ADYNOVATE Drug Use-Results Survey
Conditions: Hemophilia A
Sponsor: Takeda

Clinical Study Protocol 
NCT Number: NCT03169972 
Title: ADYNOVATE Drug Use-Results Survey 
Study Number: 261601 
Document Version and Date: Version 6.0 / 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. 

DRUG USE-RESULTS SURVEY 
PRODUCT: ADYNOVATE 
PROTOCOL NUMBER: 261601 
VERSION 6: 23 Aug 2023 
Drug Name 
rurioctocog alfa pegol (recombinant) 
Marketing Authorization Holder 
Takeda Pharmaceutical Company Limited 
4-1-1 Dosho-machi Chuo-ku, Osaka, Japan
Version 
6.0 
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TABLE OF CONTENTS 
SUMMARY OF CHANGES .......................................................................................................... 2 
Table of Contents ............................................................................................................................ 3 
1. Purpose ........................................................................................................................................ 4 
2. Safety specification ..................................................................................................................... 4 
3. Implementation Plan for the Survey (draft) ................................................................................ 4 
3.1 Estimated number of patients in the survey and rationale .................................................... 4 
3.2 Target patients ....................................................................................................................... 5 
3.3 Estimated number of centers (departments) ......................................................................... 5 
3.4 Survey Method ...................................................................................................................... 5 
3.5 Estimated implementation period of the survey ................................................................... 6 
3.6 Items for investigation .......................................................................................................... 6 
3.7 Statistical Analysis and Analysis Method............................................................................. 8 
3.8 Organization Structure for Surveillance ............................................................................... 9 
3.9 Outsource Details .................................................................................................................. 9 
4. Additional measures to be possibly taken based on the results of the survey and decision
criteria for the initiation ................................................................................................................ 10 
5. Milestones for the implementation status of the survey and the assessment of the results, or
anticipated timing for reporting to pmda and the justification ..................................................... 10 
6. other necessary matters ............................................................................................................. 10 
APPENDIX:  PROTOCOL HISTORY ........................................................................................ 12 
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1. PURPOSE
This survey will be conducted to understand the following items in the actual clinical use of 
ADYNOVATE in patients: 
1)
Unexpected adverse drug reactions
2)
Occurrence of adverse drug reactions in the actual clinical use
3)
Factors that may affect safety and efficacy
4)
Occurrence of Factor VIII inhibitor development in patients with coagulation factor VIII
deficiency (hereinafter hemophilia A)
5)
Safety and efficacy for hemophilia A patients who received routine prophylactic therapy
and on-demand therapy
2. SAFETY SPECIFICATION
1)
Inhibitor development (Factor VIII inhibitor)
2)
Shock, anaphylaxis
3. IMPLEMENTATION PLAN FOR THE SURVEY (DRAFT)
3.1 Estimated number of patients in the survey and rationale
Estimated number of patients for the survey: 
-Previously treated patients (PTPs) with haemophilia A: 140 patients
-Previously untreated patients (PUPs) with haemophilia A: 25 patients
Rationale:
Of the patients with Haemophilia A in Japan, approximately 4000 receive genetically 
recombinant blood coagulation factors, of whom approximately 10% are expected to switch from 
the conventional preparation to ADYNOVATE in the period of 3 years after launching. 
However, launching and developments of other extended half-life recombinant human 
coagulation factor VIII (rFVIII) products for Haemophilia A have been progressing. The number 
of patients who are actually going to receive ADYNOVATE is expected to fall below 
approximately one-half of the estimated number described above. Therefore, the target patient 
number was set to 140 PTPs as the number of collectable cases for ADYNOVATE safety 
examination. For PUPs, statistics show the birthrate of Hemophilia A patients to be 1 out of 5000 
males ("Basics and Clinical of Hemophilia", Shirahata) and the number of annual male births to 
be 515,000 (Demographic Statistics 2015), providing an estimated annual number of births with 
Hemophilia A of 103. With a percentage of severe and moderate hemophilia A patients of 79.3% 
(2,137/2,696) (Nationwide Survey on Coagulation Disorders 2015), it is estimated that there are 
82 new patients receiving FVIII annually. However, the target number of PUPs for 3 years after 
approval of SNDA for pediatrics is estimated at approximately 10 % of the above –indicated 
number of patients treated with ADYNOVATE in view of the progress of clinical development 
or launch of similar products by competitors nowadays. 
 
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3.2 Target patients 
Hemophilia A patients who receive ADYNOVATE in the real world clinical setting are eligible 
for enrollment in this survey. This includes previously treated patients with Factor VIII 
deficiency (PTPs), and all previously untreated patients with Factor VIII deficiency (PUPs) who 
are treated with ADYNOVATE at the contracting medical institutions. 
ADYNOVATE will be used per the Japan prescribing information (PI). 
•
Indications: Suppression of bleeding tendency in patients with factor VIII deficiency.
•
Administration method and dosage: ADYNOVATE is reconstituted with 5 mL of the
attached reconstitution diluent and administered by slow intravenous injection. Do not
infuse any faster than 10 mL per minute.
Normally, administer 10 - 30 international units per kg per body weight per time. Adjust
the dose based on the patient’s condition.
For routine dosing, normally, for adults and children ≥ 12 years, administer 40-50
international units per kg body weight per time twice a week.  May increase a dose to 60
international units per kg body weight based on the patient’s condition.   For children <
12 years, administer 40-60 international units per kg body weight per time twice a week.
May increase a dose in the range not exceeding 80 international units per kg body weight
based on the patient’s condition.
3.3 Estimated number of centers (departments) 
Approximately 100 departments (or centers) are expected to be involved nationwide, including 
internal medicine (hematology) department and others. 
3.4 Survey Method  
This survey is conducted using EDC to collect data based on the following procedures: 
1) Request and contract of the survey
Medical representatives in the Company request medical institutions to conduct the
surveillance in writing after confirming the list below and conclude a contract.
•
There are physicians with experience in hemophilia therapy in the medical institution.
•
ADYNOVATE is planned to be used for patients who are targeted in this surveillance in
the medical institution.
Upon agreement of implementation of the drug use surveillance, the MAH will enter into 
agreement with the medical institution using a designated contract document. 
2) Registration of patient
The central registration procedure will be used in EDC system.
The investigators register PTPs receiving ADYNOVATE within approximately 3 months 
after the administration (in principle), and all PUPs receiving ADYNOVATE after its
 
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launching at participating medical institutions. 
The investigators will access to their designated sites of EDC system and complete the 
required information for registration. 
The registration form includes the following information; 
•
site management patient number
•
gender
•
date of birth
•
starting date of administration
•
EDs of other factor VIII products before ADYNOVATE administration (0-3, 4-50,
51-150, or >150 days)
3) CRF collection and observation period duration of the survey
The survey is conducted using multiple CRFs in parts with 6-month observation period per
CRF. The total observation period per subject is as follows.
• PTPs (Previously treated patients who had 4 or more days to other products): One year
after the beginning of ADYNOVATE administration
• PUPs (Previously untreated or minimally treated patients who had 3 or less previous
exposure days to other products): Two years after the beginning of ADYNOVATE
administration
3.5 Estimated implementation period of the survey 
The surveillance period is as follows: 
•
Estimated Period of survey:  February 1st, 2017 to January 31st, 2023
•
Estimated period of registration:  February 1st , 2017 to January 31st,  2022
3.6 Items for investigation 
1) Patient demographics at the start of administration
Pregnancy status (in case of female), body height, body weight, inpatient/outpatient status,
race, past history of serious bleeding episode (date, hemorrhage intracranial, gastrointestinal
hemorrhage, bleeding into the iliopsoas muscle and others), past surgical history (surgery
name, surgery date), other past history(HCV etc.), hemophilic arthropathy, target joint,
complication (including renal and hepatic complications), allergy, date of diagnosis (age),
congenital/acquired disease, family history of hemophilia, clinical severity of hemophilia
(residual factor VIII activity, date of measurement), annualized bleeding rate (ABR)i,
history of factor VIII inhibitor  measurement (date, value and result of measurement, date
and value of peak inhibitor record), family history of inhibitor development, previous
administration of other factor VIII products (product name, regimens (prophylaxis, on-
demand, prophylaxis/on-demand)
i Patient diary and medical records will be used for the calculation of ABR. 
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2) Concomitant drugs and concomitant therapies
3) Administration status of ADYNOVATE
In terms of the treatment during surveillance period of ADYNOVATE, administration status
and number of bleeding events will be investigated for regular replacement (prophylaxis)
therapy, and on-demand replacement therapy.
Prophylaxis therapy: 
Administration period for prophylaxis, body weight and date of measurement, dosage, 
frequency of administration, total number of doses, purpose of prophylaxis* 
In case of bleeding during the prophylaxis therapy:  numberii of bleeding events(site and 
date), dosage, number of doses to treat a bleed. 
*Purpose of prophylaxis:
• Long-term prophylaxis: Therapy for the purpose of long term (at least 6 months of
duration) prevention of bleeding with dosing interval of more than once a week. Less
than 2 weeks of untreated periods may be allowed during 6 months.
• Short-term prophylaxis: Therapy for the purpose of relatively short term (less than
6 months of duration) prevention of bleeding with dosing interval of more than once a
week.
• Preventive treatment: dosing before events; sports, physical activities, rehabilitations,
etc. that may cause bleeding.
On-demand replacement therapy: 
Administration period for on-demand, body weight and date of measurement, dosage, 
number of doses to treat a bleed, number of bleeding events (site and date). 
4) Factor VIII inhibitor titer, plasma factor VIII levels
Date of measurement, measured value, and others as well as inhibitor development and
plasma factor VIII levels during the surveillance period are investigated routinely.
5) Discontinuations/withdrawals
The timing and reasons for discontinuation/withdrawal will be investigated, if any.
6) Efficacy of ADYNOVATE
The hemostatic effectiveness of ADYNOVATE for bleeding during prophylactic therapy
and on-demand replacement therapy is assessed in reference to Outcome measures of
Treatment Response are shown in the Attached Form. The number and the amount of given
doses before hemostasis was achieved. Change of target joints.
7) Laboratory tests
ii To enable the calculation of ABR, please record information about bleeding in a patient’s diary, etc. . if 
breakthrough bleeding occurs during the prophylaxis therapy. 
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Review values which were voluntarily measured in any medical institution before the start 
of, and during ADYNOVATE administration. In addition, review clinically significant 
abnormal fluctuation of the laboratory values that were measured in any medical institution 
at the end of any X-month observation period or at the time of discontinuation/withdrawal 
during the maximum X-year of a total observation period, if any. 
8) Adverse Events
Adverse event name, onset date, seriousness, severity, presence of treatment, treatment
details, outcome, outcome date, causal relationship to ADYNOVATE, presence of autopsy
in death case.
• Inhibitor to FVIII
Date(s) of inhibitor detection 
Date(s) of inhibitor disappearance 
FVIII inhibitor titer(s) 
• Other adverse events
Event 
Onset Date 
Stop Date 
Seriousness (and seriousness criteria) 
Severity 
Disease progression (if applicable) 
Outcome 
Action Taken 
Date of death (if applicable) 
Cause of death (if applicable) 
Causality assessment by Investigator 
9) Additional investigation items at the onset of adverse events
Upon the occurrence of inhibitor development or events such as anaphylactic shock, or
anaphylaxis additional investigation will be conducted for the following items:
Lot number of ADYNOVATE, administration rate of ADYNOVATE, status of concomitant
drugs administration (concomitant drug name, whether suspected drug or not, administration
route, dosage form, dose, number of doses per day, administration period, reason for use),
concomitant therapies, re-administration of suspected drugs, clinical course of the case, etc.,
laboratory tests (if performed, including abnormal values with clinical significance)
3.7 Statistical Analysis and Analysis Method 
1. Analysis items
a. Patient population
Number of registered subjects, number of subjects whose CRFs are collected, number of 
subjects in safety analysis set, number of subjects in the effectiveness analysis set, 
number of withdrawal/discontinuation, reasons for and details of 
withdrawal/discontinuation, and others. 
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4. ADDITIONAL MEASURES TO BE POSSIBLY TAKEN BASED ON THE RESULTS
OF THE SURVEY AND DECISION CRITERIA FOR THE INITIATION
The Risk Management Plan will be reviewed at appropriate timepoints in consideration of the 
following: 
•
Necessity to modify risk minimization activities for the current safety investigation items
•
Necessity to modify the protocol (such as continuation of the surveillance and
implementation of additional surveillances), including necessity to add another safety
investigation item
•
Necessity to develop risk minimization measures for added safety investigation items, if
any
5. MILESTONES FOR THE IMPLEMENTATION STATUS OF THE SURVEY AND
THE ASSESSMENT OF THE RESULTS, OR ANTICIPATED TIMING FOR
REPORTING TO PMDA AND THE JUSTIFICATION
Milestones were set at the time of creating periodic safety update report and at application for re-
examination to assess comprehensive safety data. 
The milestones are the time points when the interim report and the final report are created. To 
conduct safety evaluation including the comparison with the clinical study results, as well as to 
consider whether any amendments are needed including the addition of the number of 
investigated cases to examine the safety of ADYNOVATE. 
6. OTHER NECESSARY MATTERS
1. Revision of the protocol
Based on new findings that may be obtained as the survey proceeds, the protocol will be
revised as necessary after considering whether or not amendment is needed.
2. Actions to be taken if issues or questions are found
A hypothesis will be established, and an implementation of specific use result survey will
be considered in order to verify that hypothesis when the occurrence of serious
unexpected adverse drug reaction is indicated, or a significant increase in frequency of
adverse drug reaction is found, or any issues in efficacy and safety are found as compared
with the period prior to the approval, or the occurrence of heterogeneous adverse drug
reaction is indicated.
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Attached Form 
Outcome Measure of Treatment Response 
Outcome is measured based on the following criteria by the physician 
Table: Hemostatic Effectiveness 
Excellent 
Full relief of pain and cessation of objective signs of bleeding (e.g., swelling, tenderness, and 
decreased range of motion in the case of musculoskeletal hemorrhage) 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. 
Poor 
 No improvement or condition worsens 
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