Chemistry (local laboratory)
Hematology (local laboratory)
•
Sodium
•
Potassium
•
Chloride
•
Bicarbonate
•
Total protein
•
Albumin
•
ALT
•
AST
•
GGT
•
Bilirubin
•
ALP
•
Urea/BUN test
•
Creatinine
•
Glucose
•
Cholesterol
•
Very low-density lipoprotein
•
Low-density lipoprotein
•
High-density lipoprotein
•
Triglycerides 
•
Hemoglobin
•
Hematocrit
•
Erythrocytes (ie, RBC count)
•
Leukocytes (ie, WBC count) with differential 
(ie, basophils, eosinophils, lymphocytes, 
monocytes, and neutrophils)
•
Platelet count
Immunology (local laboratory as first choice and central 
laboratory as back-up)
Coagulation Function (local laboratory)
•
HIV-1/HIV-2 antibody
•
HCV antibody 
•
HCV PCR testing a
•
HbsAg
•
HbsAb
•
HbcAb
•
CD4 Counts b
•
aPTT d
•
INR
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Immunogenicity (central laboratory)
Others (central and/or local laboratory)
•
Inhibitory antibodies to FVIII c
•
Binding antibodies to ADYNOVATE
•
Binding antibodies to CHO proteins
•
FVIII activity levels (central and/or local 
laboratory)
•
FVIII antigen levels (central laboratory)
•
VWF antigen levels (central laboratory)
•
Blood typing (local laboratory)
ALP=alkaline phosphatase; ALT=alanine aminotransferase; aPTT=activated partial thromboplastin time; 
AST=aspartate aminotransferase; BUN=blood urea nitrogen; CHO=Chinese hamster ovary; FVIII=factor VIII; 
GGT=gamma-glutamyl transferase; HbcAb=hepatitis B core antibody; HbsAb=hepatitis B surface antibody; 
HbsAg=hepatitis B surface antigen; HCV=hepatitis C virus; HIV=human immunodeficiency virus; 
INR=international normalized ratio; PCR=polymerase chain reaction; RBC=red blood cell; VWF=von 
Willebrand factor; WBC=white blood cell
a Polymerase chain reaction will be used to confirm a positive HCV titer
b If a subject is HIV-positive, CD4 count is measured to determine the subject’s eligibility.
c Emergency clinical management of the subject may be based on FVIII inhibitor results generated at the local 
laboratory. An additional blood sample will need to be drawn for testing at the central laboratory to confirm the 
result determined at the local laboratory.
d Assessed, as needed, for surgery.
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Appendix 3 ADVERSE EVENTS: DEFINITIONS AND PROCEDURES FOR 
RECORDING, EVALUATING, FOLLOW-UP, AND REPORTING
Appendix 3.1 Adverse Event Definitions
Per standard definition, 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 (IP) 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).
For this study, AEs are collected from the time informed consent is signed.
Treatment-emergent Adverse Event
A treatment-emergent AE (TEAE) is defined as any event emerging or manifesting at or after the 
initiation of treatment with an IP or any existing event that worsens in either intensity or 
frequency following exposure to the IP.
Non–treatment emergent AEs are events occurring before the first exposure to IP and are not 
considered TEAEs. However, each serious non-TEAE experienced before the first IP exposure 
(ie, from the time of signed informed consent up to but not including the first IP exposure) will 
be described on the serious AE (SAE) electronic case report form (eCRF) in English, or the 
paper Takeda Safety Report Form (as back-up). These events will be considered as SAEs and 
will not be included in the analysis of SAEs.
For the purposes of this study, each nonserious non-TEAE occurrence experienced by a subject 
undergoing study-related procedure(s) before the first IP exposure will be recorded on the AE 
eCRF; these events will be considered as AEs and will not be included in the analysis of AEs.
Serious Adverse Event
An SAE is any untoward clinical manifestation of signs, symptoms, or outcomes (whether 
considered related to IP or not and at any dose) that:
•
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 that hypothetically might have caused death if it were more severe.
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•
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.
•
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:
-
Any hospitalization due to a planned surgical intervention or the placement or 
planned removal of a central venous device is not considered an SAE. However, any 
planned surgery becoming necessary due to a worsening condition of the subject 
during the study period constitutes an SAE. 
-
Development of a confirmed inhibitory antibody based on a second blood draw to 
factor VIII within 2 weeks of study site notification of an inhibitor determined at the 
central laboratory with an inhibitor level ≥0.6 BU/mL using the Nijmegen
modification of the Bethesda assay
-
Intensive treatment in an emergency room or at home for allergic bronchospasm, 
blood dyscrasias, or convulsions that do not result in hospitalization, or development 
of drug dependence or drug abuse
-
Reviewed and confirmed seroconversion for human immunodeficiency virus, 
hepatitis A virus (HAV), hepatitis B virus (HBV), hepatitis C virus, hepatitis E virus, 
or parvovirus B19
-
Thromboembolic events (eg, stroke, myocardial infarction, deep vein thrombosis, 
pulmonary embolism)
-
Severe hypersensitivity/allergic reactions to ADYNOVATE
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Unexpected Adverse Event
Per standard definition, an unexpected AE is an AE whose nature, severity, specificity, or 
outcome is not consistent with the term, representation, or description used in the reference 
safety information (RSI). “Unexpected” also refers to the AEs that are mentioned in the 
investigator’s brochure (IB) and/or prescribing information 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 SAEs will be determined by the sponsor using the IB and/or prescribing 
information as the RSI (as applicable). This determination will include considerations such as the 
number of AEs previously observed, but not on the basis of what might be anticipated from the 
pharmacological properties of a product.
For this study, expectedness of SAEs will be determined by the sponsor using the RSI section of 
the IB.
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. 
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.
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Symptoms of the Disease Under Study
Symptoms of the disease under study should not be classified as AEs as long as they are within 
the normal day-to-day fluctuation or expected disease progression and are part of the efficacy or 
effectiveness data collected in the study. Significant worsening of symptoms should be recorded 
as an AE.
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 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 eCRF.
Clinical Laboratory and Other Safety Assessments
A change in the value of a clinical laboratory parameter or vital sign measure can represent an 
AE if the change is clinically relevant or if, during administration of IP, 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 IP), and the range of variation of the respective parameter within its 
reference range should also be considered.
If, at the end of the treatment phase, there are abnormal clinical laboratory values (such as 
hematology panel or clinical chemistry panel) or vital signs that 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 or vital sign is clinically significant and 
represents an AE.
Appendix 3.2 Collection of Adverse Events
All AEs are collected from the time the informed consent document is signed until the defined 
follow-up period stated in Section 8.1.4. This includes events occurring during the screening 
phase of the study, regardless of whether or not IP is administered.
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All AEs must be followed to closure (ie, the subject’s health has returned to their 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. If the severity rating for an ongoing AE changes before the event resolves, the original AE 
report will be revised (ie, the event will not be reported as a separate AE). During the course of 
any AE, the highest severity rating will be reported. However, worsening medical conditions, 
signs, or symptoms present prior to initiation of IP must be recorded as new AEs.
For example, if a subject reports mild intermittent dyspepsia prior to initiation of dosing with the 
IP and the dyspepsia becomes severe and more frequent after the first dose, a new AE of severe 
dyspepsia (with the appropriate date of onset) should be documented in the source.
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, significantly affects 
clinical status, or may require intensive therapeutic intervention.
Relationship Categorization
A physician/investigator must make the assessment of relationship to IP 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 IP. 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 IP and the occurrence of the AE, then the AE should be considered 
“related”. The causality assessment must be documented in the source.
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The following additional guidance may be helpful:
Table A1.
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.
For the purposes of this study, the following nonserious events experienced after the first IP 
exposure will not be considered an AE and thus not included in the analysis of AEs:
•
Hospital or clinic visits for administration of ADYNOVATE
•
Hospitalization for routine bleeding episode management that could be managed in the 
clinic or home setting but for which the subject was hospitalized
•
Hospitalizations for planned medical or surgical procedures, eg, placement of a central 
venous line
•
Hospitalization or prolongation of hospitalization intended only for social reasons
•
Hospital admittance without in-patient hospitalization or emergency room visit/admittance 
in itself (although the event triggering the visit may be an SAE)
•
Seroconversion after documented HAV/HBV vaccination prior to or during the study 
period
•
Bleeding episodes/hemophilia-related events: 
Bleeding episodes are part of the underlying disease and therefore are not AEs. If a 
bleeding episode was caused by an injury (eg, a fall), the injury would not be reported as 
an AE unless it resulted in a medical finding other than a bleeding episode (eg, abrasion of 
skin; fractured tibia). Therefore, any hemophilia-related event (eg, hemarthrosis, 
bruising, hemorrhage) will not be reported as an AE, but these events will be recorded 
on the bleeding event CRF. However, hemophilia-related events meeting the criteria for 
seriousness (eg, a gastrointestinal hemorrhage requiring hospitalization) will be reported 
as SAEs and described on the SAE report.
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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 eCRF.
Appendix 3.4 Safety Reporting
Reference Safety Information
The RSI for this study is the RSI section of the IB. The sponsor has provided the IB under 
separate cover to all investigators.
Reporting Procedures
The investigator should complete an SAE eCRF in English, or report via the paper Takeda Safety 
Report Form (as back-up), 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 Appendix 3.9) unless they result in an SAE. The fax number and e-mail 
address are provided in the Form Completion Instructions.
Medical Device Safety Reporting
All serious injuries and UADEs must be reported to the sponsor as an SAE in the same process 
as described above. Serious injury is defined as:
•
Led to death
•
Led to a serious deterioration in health of a patient, user, or others that:
-
resulted in a life-threatening illness or injury
-
resulted in permanent impairment/damage of a body function or body structure
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-
required inpatient hospitalization or prolongation of existing hospitalization
-
resulted in medical or surgical intervention to prevent permanent impairment/damage 
to a 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 IP) are collected from the time the subject signs the 
informed consent form until the defined follow-up period stated in Section 8.1.4 and must be 
reported via the eCRF in English, or the paper Takeda Safety Report Form (as back-up), within 
24 hours of becoming aware of the event.
In addition, any SAE(s) considered “related” to the IP and discovered by the investigator at any 
interval after the study has completed must be reported to the Takeda Global Patient Safety 
Evaluation (GPSE) 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 
date 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, 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.
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 IP action was previously taken (eg, drug interrupted, reduced, withdrawn), the action 
taken with the IP should be recorded as “dose not changed” or “not applicable” (if the subject 
never received IP). The IP action of withdrawn should not be selected solely as a result of the 
subject’s death.
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Appendix 3.8 Pregnancy
All pregnancies are reported from the time informed consent is signed until the defined 
follow-up period stated in Section 8.1.4.
Any report of pregnancy for any partner of a study participant must be reported within 24 hours 
to the Takeda GPSE using the pregnancy report form. The fax number and e-mail address are 
provided in the form completion instructions.
A copy of the pregnancy report form (and any applicable follow-up reports) must also be sent to 
the CRO/sponsor using the details specified in the emergency contact information section of the 
protocol.
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 abortion/miscarriage or congenital abnormality are considered 
SAEs and must be reported using the same procedure described for SAE reporting.
In addition to the above, if the reported pregnancy meets serious criteria, it must be reported as 
an SAE using the same procedure described for SAE reporting as well as the pregnancy report 
form. The test date of the first positive serum/urine β-human chorionic gonadotropin 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 
using the Takeda Safety Report Form whether or not they result in an AE/SAE as described in 
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 IP when used for a nonmedical 
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
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•
Misuse – Intentional use of IP other than as directed or indicated at any dose (Note: this 
includes a situation where the IP is not used as directed at the dose prescribed by the 
protocol)
•
Overdose – Intentional or unintentional intake of a dose of IP higher than the 
protocol-prescribed dose
•
Medication Error – An error made in prescribing, dispensing, administration, and/or use of 
an IP. For studies, medication errors are reportable to the sponsor only as defined below.
Cases of subjects missing doses of the IP 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 IP should be considered as a reportable medication 
error.
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 do 
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.
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Appendix 3.11 Regulatory Authority, Institutional Review Board, Ethics Committee, and 
Site Reporting
The sponsor or designee is responsible for reporting all SUSARs and any other applicable SAEs 
to regulatory authorities, investigators, and ECs/institutions as applicable, in accordance with 
national regulations in the countries where the study is conducted. The sponsor will also prepare 
an expedited report for other safety issues where these might materially alter the current 
benefit-risk assessment of an investigational medicinal product or that would be sufficient to 
consider changes in the investigational medicinal products administration or in the overall 
conduct of the trial. In addition, the sponsor is responsible for notifying active sites of all related, 
unexpected SAEs occurring during all interventional studies across the ADYNOVATE program.
The investigator is responsible for notifying the local IRB/EC of all safety reports or significant 
safety findings that occur at his or her site as required by IRB/EC procedures and applicable 
safety regulations (see Appendix 1.5).
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Appendix 4 SCALES AND ASSESSMENTS
The following scale/assessment will be utilized in this study:
Full Title of Scale/Assessment
Version Number
Date Issued
European Quality of Life 
Questionnaire in 5 dimensions 
(EQ-5D)
EQ-5D 5-level version (EQ-5D-5L)
30 Nov 2021
A separate master file containing the scale/assessment listed above will be provided to the site. 
Updates to scale/assessment during the study (if applicable) will be documented in the table 
above and a new master file containing the revised scale/assessment will be provided to the site.
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Appendix 5 ABBREVIATIONS
Abbreviation
Definition
ABR
annualized bleeding rate
AE 
adverse event
ALT
alanine aminotransferase
aPTT
activated partial thromboplastin time
AST
aspartate aminotransferase 
AUC
area under the concentration versus time curve between defined 
timepoints
BU
Bethesda unit(s)
BUN
blood urea nitrogen
CHO
Chinese hamster ovary
CI
confidence interval
CL
clearance
Cmax
maximum concentration
Cpredose
predose concentration
COVID-19
coronavirus disease of 2019
CRA
clinical research associate
CRO
contract research organization
EC
ethics committee
eCRF
electronic case report form
ED
exposure day
eDiary
electronic diary
EHL
extended half-life
ELISA
enzyme-linked immunosorbent assay
EMA
European Medicines Agency
ePRO
electronic patient-reported outcome 
EQ-5D-5L
European Quality of Life Questionnaire in 5 dimensions 5-level 
version
EUDRACT
European Union clinical trials database
FAS
full analysis set
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Abbreviation
Definition
FDA
Food and Drug Administration 
FIX
factor IX
FVIII
factor VIII
GCP
Good Clinical Practice
GHEA
Global Hemostatic Efficacy Assessment
HCV
hepatitis C virus
HIV
human immunodeficiency virus
HRQoL
health-related quality of life
IB
investigator’s brochure
ICF
informed consent form
ICH
International Council for Harmonisation
IND
investigational new drug
INR
international normalized ratio
IP
investigational product
IR
incremental recovery
IRB
institutional review board
IU
international units
MRT
mean residence time
NCA
noncompartmental analysis
PEG
polyethylene glycol
PK
pharmacokinetic(s)
PK AS
pharmacokinetic analysis set
PK FAS
pharmacokinetic full analysis set
PPAS
per protocol analysis set
pRBC
packed red blood cell
PRO 
patient-reported outcome
PT
preferred term
PTP
previously treated patient
PUP
previously untreated patient
rFVIII
recombinant human coagulation factor VIII
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Abbreviation
Definition
RSI
reference safety information
SAE
serious adverse event
SAP
statistical analysis plan
SA set
safety analysis set
SD
standard deviation
SOC
system organ class
SUSAR
suspected unexpected serious adverse reaction
SWFI
sterile water for injection
T1/2
half-life
UADE
unanticipated adverse device effect
TEAE
treatment-emergent adverse event
ULN
upper limit of normal
US
United States
V
volume of distribution
VWF
von Willebrand factor
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Appendix 6 PROTOCOL HISTORY 
Document
Date
Amendment Type
Global/Country/Site Specific
Amendment 1
16 Apr 2023
Non-substantial
China
Original Protocol
21 Jun 2022
Not applicable
China
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