RIXUBIS Drug Use-Result Survey (Japan)
Conditions: Hemophilia B
Sponsor: Baxalta now part of Shire

 
 
Title: RIXUBIS Drug Use-Result Survey (Japan) 
 
NCT Number: NCT02937831 
Protocol Approve Date: 01-Oct-2020 
 
Certain information within this protocol has been redacted (ie, specific content is 
masked irreversibly from view with a black bar) to protect either personally identifiable 
information or company confidential information. 
 
Note; This document was translated into English as the language on original version 
was Japanese. 

RIXUBIS 
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Protocol Identifier: 251601 
 
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DRUG USE-RESULT SURVEY 
PRODUCT: RIXUBIS 
PROTOCOL IDENTIFIER: 251601 
VERSION 4.0: 2020 Oct 01 
 
 
MARKETING 
AUTHORISATION 
HOLDER 
Takeda Pharmaceutical Company Limited 
4-1-1 Dosho-machi Chuo-ku, Osaka 
Japan 
 
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RIXUBIS 
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Protocol Identifier: 251601 
 
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SUMMARY OF CHANGES 
 
Protocol Amendments 
Summary of Change(s) since Last Version of Approved Protocol 
Amendment Number 
4 
Amendment Date 
01 Oct 2020 
 
Description of Change 
Section(s) Affected by Change 
MAH for RIXUBIS changed from Shire Japan KK to 
Takeda Pharmaceutical Company Limited 
Cover page 1 
Address changed to 
Takeda Pharmaceutical Company Limited 
4-1-1 Dosho-machi Chuo-ku, Osaka Japan 
Cover page 1 
Version number changed 
Cover page 1 
Delete outsourcing 
Section 3.9 Outsource Details 
 
See Appendix 2 for protocol history, including all amendments 
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RIXUBIS 
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TABLE OF CONTENTS 
SUMMARY OF CHANGES ............................................................................................ 2 
1. PURPOSE ...................................................................................................................... 4 
2. SAFETY SPECIFICATION ........................................................................................ 4 
3. PROTOCOL .................................................................................................................. 4 
3.1 Estimated number of patients in the survey and the rational ............................ 4 
3.2 Targeted patients .................................................................................................... 4 
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 ............................................................. 9 
3.8 Organization Structure for Surveillance ............................................................ 10 
3.9 Outsource Details .................................................................................................. 10 
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 .............................. 11 
6. OTHER NECESSARY MATTERS .......................................................................... 11 
APPENDIX 1 ................................................................................................................... 12 
APPENDIX 2:  PROTOCOL HISTORY .................................................................... 14 
 
Tables 
Table 1: Hemostatic effectiveness ............................................................................ 12 
Table 2: In-surgery hemostatic effectiveness ........................................................... 12 
Table 3: Post-surgery hemostatic effectiveness ........................................................ 13 
 
 
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RIXUBIS 
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1. PURPOSE 
This survey will be conducted to understand the following items observed in the actual 
clinical use of RIXUBIS 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 effectiveness 
4. Occurrence of Factor IX inhibitor development in patients with coagulation factor 
IX deficiency (hereinafter hemophilia B) 
5. Safety and effectiveness for hemophilia B patients who received routine 
prophylactic therapy, on-demand therapy and perioperative therapy 
2. SAFETY SPECIFICATION 
1. Inhibitor development (Factor IX inhibitor) 
2. Shock, anaphylaxis 
3. Thromboembolism 
3. PROTOCOL 
3.1 Estimated number of patients in the survey and the rational 
Estimated number of subjects for the survey: 30 
Rational: There are currently about 250 hemophilia B patients who receive recombinant 
formulation of Factor IX in Japan. The expectation of the number of patients switching 
from current products to RIXUBIS is supposed to be limited while other new products 
are under development, resulting in the determining of the collectible subject number of 
30. Of note, the number is considered enough to retain 95% reliability for detecting 
unexpected adverse reactions with incidence of 10%. 
3.2 Targeted patients 
All patients with hemophilia B receiving RIXUBIS after its launching at medical 
institutions which contracted this investigation. 
Indications: Suppression of bleeding tendency in patients with factor IX deficiency. 
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Administration method and dosage: RIXUBIS is reconstituted with the attached 5 mL 
reconstitution diluent and administered by intravenous injection. Do not infuse any faster 
than 10 mL per minute. Normally, administer 50 international units per kg body weight 
per time. Adjust a dose based on a patient's condition. 
For routine dosing, normally administer 40-75 international units per kg body weight 
twice a week. For pediatric subjects under the age of 12 years, administer 40-
80 international units per kg body weight twice a week. 
3.3 Estimated number of centers (departments) 
Thirty departments (or centers) are expected to be involved nationwide, including 
pediatrics department, internal medicine (hematology) department and others. 
3.4 Survey Method 
This survey is conducted using paper-based case report forms (CRFs). The procedure is 
as follows. 
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 
 RIXUBIS 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. 
 The investigator registers all patients receiving RIXUBIS after its launching at 
medical institutions(in principle). 
The investigator will complete the required information for registration on case 
registration forms (site name, medical department name, physician’s name, site 
management patient number, sex, date of birth, starting  date of administration, 
EDs of other factor IX products before RIXUBIS administration  
(0-3, 4-50, 51-150, or >150 days), and send them to registration office for drug 
use surveillance office. 
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3. CRF collection and observation period during 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 i (Previously treated patients who had more than 4 previous exposure 
days to other products): One year after the beginning of RIXUBIS 
administration 
 PUPs (Previously untreated patients who had 3 or less previous exposure days 
to other products: Two years or 100 EDs after the beginning of RIXUBIS 
administration whichever comes first 
3.5 Estimated implementation period of the survey 
The surveillance period is as follows: 
Period of survey: June 2016 - May 2022 
Period of registration: June 2016 - May 2021 
Of note, if 30 subjects are successfully registered before the end of registration period, 
registration should be sustained as long as possible until the registration period ends. 
3.6 Items for investigation 
1. Patient demographics at the start of administration 
Identification number, gender, date of diagnosis (age), date of birth, 
congenital/acquired disease, family history of hemophilia, body height, body 
weight, inpatient/outpatient status, race, clinical severity of hemophilia (residual 
factor IX activity, date of measurement), annualized bleeding rate (ABR)ii, history 
of factor IX inhibitor measurement (date, value and result of measurement, date 
and value of peak inhibitor record), family history of inhibitor development, 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, hemophilic arthropathy, target 
joint, complication (including renal and hepatic complications), allergy, previous 
administration of other factor IX products (product name, EDs, regimens 
(prophylaxis, on-demand, prophylaxis/on-demand) 
2. Concomitant drugs and concomitant therapies 
 
i Includes MTPs - Minimally treated patients (>3 exposure days and less than 150 exposure days (Adults) 
and >3 exposure days and less than 50 exposure days (Pediatrics)) 
ii Patient diary and medical records will be used for the calculation of ABR. 
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3. Administration status of RIXUBIS 
In terms of the treatment during surveillance period of RIXUBIS, administration 
status and number of bleeding events will be investigated for regular replacement 
(prophylaxis) therapy, on-demand replacement therapy, and perioperative therapy. 
Prophylaxis therapy: 
administration period for prophylaxis, frequency of administration, body weight 
and date of measurement, dosage, total number of doses, number of doses to treat 
a bleed, numberiii of bleeding events will be collected. 
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. 
Perioperative therapy: 
Surgery (minor/major, operative method, date, diagnosis), administration period, 
body weight and date of measurement, loading dose, subsequent doses during 
procedure total number of doses, blood transfusion (product type, volume), total 
number of units, method of administration (administration rate, administration 
interval). 
4. Factor IX inhibitor titer 
Date of measurement, measured value, measurement method and others as well as 
inhibitor development during the surveillance period are investigated routinely. 
5. Discontinuations/withdrawals 
The timing and reasons for discontinuation/withdrawal will be investigated, if 
any. 
 
iii 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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6. Effectiveness of RIXUBIS 
The effectiveness of RIXUBIS is assessed every six months for regular 
replacement therapy and on-demand replacement therapy, respectively. Outcome 
measures are shown in the Appendix. 
7. Laboratory tests 
Review values which were voluntarily measured in any medical institution before 
the start of, and during RIXUBIS administration. In addition, review clinically 
significant abnormal fluctuation of the laboratory values that were measured in 
any medical institution at the end of any 6-month observation period or at the time 
of discontinuation/withdrawal during the maximum 2-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 RIXUBIS, 
presence of autopsy in death case. 
 Inhibitor to RIXUBIS 
 Date(s) of inhibitor detection 
 Date(s) of inhibitor disappearance 
 FIX inhibitor titer(s) 
 Other serious adverse events  
 Event 
 Onset Date 
 Stop Date 
 Severity 
 Disease progression 
 Outcome 
 Action Taken 
 Date of death (if applicable) 
 Cause of death (if applicable) 
 Causality assessment by Investigator 
 Incidence of non-serious adverse events coincident with use of RIXUBIS 
 Event/Type 
 Onset Date 
 Stop Date 
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 Severity 
 Progression 
 Outcome 
 Action Taken 
 Causality assessment by Investigator 
9. Additional investigation items at the onset of adverse events 
Upon the occurrence of inhibitor development, shock, anaphylaxis, 
thromboembolism and others or in the event of adverse drug reactions for which 
causal relationship to RIXUBIS cannot be denied, additional investigation will be 
conducted for the following items: 
Lot number of RIXUBIS, administration rate of RIXUBIS, 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. Subject 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 
b. Items related to Safety 
All patients, PTP/PUP 
c. Hemostatic efficacy 
 Prophylaxis: ABR  
 On-demand: hemostatic effectiveness, number of doses to treat a bleed 
 
 Surgery: In- and post-surgery hemostatic effectiveness 
Physician rated effectiveness (“none”, “moderate”, “good”, or “excellent”) 
2. Analysis method 
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Mainly, frequency tabulation is performed for classified data and summarization 
based on mean values and standard deviation is for sequential data. The detail is 
described in Statistics Analysis Plan. 
3.8 Organization Structure for Surveillance 
Same as described in Risk Management Plan 
3.9 Outsource Details 
Contractor for the operations 
IQVIA Services Japan KK 
Keikyu Dai-Ichi Building 4-10-8 Takanawa Minato-ku Tokyo 
Scope of the contract 
Registration center, progress management, data management, tabulation analysis, and 
others. 
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 suitable points 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. 
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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 
At the time of preparing regular safety report and applying the re-examination: 
For comprehensive consideration on safety information  
At the time of conducting interim analysis and preparing the final report 
Once information for 30 subjects is collected, an interim analysis will be conducted 
including comparison with the results of clinical trials. Then, necessity for continuing 
further CRF collection will be examined, the conclusion of which is to be reported to 
PMDA by attaching analysis results obtained at the completion of collecting 30-subject 
information or in other ways. 
6. OTHER NECESSARY MATTERS 
1. Revision of the protocol 
Necessity for revising the protocol will be examined based on new findings 
obtained as the surveillance proceeds, and the protocol will be revised as needed. 
2. Actions to be taken when issues or questions are raised 
Propose a hypothesis and then examine necessity of implementing specific drug 
use surveillance to test it, when occurrence of serious unexpected adverse drug 
reactions is suggested; when a large increase is found in frequency of adverse 
drug reactions; when any problem is found in terms of effectiveness or safety 
compared with the period until the approval of RIXUBIS; or, when occurrence of 
any abnormal adverse drug reactions is suggested. 
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APPENDIX 1 
Outcome Measure of Treatment Response 
Outcome is measured based on the following criteria by the physician/ the investigator or 
patients 
Table 1: Hemostatic effectiveness 
Excellent 
After a single infusion, complete disappearance of pain and objective decrease of bleeding 
symptom (swelling, tenderness, and increase in range of motion in musculoskeletal 
bleeding case) were observed. Additional infusion was not required for haemostasis. Of 
note, additional infusion for haemostasis maintenance has no impact on this assessment.  
Good 
After a single infusion, there were definitive relief of pain and improvement of bleeding 
symptom. In some circumstances, more than 1 infusion may be required for complete 
resolution.  
Fair 
After a single infusion, there were a probable or slight relief of pain and a mild 
improvement of bleeding signs. However, more than 1 infusion was required for complete 
resolution.  
Poor 
Improvement was not observed or symptom was aggravated. 
In case the subject required an additional infusion prior to the resolution of the bleed, 
effectiveness was to be assessed at 12 ± 1 and 24 ± 1 hours following the subsequent 
infusion, and/or at resolution of bleed, if prior to the 12 ± 1 or 24 ± 1 hour post-treatment 
time-point. If a bleed occurred following resolution of the bleed, this was to be 
considered a “new” bleed and recorded accordingly. 
Overall outcome in perioperative therapy  
Outcome is measured based on the following criteria by the physician performing the 
surgery or the investigator in charge of controlling hemostasis: 
Table 2: In-surgery hemostatic effectiveness 
Excellent 
Amount of bleeding is smaller than expected.  
Good 
Amount of bleeding is within the expected range 
Fair 
Amount of bleeding is greater than expected, with use of additional concomitant 
medication 
Poor 
Hemostasis difficulty. 
 
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Table 3: Post-surgery hemostatic effectiveness 
Excellent 
Sufficient control of hemostasis.  
Good 
Hemostasis controlled by increased dose 
Fair 
Hemostasis with the use of additional concomitant medication 
Poor 
Hemostasis difficulty. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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APPENDIX 2:  PROTOCOL HISTORY 
Document 
Date 
Comment 
Original Protocol/ Version 1.0 
20 MAY 2016 
Approved 
Version 2.0 
05 APR 2018 
Administrative changes to the 
protocol 
Version 3.0 
19 Mar 2019 
The extension of survey period 
and additional outsourcing 
Version 4.0 
01 Oct 2020 
MAH and outsource details 
change 
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