Agrylin Capsules 0.5 mg Drug Use-Result Survey
Conditions: Essential Thrombocythemia (ET)
Sponsor: Takeda

Title: AGRYLIN Capsules 0.5mg Drug Use Results Survey 
NCT Number: NCT03625895 
Protocol Approve Date: 27-MAR-2019 
Certain information within this protocol has been redacted (ie, specific content is masked 
irreversibly from view with a black/blue bar) to protect either personally identifiable 
information or company confidential information. 
This may include, but is not limited to, redaction of the following: 

Named persons or organizations associated with the study.

Patient identifiers within the text, tables, or figures or in by-patient data listings.

Proprietary information, such as scales or coding systems, which are considered
confidential information under prior agreements with license holder.

Other information as needed to protect confidentiality of Takeda or partners,
personal information, or to otherwise protect the integrity of the clinical study.
If needed, certain appendices that contain a large volume of personally identifiable 
information or company confidential information may be removed in their entirety if it 
is considered that they do not add substantially to the interpretation of the data (eg, 
appendix of investigator’s curriculum vitae). 
Note; This document was translated into English as the language on original version 
was Japanese. 

AGRYLIN Capsules 0.5mg 
Drug Use Results Survey Protocol SHP422-406                                                Version 3.0 (Amendment 3)    
27 MAR 2019 
Shire 
 
1 
 
  
 
 
 
 
 
 
 
 
 
 
 
SHP422-406 
Protocol of drug use-result survey  
Shire Japan KK 
Ammendment3, 27 Mar 2019 
Ammendment2, 01 Apr 2018 
Amendment 1, 25 May 2017 
(Replaces Original, 30 Oct 2014) 
 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

AGRYLIN Capsules 0.5mg 
Drug Use Results Survey Protocol SHP422-406                                                Version 3.0 (Amendment 3)    
27 MAR 2019 
Shire 
 
2 
Table of Contents 
TABLE OF CONTENTS ...................................................................................................... 2 
1 
PURPOSE OF THE SURVEY ...................................................................................... 3 
2 
SAFETY ISSUE ............................................................................................................ 3 
3 
ESTIMATED NUMBER OF PATIENTS AND RATIONALE ..................................... 3 
3.1 
Target number of cases and rationale ................................................................... 3 
4 
TARGET PATIENT POPULATION............................................................................. 3 
5 
DOSAGE AND ADMINISTRATION ........................................................................... 3 
6 
PLANNED NUMBER OF CENTERS (DEPARTMENTS) WHICH WILL TAKE 
PART IN THE SURVEY .............................................................................................. 3 
7 
SURVEYING METHOD .............................................................................................. 3 
8 
ESTIMATED DURATION OF THE SURVEY ............................................................ 6 
9 
WHAT IS INVESTIGATED IN THE SURVEY ........................................................... 6 
9.1 
Items for investigation ......................................................................................... 6 
9.2 
Important items for investigation ......................................................................... 8 
10 ITEMS FOR ANALYSIS AND THE ANALYSIS METHOD ....................................... 8 
11 ORGANIZATION FOR IMPLEMENTING THE SURVEY ......................................... 9 
12 NAME AND ADDRESS OF TRUSTEE ....................................................................... 9 
13 ADDITIONAL MEASURES WHICH MAY BE TAKEN DEPENDING ON THE 
OUTCOME OF THE SURVEY AND THE DECISION CRITERIA FOR INITIATING 
THE MEASURES ....................................................................................................... 10 
14 MILESTONES FOR THE IMPLEMENTATION OF THE SURVEY AND THE 
ASSESSMENT OF THE RESULTS, OR REPORTING TO THE PMDA, AND THE 
JUSTIFICATION ........................................................................................................ 10 
15 OTHER NECESSARY ITEMS ................................................................................... 10 
APPENDIX 1 
VERSION HISTORY .............................................................................. 11 
 
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AGRYLIN Capsules 0.5mg 
Drug Use Results Survey Protocol SHP422-406                                                Version 3.0 (Amendment 3)    
27 MAR 2019 
Shire 
 
3 
1 
Purpose of the Survey 
The objectives of this survey are to collect data to evaluate the safety and efficacy of Agrylin  
(anagrelide hydrochloride) in the post-marketing phase in patients diagnosed with Essential 
Thrombocythemia (ET).  
Data will be collected to address the following specifications:  
• Safety data from real life experience. 
• Efficacy in real life experience  
 
2 
Safety issue 
Use of Agrylin in patients with cardiac disorders, QT/QTc prolongation, blood toxicity, 
thrombohaemorrhagic events, interstitial lung disease, headache and use in patients with 
hepatic function disorders. 
3 
Estimated Number of Patients and Rationale  
3.1 
Target number of cases and rationale 
Target number of cases: 474 cases 
 
It is estimated that there will be 474 patients prescribed this drug at the end of the second year 
of marketing which is adequate to potentially observe with 95% confidence interval common 
events that occur classified as important investigation items in this all-case survey except less 
common events such as ILD or some cardiac disorders (e.g. Torsade de pointes).  
 
4 
Target patient population  
- 
All cases who received treatment with Agrylin.  
 
5 
Dosage and Administration 
Appropriately administer the drug in accordance with description of package insert. 
6 
Planned number of centers (departments) which will take part in the survey 
All treatment centers who prescribe Agrylin will be approached to participate on the survey.  
Hematology centers: 450 sites 
Hematology Oncology centers: 286 of 450 sites 
Internal Medicine centers: 633 sites 
Total 1083 treatment centers 
7 
Surveying method 
Study methods employ a central enrollment system. The following steps will be completed: 
 
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AGRYLIN Capsules 0.5mg 
Drug Use Results Survey Protocol SHP422-406                                                Version 3.0 (Amendment 3)    
27 MAR 2019 
Shire 
 
4 
7.1. Request for investigation to Medical institutions 
(1) Medical representatives  will explain the purpose of the survey, targeted patients, 
investigation method, issues to be investigated, and the survey period etc. to the 
investigators at the medical institutions where Agrylin will be used, and make a 
request to the principal at the respective institutions (e.g. head of the hospital) to 
conduct the investigation.  A written contract must be executed.  
As a rule, Agrylin will be delivered to the medical institutions after the execution of 
the contract. If there is an urgent need for Agrylin to be administrated to the patient, 
and if Agrylin is delivered before the execution of the contract, the medical institution 
must comply with our request for a contract even after administration.  
(2) This survey shall comply with “Good post-marketing study practice (GPSP)” 
ordinance at all times during the implementation of the investigation after the contract 
entered into with each medical institution. 
 
7.2. Collection for the registration form and Case Report Forms (CRFs)  
(1) Registration form 
The investigation method is an all-case surveillance system. The investigators must 
populate the Registration Form with all required items (name of institution, name of 
department, name of investigator, patient identified number, start (expected) date of 
Agrylin) for all the patients who have been or will be prescribed Agrylin and, as a rule, 
the form must be sent to the registration center by FAX within 7 days from the start 
date of Agrylin.  
If there are patients who have already been prescribed Agrylin at the time the contract 
is executed, the investigator must register all cases and investigations retrospectively. 
Registration center  
FAX 
 
(Within the office of IQVIA Services Japan K.K.) 
 
Address 
4-10-18 Takanawa, Minato-ku, Tokyo 108-0074 Japan 
TEL：
 
 
(2) CRFs 
At dates 6 months and 12 months (the end of the survey or discontinuation of the 
survey) after the initiating treatment with Agrylin, the investigator completes the CRFs 
for all registered cases and promptly provides these to the Medical representatives. If a 
case is discontinued the survey cause of death etc, the investigator must record 
information until this point and promptly provide CRF to the Medical representatives. 
PPD
PPD
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AGRYLIN Capsules 0.5mg 
Drug Use Results Survey Protocol SHP422-406                                                Version 3.0 (Amendment 3)    
27 MAR 2019 
Shire 
 
5 
(3) Confirmation that all cases are registered  
After the registration period, the investigator must confirm that he/she completed 
registration forms for all cases who were administered Agrylin and complete the “All 
Cases Registered Confirmation Form” and provide it to the Medical representatives. 
This form is required once a year for confirmation of the registered patient in previous 
year. 
7.3. Report Adverse Events  
If adverse events (Adverse drug reactions/infections, subjective/objective symptoms, 
aggregated complications) occur after initiation of treatment with Agrylin, the investigator 
must contact the Medical representatives and record the details of the adverse event in the AE 
section of the CRF. The investigator must attempt to follow the case until the event is 
resolved and must confirm the outcome of the event. 
7.4. Schedule 
  
Registration 
Form 
Book 1 
Book 2 
Registration 
Additional 
Visit 
6 Month 
visit 
Additional 
Visit 
12 Month 
visit 
Patient identified number 
● 
● 
  
  
  
  
Patient initials 
● 
  
  
  
  
  
Date of birth (Age) 
● 
● 
  
  
  
  
Sex 
● 
● 
  
  
  
  
Race 
  
● 
  
  
  
  
Diagnosis of ET 
  
● 
  
  
  
  
JAK2 status 
  
● 
  
  
  
  
Testing for pathogenetic 
mutations 
  
● 
  
  
  
  
Bone marrow biopsies 
  
● 
  
  
  
  
Testing to rule out other 
hematological malignancies 
  
● 
  
  
  
  
Prior treatments for ET 
  
● 
  
  
  
  
Medical history/Complication 
  
● 
  
  
  
  
Echocardiogram (If Applicable) 
  
● 
● 
● 
● 
● 
Electrocardiogram (If 
Applicable) 
  
● 
● 
● 
● 
● 
Vital signs (Blood Pressure, 
Pulse) 
  
● 
● 
● 
● 
● 
Height 
  
● 
  
  
  
  
Weight 
  
● 
● 
● 
● 
● 
Pregnancy status (Urinalysis) 
  
● 
● 
● 
● 
● 
Administration status 
  
● 
● 
● 
● 
● 
Concomitant therapy 
  
● 
● 
● 
● 
● 
Safety (Adverse Event) 
  
● 
● 
● 
● 
● 
Efficacy (Platelet count) 
  
● 
● 
● 
● 
● 
Date of Discontinuation/ 
Reason for Discontinuation 
  
  
●  
●  
●   
●   
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AGRYLIN Capsules 0.5mg 
Drug Use Results Survey Protocol SHP422-406                                                Version 3.0 (Amendment 3)    
27 MAR 2019 
Shire 
 
6 
Important Items for 
investigation (Cardiac 
disorders, QT/QTc 
prolongation, 
Thrombohaemorrhage events,  
Interstitial lung disease）  
  
● 
● 
● 
● 
● 
 
 
8 
Estimated duration of the survey 
Planned implementation period of this survey is as follows 
1. Implementation period: from the approval to the approval condition regarding to all case 
survey is removed.  
2. Patient registration: from the approval to the approval condition regarding to all case 
survey is removed.  However, for all patients who were prescribed Agrylin prior to 31 
May, 2015 , all CRFs must be completed and included in the analysis. Patients who were 
prescribed Agrylin after 31 May, 2015, should be included in the analysis if CRF has 
already been completed.  After 31 May, 2015, it is planned that only patient registration 
will continue until the approval condition is removed.  All CRFs will be collected and 
fixed by 31, Dec, 2017. 
3. Observation period: efficacy and safety will be observed for 1 year.  
 
9 
What is investigated in the survey 
Safety and efficacy data that are available as part of routine clinical practices related to the 
treatment with anagrelide.  
9.1 
Items for investigation 
a. Information for patient identification (at survey entry) 
 
• Patient identified number 
• Patient initials 
 
b. Patient background 
 
• Date of birth 
• Sex  
• Race 
• Diagnosis  of ET 
• JAK-2 status 
• Testing for pathogenetic mutations 
• Bone marrow biopsies 
• Testing to rule out other hematological malignancies  
• 
Prior treatments for ET (including refractory or intolerant response) 
• 
Medical  history/Complication (including hepatic impairment, renal impairment, cardiac 
disorders, QT/QTc prolongation, thrombohaemorrhagic events and interstitial lung 
disease) 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

AGRYLIN Capsules 0.5mg 
Drug Use Results Survey Protocol SHP422-406                                                Version 3.0 (Amendment 3)    
27 MAR 2019 
Shire 
 
7 
• 
Echocardiogram (If Applicable) 
• 
Electrocardiogram (If Applicable) 
• Vital signs (Blood Pressure, Pulse) 
• Height 
• Weight 
• Pregnancy status (Urinalysis) 
 
c. Each visit 
• Echocardiogram (If Applicable) 
• Electrocardiogram (If Applicable) 
• Vital signs (Blood Pressure, Pulse) 
• Weight 
• Pregnancy status (Urinalysis) 
 
d. Administration status 
 
• Record the details of the initial dose and every time the dose amount is adjusted: Start and 
stop date of each new dosage administration, indication/purpose of use 
• Reason for change (adverse event or platelet optimization) 
 
e. Concomitant therapy 
 
• Presence or absence of concomitant therapy 
• Names of concomitant drugs including anti-platelet therapies, anti-coagulant or 
Thrombolytic agents 
• Indication/purpose of use, start and stop date 
 
f. Safety   
 
• Presence or absence of Adverse event 
• Name of Adverse event 
• Start date and stop date 
• Severity 
• Relationship to Agrylin 
• Outcome 
• Action Taken regarding Agrylin 
• Seriousness 
• Treatment received for the AE 
Collected safety assessments include all adverse events (AEs) occurring following initiation 
of treatment with anagrelide regardless of the seriousness or relationship to anagrelide. Vital 
signs and abnormal laboratory assessments associated with AE will be collected. Laboratory 
assessments include any parameters the physician deems to be associated with and pertinent 
to the adverse event in question including hematology, biochemistry, urinalysis, and other 
relevant tests e.g. cardiac testing including ECG and echocardiograms.  Relationship of AE to 
Agrylin, underlying disease, concomitant drug, concomitant medical condition or other will 
be collected. 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

AGRYLIN Capsules 0.5mg 
Drug Use Results Survey Protocol SHP422-406                                                Version 3.0 (Amendment 3)    
27 MAR 2019 
Shire 
 
8 
An adverse reaction or adverse event is a serious adverse reaction or serious adverse event, 
respectively, if the reaction or event results in any of the following seriousness criteria: 
• results in death 
• life-threatening (NOTE: The term “life-threatening” in the definition of “serious” refers 
to an event/reaction in which the patient was at risk of death at the time of the 
event/reaction; it does not refer to an event/ reaction which hypothetically might have 
caused death if it were more severe) 
• requires inpatient hospitalization or results in prolongation of existing hospitalization 
• results in persistent or significant disability/incapacity 
• a congenital anomaly/birth defect 
• a medically important event or reaction 
 
g. Efficacy 
 
• Platelet count 
h. Survey Discontinuation 
• 
Date of discontinuation, reason for discontinuation if the subject has discontinued 
9.2 
Important items for investigation 
Cardiac disorders, QT/QTc prolongation, thrombohaemorrhagic events and interstitial lung 
disease 
 
10 Items for analysis and the analysis method 
10.1. Items for analyses 
a. Items on patient constitution 
 
• Number of cases enrolled  
• Number of cases collected CRF 
• Number of cases evaluable for safety  
• Number of cases evaluable for efficacy  
• Number of cases excluded from the survey with reason 
 
b. Safety issues 
 
• Adverse reactions (including unknown events), as well as adverse events by severity, 
incidence, etc.  
• Adverse reactions as well as adverse events according to the background factor 
• Serious adverse reactions as well as adverse events by type of event (by system order 
class) 
 
c. Efficacy issues 
 
• Absolute value and change from registration visit  platelet count 
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AGRYLIN Capsules 0.5mg 
Drug Use Results Survey Protocol SHP422-406                                                Version 3.0 (Amendment 3)    
27 MAR 2019 
Shire 
 
9 
• Clinical efficacy (as defined by absolute value and change from registration visit platelet 
count) in patients with special backgrounds; pediatric, elderly, hepatically impaired, 
renally impaired, pregnant, treatment-naïve  
 
d. Important items for investigation 
 
• Cardiac disorders, QT/QTc prolongation, thrombohaemorrhagic events and interstitial 
lung disease 
 
10.2. Analysis method 
 
Safety will be assessed through the recording of adverse events and any abnormal clinical 
laboratory tests including ECGs. Summaries of patient background including prior treatment 
for ET, prior history of hepatic impairment, anti-aggregatory, anti-coagulant or Thrombolytic 
agents prior and concomitant therapies as well as patient drug usage, especially at higher 
doses as well as treatment emergent adverse events (TEAEs), serious adverse events, TEAEs 
considered related to anagrelide, TEAEs leading to withdrawal (dose discontinuation), and 
TEAEs by severity and relationship to anagrelide will be presented. All patients who receive 
any dose of anagrelide, and provide any post-registration data, will be included in the Safety 
Population. 
 
The primary efficacy variable is platelet count, for which the absolute value and the change 
from the registration visit will be summarized, by visit, using descriptive statistics (number of 
observations, mean, standard deviation, median, minimum, and maximum values). In 
addition, the two-sided 95% confidence intervals (CIs) for the parameters of interest will be 
estimated as appropriate. No formal statistical tests will be performed. 
The safety data will be presented periodically for regulatory submissions per the regulation of 
the Safety Periodic Reporting System.  In addition, summaries of the accumulating data 
including efficacy data may be assessed during the conduct of the study for exploratory and 
administrative purposes, if deemed necessary.  The statistical analysis methods will be 
prospectively specified in detail in the statistical analysis plan. 
11 Organization for implementing the survey 
The same as shown in the Risk Management Plan section 6.3.   
12 Name and address of trustee 
Contractor for the operations 1 (From April, 2019) 
Takeda Pharmaceutical Company Limited 
4-1-1 Dosho-machi Chuo-ku, Osaka 
Request the site to conduct the survey, Contract with the site, Status management of the 
survey, AE information collection, CRF and/or DCF collection 
Contractor for the operations 2 
 
 
 
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AGRYLIN Capsules 0.5mg 
Drug Use Results Survey Protocol SHP422-406                                                Version 3.0 (Amendment 3)    
27 MAR 2019 
Shire 
 
10 
IQVIA Services Japan K.K. 
4-10-18 Takanawa, Minato-ku, Tokyo 108-0074 Japan 
Anticipated scope of services: Operation of specified use-result survey (Request to 
hospitals/clinics, making contracts with hospitals/clinics, enrollment of patients, collection of 
CRFs and review/follow-up, progress management, information collection of adverse 
reactions/infections, data compilation/analyses). 
13 Additional measures which may be taken depending on the outcome of the survey 
and the decision criteria for initiating the measures  
Depending on the outcomes of DURS, if new safety issues or risks are identified the 
additional pharmacovigilance and risk minimization measures will be taken. 
 
14 Milestones for the implementation of the survey and the assessment of the results, 
or reporting to the PMDA, and the justification  
• 
At the time of Periodic safety report 
• 
Interim analysis: Since entire observation period (12 months) of the statistical subjects 
(patients who were prescribed Agrylin prior to 31, May, 2015) has already completed, 
only final analysis will be conducted. Initially planned interim analysis will not be 
conducted. 
• 
Final Report: The final report will be submitted in Apr, 2018, which is 4 months after 
data collection and fixing (database lock) at the end of December, 2017.  
Additional drug results utilization survey may be considered after the time of final results are 
final.  
 
15 Other necessary items 
Reference documents 
• Contract   
• Guideline for implementation of the use-result survey  
• Registration form for the use-result survey  
• Questionnaire for the use-result survey  
• All Cases Registered Confirmation Form 
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