Adynovate Special Drug Use Result Survey (Perioperative Administration)
Conditions: Hemophilia A
Sponsor: Takeda

Clinical Study Protocol 
NCT Number: NCT04941898 
Title: ADYNOVATE SPECIAL DRUG USE RESULT SURVEY (Perioperative 
Administration) 
Study Number: TAK-660-5002 
Document Version and Date: Version 4 / 23-Aug-2023 
Certain information within this document has been redacted (ie, specific content is 
masked irreversibly from view) to protect either personally identifiable information or 
company confidential information. 
A summary of changes to previous protocol versions is appended to the end of the 
document. 
Note; This document was translated into English as the language on original version 
was Japanese. 

PROTOCOL FOR SPECIAL DRUG USE RESULT 
SURVEY 
ADYNOVATE SPECIAL DRUG USE RESULT 
SURVEY 
(Perioperative Administration) 
Sponsor 
Takeda Pharmaceutical Company Limited 
Protocol No.
TAK660-5002 
Version No.
4  
Date of 
preparation 
23 August 2023
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TABLE OF CONTENTS 
 
BACKGROUND OF THE SURVEY................................................................................................. 1 
 
OBJECTIVE ....................................................................................................................................... 1 
 
SAFETY SPECIFICATIONS ............................................................................................................. 1 
 
PLANNED SAMPLE SIZE AND RATIONALE .............................................................................. 1 
 Planned Sample Size ........................................................................................................................ 1 
 Rationale ........................................................................................................................................... 1 
 
TARGET PATIENTS ......................................................................................................................... 1 
 
DOSAGE AND ADMINISTRATION ............................................................................................... 2 
 
PLANNED NUMBER OF MEDICAL INSTITUTIONS BY DEPARTMENT ................................ 2 
 
METHODOLOGY ............................................................................................................................. 2 
 Observation Period ........................................................................................................................... 2 
 Contract With Medical Institutions .................................................................................................. 2 
 Patient Registration Method ............................................................................................................. 2 
 Preparation and Submission of Survey Forms .................................................................................. 3 
 
PLANNED SURVEY PERIOD ......................................................................................................... 3 
 
SURVEY ITEMS ............................................................................................................................... 3 
 Patient Registration .......................................................................................................................... 3 
 Patient Background .......................................................................................................................... 4 
 Details of the Treatment ................................................................................................................... 4 
 Details of the Surgery ....................................................................................................................... 4 
 Efficacy Assessment ......................................................................................................................... 5 
 Test/Observation Items ..................................................................................................................... 5 
10.6.1 
Laboratory Tests ................................................................................................................. 5 
10.6.2 
Other Observations ............................................................................................................ 5 
 Adverse Events ................................................................................................................................. 5 
 
ANALYSIS ITEMS AND METHODS .............................................................................................. 7 
 Matters Related to Patient Disposition ............................................................................................. 7 
 Patient Background .......................................................................................................................... 7 
 Details of Treatment ......................................................................................................................... 7 
 Matters Related to Safety ................................................................................................................. 7 
11.4.1 
Occurrence of Adverse Events ........................................................................................... 7 
11.4.2 
Factors Expected to Affect the Safety ................................................................................ 7 
 Matters Related to Efficacy .............................................................................................................. 7 
11.5.1 
Hemostatic Efficacy ........................................................................................................... 8 
 
REGISTRATION OF SURVEY INFORMATION............................................................................ 8 
 
ORGANIZATIONAL STRUCTURE................................................................................................. 8 
 Organizational Chart for Operations for Postmarketing Surveillances ............................................ 8 
 
CONTRACT ORGANIZATIONS ..................................................................................................... 8 
 
MILESTONES FOR EVALUATION OF THE SURVEY IMPLEMENTATION STATUS AND 
RESULTS OBTAINED OR FOR REPORTING TO THE PHARMACEUTICALS AND 
MEDICAL DEVICES AGENCY AND THEIR RATIONALES....................................................... 8 
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ADDITIONAL MEASURES THAT MAY BE TAKEN ON THE BASIS OF THE SURVEY 
RESULTS AND THE CRITERIA FOR THE INITIATION ............................................................. 8 
 
OTHER NECESSARY INFORMATION .......................................................................................... 8 
 Revision of the Protocol ................................................................................................................... 8 
 Measures to Be Taken in Case of Any Problem or Question ........................................................... 9 
 
 
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1 
 
 
BACKGROUND OF THE SURVEY 
This special drug use result survey (hereinafter, “this survey”) has been planned to 
investigate the safety and efficacy of Adynovate Intravenous (hereinafter, “Adynovate”) 
administered perioperatively under actual use conditions in routine clinical practice 
although no specific safety issues were identified in the phase 3 clinical study (Study 
261204) of Adynovate investigating the efficacy and safety of a PEG-rFVIII (pegylated, 
full-length, recombinant coagulation factor VIII) product (BAX855) when administered 
perioperatively in patients with severe hemophilia A. This survey will be conducted in 
compliance with the Good Post-marketing Study Practice Ordinance (GPSP) Ordinance 
and related regulatory requirements. 
 
 
OBJECTIVE 
To investigate the safety and efficacy of Adynovate administered in the perioperative 
period of surgeries or other invasive procedures such as tooth extractions under actual 
clinical use conditions. 
 
 
SAFETY SPECIFICATIONS 
Development of inhibitors, shock, and anaphylaxis 
 
 
PLANNED SAMPLE SIZE AND RATIONALE 
 
Planned Sample Size 
10 patients (However, 15 surgeries are planned to be included.) 
* Patient registration at each site will be continued until the end of the patient registration 
period even after the target number of patients is reached. 
 
 
Rationale 
Although there are limited national statistics on the number and details of surgeries 
performed in patients with hemophilia, the number of surgeries performed in patients 
with hemophilia A was estimated to be approximately 120 per year using a commercial 
database. On the basis of the above data and in consideration of the patient registration 
period as well as the estimated share of Adynovate (approximately 7%) for perioperative 
administration, the target sample size was set at “10 patients.” 
In “Advate Special Drug Use Result Survey for Perioperative Administration (Including 
Tooth Extractions),” data on 74 surgeries in 58 patients were collected, including 11 
surgeries in patients aged under 12 years. It is therefore estimated that data on 
approximately 2 patients aged under 12 years and 15 surgeries (11 major and 4 minor 
surgeries) can be collected from the planned 10 patients. 
 
 
TARGET PATIENTS 
Patients with coagulation factor VIII (hereinafter, “FVIII”) deficiency who received 
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Adynovate for surgery/procedure on or after the start date of this survey 
 
 
DOSAGE AND ADMINISTRATION 
Adynovate to be dissolved in 5 mL of the supplied diluent, and slowly injected 
intravenously. The infusion rate should not exceed 10 mL/min. 
The usual dosage is 10 to 30 IU/kg body weight per dose. The dosage may be adjusted 
according to the patient's condition. 
< Precautions for Dosage and Administration > 
For perioperative use, the dose and dosing frequency should be adjusted to maintain 
FVIII at the required or higher level depending on the surgery/procedure.  
 
Approximate Dose and Dosing Frequency in the Perioperative Period 
Type of Surgery 
Required FVIII 
Level 
(% or IU/dL) 
Dose 
(IU/kg) 
Dosing Frequency 
Minor 
Including tooth 
extractions 
30-60 
15-30 
Repeat every 8-24 hours 
until the bleeding is resolved 
Major 
Intracranial, intra- 
abdominal, or 
intrathoracic surgery, 
joint replacement surgery 
80-100 
40-50 
Repeat every 8-24 hours 
until wound healing 
Refer to the package insert. 
 
 
PLANNED NUMBER OF MEDICAL INSTITUTIONS BY DEPARTMENT 
Department of Hematology, Department of Pediatrics, and other departments 
Approximately 10 medical institutions 
 
 
METHODOLOGY 
 
Observation Period 
From the start to completion of perioperative management, *1 in principle 
*1 Perioperative management: Management from administration before, during, and after 
the surgery to completion of the surgical treatment. 
 
 
Contract With Medical Institutions 
Prior to the conduct of this survey, Takeda Pharmaceutical Company Limited will 
conclude a written contract with medical institutions. 
 
 
Patient Registration Method 
Patients will be registered through a “central registration system” by fax. 
For patients who were prescribed Adynovate, the investigator/subinvestigator will send 
the “Patient Registration Form” to the central registration center by fax by Day 30 after 
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the start of Adynovate administration for perioperative management (with the day of the 
initial administration of Adynovate defined as “Day 0” and the next day defined as 
“Day 1”), in principle. Note that a patient may be registered retrospectively if he/she 
meets the conditions shown in “5.0 Target Patients” even if the patient has received 
Adynovate for surgery/procedure at a contract medical institution before concluding the 
contract. If Adynovate is used for a different surgery/procedure in the same patient, the 
use will be newly registered as a separate episode (1 episode/time). 
(For example, if 1 patient undergoes 2 surgeries using Adynovate, 2 episodes will be 
registered in 1 patient.) 
 
 
Preparation and Submission of Survey Forms 
Paper survey forms will be used to collect information. 
Investigators/subinvestigators will prepare survey forms for all registered patients 
promptly after necessary observation. If perioperative administration of Adynovate 
cannot be documented because of prior cancellation of surgery, this should be described. 
(No entry is required for the subsequent items.) 
If an adverse event leads to discontinuation of Adynovate during the observation period, 
observation should be continued to the extent feasible after discontinuation of 
administration until resolution of the adverse event, and the survey form should be 
prepared. 
The investigator will sign or affix the name and seal on the survey forms to ensure the 
accuracy and reliability of the data in the survey forms and promptly submit them to 
Takeda Pharmaceutical Company Limited. 
 
 
PLANNED SURVEY PERIOD 
Survey period: June 2021 to 31 December 2023 
Patient registration period: June 2021 to 31 August 2023 
Survey completion date (final analysis completion date): February 2024 (planned) 
 
 SURVEY ITEMS 
Investigators/subinvestigators will enter the following information in the patient 
registration form and survey form:  
 
 Patient Registration 
1) Survey items 
Patient identification number (optional), sex, date of birth or age (at the start of 
perioperative management with Adynovate), (planned) start date of administration of 
Adynovate for perioperative management, and name of the (planned) surgery 
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(If the same patient is registered for the second time or later in this survey, the 
previous patient identification number [optional] or the [planned] start date of 
administration of Adynovate for the previous perioperative management) 
2) Timing of the survey 
At the time of patient registration 
 
 Patient Background 
1) Survey items 
Height, body weight, complications (presence/absence and details), medical history 
(presence/absence and details), predisposition to hypersensitivity (presence/absence 
and details), history of surgery (presence/absence and details), pregnancy status 
(women only), time of diagnosis of hemophilia A, severity of hemophilia A, family 
history of hemophilia A (presence/absence and details), history of development of 
FVIII inhibitors, history of administration of Adynovate before the perioperative 
management, and (latest) hemophilia A treatment before the start of perioperative 
management (presence/absence and details) 
2) Timing of the survey 
At the start of perioperative management 
 
 Details of the Treatment 
1) Survey items 
Status of administration of Adynovate (timing of administration, method of 
administration, dose, date and time of treatment initiation, and date and time of 
treatment completion [or discontinuation]), status of administration of FVIII 
formulations other than Adynovate or bypassing drug products (presence/absence and 
details), and status of treatment with concomitant drugs (other than FVIII 
formulations or bypassing drug products; presence/absence, name of drug product, 
and purpose of treatment) 
2) Timing of the survey 
From the start of perioperative management to the completion of perioperative 
management (or discontinuation of treatment) 
 
 Details of the Surgery 
1) Survey items 
Diagnosis of the disease requiring surgery, operative technique (details of the 
surgery), type of surgery (major/minor surgery: see Appendix 1), whether or not the 
surgery is scheduled (emergency/elective surgery), date and time of the surgery, 
amount of bleeding during surgery, blood transfusion (presence/absence and details), 
and drainage (presence/absence and details) 
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2) Timing of the survey 
At the time of the surgery 
 
 Efficacy Assessment 
1) Survey items 
Evaluation of hemostatic efficacy (see Appendix 2) 
2) Timing of the survey 
During surgery, on postoperative Day 1, and at completion of perioperative 
management (or at discontinuation of administration) 
 
 Test/Observation Items 
Information will be entered in the survey form when each test/observation is performed 
at each timing of survey under actual use conditions in routine clinical practice. 
 
10.6.1 Laboratory Tests 
1) Test items 
FVIII activity (FVIII:C), FVIII inhibitors, and FVIII recovery 
2) Timing of the survey 
Before the start of perioperative management, from the start of perioperative 
management to the time of testing upon completion of perioperative management (or 
discontinuation of treatment) 
 
10.6.2 Other Observations 
1) Observation items 
Date of completion of perioperative management (or discontinuation of treatment) and 
reason for discontinuation of treatment (in the case of premature discontinuation) 
2) Timing of the survey 
At the completion of perioperative management (or discontinuation of treatment) 
 
 Adverse Events 
1) Survey items 
Presence or absence of adverse events (see Table 1), adverse event terms, date of 
onset, seriousness and the reason for assessing as serious (see Table 2), cause of 
discontinuation of Adynovate, date of outcome assessment, outcome, causal 
relationship with Adynovate *2 (see Table 3) 
If the outcome is assessed as not recovered or unknown, a follow-up investigation 
should be performed to the extent feasible. 
*2 If the event is assessed as unrelated to Adynovate, the rationale for that assessment will be 
collected. 
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2) Timing of the survey 
From the start of perioperative management to the completion of perioperative 
management (or discontinuation of treatment) 
If the perioperative management period is short (eg, for tooth extractions), the 
presence/absence of adverse events will be observed until Day 30 after surgery, as a 
rule.  
 
Table 1 Definition of Adverse Events 
An adverse event (AE) is any untoward medical occurrence in a patient administered a 
pharmaceutical product. It need not have a causal relationship with this treatment. 
An AE can therefore be any unfavorable and unintended sign (including abnormal laboratory 
findings), symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product. 
AE: adverse event 
 
Table 2 Criteria for Assessment of Seriousness  
1. Results in death 
2. Is life-threatening 
The term “life-threatening” refers to an event in which the patient was at risk of death at the 
time of the event; it does not refer to an event which hypothetically might have caused death 
if it was more severe 
3. Requires inpatient hospitalization or prolongation of existing hospitalization 
(hospitalization/prolongation of hospitalization) 
4. Results in persistent or significant disability/incapacity (disability) 
5. Results in congenital anomaly/birth defect (congenital anomaly) 
6. May not be immediately life-threatening or result in death or hospitalization but may require 
intervention to prevent one of the outcomes listed in 1 to 5 above or may jeopardize the 
patient 
* If an AE listed in the “Takeda Medically Significant AE List” is reported, Takeda 
Pharmaceutical Company Limited will handle it as a serious adverse event. 
AE: adverse event 
 
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11.5.1 Hemostatic Efficacy 
Assessments of hemostatic efficacy (see Appendix 2) during surgery, after surgery, and 
on Day 1 and later after surgery (at the completion of perioperative management on 
Day 1 after surgery or later [or at discontinuation of treatment]) will be tabulated. 
 
 REGISTRATION OF SURVEY INFORMATION 
Information about this survey will be registered on the following public websites prior to 
the start of this survey: 
 Japan Registry of Clinical Trials 
 Clinical trials registry system of the National Institutes of Health (ClinicalTrials.gov) 
 
 ORGANIZATIONAL STRUCTURE 
 Organizational Chart for Operations for Postmarketing Surveillances 
See Appendix. 
 
 CONTRACT ORGANIZATIONS 
(1) 
 
 
Responsibilities: Operations of the central registration center, data management 
operations, storage of records, support operations related to 
postmarketing surveillance, and medical writing operations 
(2) 
 
 
Responsibilities: Operations related to monitoring 
(3) 
 
 
Responsibilities: Statistical analysis operations 
 
 MILESTONES FOR EVALUATION OF THE SURVEY IMPLEMENTATION 
STATUS AND RESULTS OBTAINED OR FOR REPORTING TO THE 
PHARMACEUTICALS AND MEDICAL DEVICES AGENCY AND THEIR 
RATIONALES 
Refer to “2. Summary of Pharmacovigilance Plan” in the risk management plan. 
 
 ADDITIONAL MEASURES THAT MAY BE TAKEN ON THE BASIS OF THE 
SURVEY RESULTS AND THE CRITERIA FOR THE INITIATION 
Refer to “2. Summary of Pharmacovigilance Plan” in the risk management plan. 
 OTHER NECESSARY INFORMATION 
 Revision of the Protocol 
This protocol will be reviewed and revised if necessary as the following information is 
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collected during the implementation period: progress status, occurrence of adverse 
reactions and serious adverse reactions that cannot be predicted from the precautions, 
whether the incidence of specific adverse reactions increases, appropriateness of survey 
items, and other data. If, for example, partial changes in dosage and administration or 
indications are approved during the implementation period, the necessity of the revision 
of this protocol will be discussed as needed and it will be revised if necessary. 
 
 Measures to Be Taken in Case of Any Problem or Question 
If case of any problem in the safety or efficacy, the data will be closely examined and 
appropriate measures will be considered. 
 
 
 
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APPENDIX 1 DEFINITIONS OF TYPES OF SURGERY 
Surgical procedures are deemed as major or minor on the basis of the following definitions 
and examples:  
 
Table 4 Definitions and Examples of Types of Surgery 
Type 
Definition 
Example 
Major 
 A surgery that is expected to take more 
than 3 days from the 
surgery/intervention to hemostasis or 
recovery 
 A surgery requiring moderate or deep 
sedation, general anesthesia, or major 
conduction block to ensure patient 
comfort 
 Major orthopedic surgery (eg, joint 
replacement) 
 Major abdominal surgery 
 Intracranial surgery 
 Cardiovascular surgery 
 Other surgeries including those with a 
high risk of major blood loss or blood 
influx into anatomically closed zones 
Minor 
 A surgery that is expected to take not 
more than 3 days from the 
surgery/intervention to hemostasis or 
recovery 
 A surgery that can be safely and 
comfortably performed with minimal 
preoperative medication or 
intraoperative sedation for patients under 
local or surface anesthesia 
 Skin lesion removal 
 Arthroscopy and arthroscopic surgery (eg, 
synovectomy) 
 Simple dental procedures or tooth 
extractions 
 Placement and/or removal of central 
venous catheter 
 Synoviorthesis and arthrocentesis 
 
 
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APPENDIX 2 CRITERIA FOR EFFICACY ASSESSMENT 
Intraoperative hemostatic efficacy (see Table 5), postoperative hemostatic efficacy (see 
Table 6), and hemostatic efficacy at the completion of perioperative management on 
postoperative Day 1 and later (see Table 7) will be evaluated.  
 
Table 5 Rating Scale for Intraoperative Hemostatic Efficacy 
Rating 
Criteria 
Excellent 
Intraoperative blood loss is equal to or less than (≤100%) the values expected for a 
non-hemophilic patient population undergoing the same type of procedure. 
Good 
Intraoperative blood loss is increased by up to 50% (101%-150%) compared with 
the values expected for a non-hemophilic patient population undergoing the same 
type of procedure. 
Fair 
Intraoperative blood loss is increased by more than 50% (>150%) compared with 
the values expected for a non-hemophilic patient population undergoing the same 
type of procedure. 
Poor 
Proper administration of the product fails to provide sufficient therapeutic effect, and 
bleeding does not stop. Rescue therapy with Advate *3 or other replacement therapy 
is required. 
*3 Administration of FVIII products other than Adynovate or bypassing agents required for adequate 
hemostasis. 
 
Table 6 Rating Scale for Postoperative Hemostatic Efficacy (Postoperative Day 1) 
Rating 
Criteria 
Excellent 
Postoperative hemostatic efficacy of Adynovate is at least as good as that expected 
for a non-hemophilic patient population undergoing the same type of surgical 
procedure. 
Good 
Postoperative hemostatic efficacy of Adynovate is probably as good as that expected 
for a non-hemophilic patient population undergoing the same type of surgical 
procedure. 
Fair 
Postoperative hemostatic efficacy of Adynovate is apparently inadequate compared 
with comparable procedures, although postoperative hemostasis is maintained. 
Rescue therapy with Advate or other replacement therapy is not required. 
Poor 
Proper administration of the product fails to provide sufficient therapeutic effect, and 
bleeding does not stop. Rescue therapy with Advate or other replacement therapy is 
required. 
 
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Table 7 Rating Scale for Postoperative Hemostatic Efficacy (Upon Completion of 
Perioperative Management [or Discontinuation of Treatment]) 
Rating 
Criteria 
Excellent 
Hemostatic efficacy of Adynovate on postoperative Day 1 and later is at least as 
good as that expected for a non-hemophilic patient population undergoing the same 
type of surgical procedure. 
Good 
Hemostatic efficacy of Adynovate on postoperative Day 1 and later is probably as 
good as that expected for a non-hemophilic patient population undergoing the same 
type of surgical procedure. 
Fair 
Hemostatic efficacy of Adynovate on postoperative Day 1 and later is apparently 
inadequate compared with comparable procedures, although postoperative 
hemostasis is maintained. Rescue therapy with Advate or other replacement therapy 
is not required. 
Poor 
Proper administration of the product fails to provide sufficient therapeutic effect, and 
bleeding did not stop on postoperative Day 1 and later. Rescue therapy with Advate 
or other replacement therapy is required. 
 
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Document History 
 
Version 
Date 
Comments 
original version 
2021/06/30 
New document 
2nd version 
2021/07/21 
Minor changes to “10.1 Patient Registration” 
3rd version 
2023/05/15 
Minor changes to “13.0 ORGANIZATION STRUCTURE,” 
addition to “14.0 CONTRACT ORGANIZATIONS,” and the 
attachment of Appendix 2 
4th version 
2023/08/23 
The addition of the survey completion date (final analysis 
completion date) to “9.0 PLANNED SURVEY PERIOD” and 
minor changes to “14.0 CONTRACT ORGANIZATIONS” 
 
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