Specified Drug Use Surveillance on Zafatek Tablets 25 mg -Surveillance on Long-Term Use of Trelagliptin Tablets in Type 2 Diabetes Mellitus Patients With Severe Renal Impairment or End-Stage Renal Failure-
Conditions: Type 2 Diabetes Mellitus
Sponsor: Takeda

Clinical Study Protocol 
NCT Number: NCT04285983 
Title: Specified Drug Use Surveillance on Zafatek Tablets 25 mg—Surveillance on 
Long-Term Use of Trelagliptin Tablets in Type 2 Diabetes Mellitus Patients with Severe 
Renal Impairment or End-Stage Renal Failure— 
Study Number: Trelagliptin-4004 
Document Version and Date: Version 6/ 11-May-2022 
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. 

 
 
 
 
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SPECIFIED DRUG USE SURVEILLANCE 
PROTOCOL 
Specified Drug Use Surveillance  
on Zafatek Tablets 25 mg 
—Surveillance on Long-Term Use of Trelagliptin Tablets 
in Type 2 Diabetes Mellitus Patients with Severe Renal 
Impairment or End-Stage Renal Failure— 
 
 
 
 
 
 
 
 
 
 
Sponsor 
Takeda Pharmaceutical Company Limited 
Protocol Number 
Trelagliptin-4004 
Version Number 
Version 6 
Prepared on 
11 May 2022 
 
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TABLE OF CONTENTS 
1.0 
BACKGROUND TO THE STUDY ............................................................................................................... 1 
2.0 
OBJECTIVE .................................................................................................................................................. 1 
3.0 
SAFETY SPECIFICATION ........................................................................................................................... 2 
4.0 
PLANNED SAMPLE SIZE AND RATIONALE .......................................................................................... 2 
4.1 
Planned Sample Size .............................................................................................................................. 2 
4.2 
Rationale................................................................................................................................................. 2 
5.0 
SURVEILLANCE POPULATION ................................................................................................................ 3 
5.1 
Inclusion Criteria .................................................................................................................................... 3 
5.2 
Exclusion Criteria ................................................................................................................................... 3 
6.0 
DOSAGE AND ADMINISTRATION ........................................................................................................... 3 
7.0 
PLANNED NUMBER OF SURVEILLANCE SITES BY DEPARTMENT ................................................. 4 
8.0 
METHODS .................................................................................................................................................... 4 
8.1 
Observation Period ................................................................................................................................. 4 
8.2 
Surveillance Site Recruitment and Contracting...................................................................................... 4 
8.3 
Patient Consent ....................................................................................................................................... 4 
8.4 
Patient Enrollment Method .................................................................................................................... 5 
8.5 
Completion and Submission of Case Report Forms ............................................................................... 5 
9.0 
PLANNED DURATION OF SURVEILLANCE ........................................................................................... 6 
10.0 
SURVEILLANCE DATA ELEMENTS ......................................................................................................... 6 
10.1 
Patient Enrollment .................................................................................................................................. 6 
10.2 
Patient Demographics and Baseline Characteristics .............................................................................. 6 
10.3 
Treatment Details ................................................................................................................................... 7 
10.4 
Compliance with Zafatek 25 mg Treatment and Dietary/Exercise Therapy .......................................... 7 
10.5 
Assessments and Observations ............................................................................................................... 8 
 
Vital Signs .......................................................................................................................................... 8 
 
Laboratory Tests ................................................................................................................................. 8 
 
Electrocardiography ........................................................................................................................... 9 
 
Other Observations ............................................................................................................................. 9 
10.6 
Adverse Events ....................................................................................................................................... 9 
11.0 
ANALYSES AND METHODS .................................................................................................................... 12 
11.1 
Statistical Analysis Plan ....................................................................................................................... 12 
11.2 
Analysis Sets ........................................................................................................................................ 12 
11.3 
Patient Disposition ............................................................................................................................... 12 
11.4 
Patient Demographics and Baseline Characteristics ............................................................................ 12 
11.5 
Treatment Details ................................................................................................................................. 12 
11.6 
Safety .................................................................................................................................................... 12 
 
Adverse Event Incidence Data ......................................................................................................... 12 
 
Factors Potentially Affecting Safety ................................................................................................. 12 
 
Time Courses of Laboratory and Other Test Values ......................................................................... 12 
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11.7 
Patients with Special Backgrounds ...................................................................................................... 13 
12.0 
REGISTRATION OF SURVEILLANCE INFORMATION ........................................................................ 13 
13.0 
SURVEILLANCE ADMINISTRATIVE STRUCTURE ............................................................................. 13 
13.1 
Administrative Structure for Postmarketing Surveillance .................................................................... 13 
14.0 
CONTRACT RESEARCH ORGANIZATIONS.......................................................................................... 13 
14.1 
PRA Health Sciences Co., Ltd. ............................................................................................................. 13 
14.2 
EPS Corporation ................................................................................................................................... 13 
14.3 
PharField Corporation .......................................................................................................................... 13 
15.0 
POSSIBLE FOLLOW-UP PROCEDURES BASED ON SURVEILLANCE FINDINGS AND ADOPTION 
CRITERIA ............................................................................................................................................................... 13 
16.0 
SCHEDULED MILESTONES FOR EVALUATION OF SDUS CONDUCT & RESULTS AND PMDA 
REPORTING, AND RATIONALE THEREFOR .................................................................................................... 13 
17.0 
OTHER NECESSARY MATTERS ............................................................................................................. 14 
17.1 
Amendments to the Protocol ................................................................................................................ 14 
17.2 
Handling of Issues and Uncertainties ................................................................................................... 14 
Appendix 1 Schedule of Assessments and Observations ......................................................................................... 15 
 
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1.0 
BACKGROUND TO THE STUDY 
Zafatek Tablets—a dipeptidyl peptidase (DPP)-4 inhibitor containing trelagliptin succinate as 
its active ingredient—is an oral therapy for patients with type 2 diabetes mellitus (T2DM). 
Following submission of the marketing authorization application (MAA) in March 2014 based 
on the results of clinical studies in T2DM patients, marketing authorization for Zafatek Tablets 
was granted in Japan in March 2015. The approved Indication is “Type 2 diabetes mellitus” and 
the approved Dosage and Administration is “The usual adult dosage is 100 mg of trelagliptin 
orally administered once weekly.” 
Clinical experience with Zafatek Tablets in patients with renal impairment includes a clinical 
pharmacology study conducted outside Japan in this patient population. Based on the findings 
of this study, no dose adjustment is deemed necessary for patients with mild renal impairment 
whereas half the usual dose (i.e., 50 mg Q1W) is recommended for patients with moderate renal 
impairment. Moreover, although both the 50 mg and 100 mg Zafatek Tablets have been 
approved in Japan, administration is contraindicated in patients with severe renal impairment 
(SRI) or end-stage renal failure (ESRF) given that a quarter of the usual dose (i.e., 25 mg Q1W) 
is deemed to be appropriate in these patients. 
However, as renal impairment is a frequent complication of T2DM, an additional study of 
Zafatek Tablets 25 mg (herein “Zafatek 25 mg”) administered Q1W to patients with T2DM 
complicated by SRI or ESRF was conducted with the aim of contributing to the treatment of 
T2DM among patients in the severe or end stages of renal impairment. The study results 
demonstrated the efficacy and safety of Zafatek 25 mg, and in September 2019 this drug became 
available for clinical use in patients with T2DM complicated by SRI or ESRF. 
Therefore, as part of Takeda Pharmaceutical’s ongoing pharmacovigilance program in T2DM 
patients with comorbid SRI or ESRF, and following on from our supplementary 
pharmacovigilance and efficacy study in the form of specified drug use surveillance (SDUS) 
entitled “Surveillance on Long-Term Use of Trelagliptin Tablets in Patients with Type 2 
Diabetes Mellitus” that has been underway since May 2016 (herein “the Long-Term Zafatek 50 
mg and 100 mg SDUS on T2DM”), we are planning to conduct the SDUS entitled “Surveillance 
on Long-Term Use of Trelagliptin Tablets in Type 2 Diabetes Mellitus Patients with Severe 
Renal Impairment or End-Stage Renal Failure” (herein “the present SDUS”) to gather pertinent 
Safety Specification data according to the Risk Management Plan (RMP) for Zafatek 25 mg—
namely, important missing information on the safety of administering Zafatek 25 mg to patients 
with renal impairment, information on the important identified risk of hypoglycemia, and 
information on the important potential risk of infection. 
The present SDUS will be conducted in accordance with Japan’s Ministerial Ordinance on Good 
Postmarketing Study Practice (GPSP) and other relevant regulatory requirements. 
 
2.0 
OBJECTIVE 
This Specified Drug Use Surveillance (herein “the Surveillance” or “the present SDUS”) will 
evaluate the safety of long-term use of Zafatek Tablets 25 mg (herein “Zafatek 25 mg”) in 
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routine clinical practice in patients with type 2 diabetes mellitus (T2DM) complicated by severe 
renal impairment (SRI) or end-stage renal failure (ESRF). 
 
3.0 
SAFETY SPECIFICATION 
Important missing information: Safety of administering Zafatek 25 mg in patients with renal 
impairment 
Important identified risk: Hypoglycemia 
Important potential risk: Infection 
 
4.0 
PLANNED SAMPLE SIZE AND RATIONALE 
4.1 
Planned Sample Size 
85 patients 
 
4.2 
Rationale 
The Specified Drug Use Surveillance (SDUS) of Zafatek Tablets 50 mg and 100 mg 
entitled ”Surveillance on Long-Term Use of Trelagliptin Tablets in Patients with Type 2 
Diabetes Mellitus” (herein “the Long-Term Zafatek 50 mg and 100 mg SDUS on T2DM”) is 
being conducted in patients with T2DM without comorbid severe or end-stage renal impairment 
between 1 May 2016 and 31 October 2021, with a planned sample size of 3,000 patients and 
observation period of 36 months. The cumulative incidence of adverse drug reactions (ADRs) 
in the Safety Analysis Set consisting of 1,258 enrolled patients from whom a Case Report Form 
(CRF) had been collected by 25 March 2019 was 2.07% (26/1,258 patients). 
In a series of SDUS studies investigating the safety of once-daily (Q1D) administration of the 
dipeptidyl peptidase-4 (DPP-4) inhibitor Nesina Tablets (alogliptin benzoate) either alone or in 
combination with an alpha-glucosidase inhibitor (α-GI), in combination with a thiazolidinedione 
(TZD) drug, in combination with a sulfonylurea drug, in combination with a biguanide drug, 
and in combination with hypoglycemic drugs (insulin preparation, fast-acting insulin 
secretagogues, etc.) in patients with T2DM, 113 patients within the pooled Safety Analysis Set 
of 7,628 patients had severe or end-stage renal impairment as indicated by an estimated 
glomerular filtration rate (eGFR) < 30 mL/min/1.73 m2. 
In light of the findings of these previous SDUS studies, the incidences of ADRs in the present 
SDUS and in the Long-Term Zafatek 50 mg and 100 mg SDUS on T2DM will be compared in 
order to evaluate the safety of long-term Zafatek treatment of T2DM patients with severe or 
end-stage renal impairment (SRI or ESRF) in routine clinical practice. The present SDUS will 
also collect and evaluate safety information on the same number of T2DM patients with 
comorbid SRI or ESRF as those enrolled in the Nesina tablets SDUS studies. Specifically, the 
important identified risk of hypoglycemia and the important potential risk of infection will be 
evaluated for Zafatek 25 mg based on patient summaries including the presence/absence of these 
events and, if present, their time of onset and seriousness. 
The planned sample size needed to perform these safety assessments was set at 85 patients based 
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on the number of T2DM patients with comorbid SRI or ESRF in the Nesina tablets SDUS and 
in consideration of study feasibility. 
 
5.0 
SURVEILLANCE POPULATION 
The Surveillance will target patients with type 2 diabetes mellitus (T2DM) complicated by 
severe renal impairment (SRI) or end-stage renal failure (ESRF). Patients must meet all of the 
inclusion criteria and none of the exclusion criteria listed below. The enrollment criteria shall 
be based on the Zafatek Package Insert. 
5.1 
Inclusion Criteria 
Patients with type 2 diabetes mellitus who meet the following criteria will be eligible for 
inclusion in the Surveillance. 
Severe renal impairment (SRI) or end-stage renal failure (ESRF) with serum creatinine 
(mg/dL) or creatinine clearance (Ccr; mL/min) levels meeting the following criteria within 
3 months of starting treatment with Zafatek 25 mg 
 
 
SRI/ 
ESRF 
Serum creatinine 
(mg/dL)* 
Creatinine clearance 
(Ccr; mL/min) 
Males: >2.4 
Females: >2.0 
<30 
In patients with ESRF, the temporal relationship between Zafatek 25 mg treatment and hemodialysis will 
not be taken into consideration. 
*: Ccr equivalent for person aged 60 years with body weight of 65 kg 
 
5.2 
Exclusion Criteria 
Patients with any of the following contraindications for treatment with Zafatek 25 mg will be 
excluded from the Surveillance. 
Contraindications (Zafatek is contraindicated in the following patients.) 
(1) Patients with severe ketosis, diabetic coma or precoma, or type 1 diabetes mellitus 
(2) Patients with severe infection, patients in the perioperative period, or patients with 
serious trauma 
(3) Patients with a history of hypersensitivity to any of the ingredients of Zafatek 
 
6.0 
DOSAGE AND ADMINISTRATION 
Zafatek will be administered orally once a week (Q1W) in a single dose containing 25 mg 
trelagliptin. 
The dosage shall be based on the Zafatek Package Insert. 
 
 
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(1) In patients with moderate or more severe renal impairment, the blood concentration of trelagliptin may 
be increased due to delayed excretion. Decrease the dose according to the severity of renal impairment 
as per the following table. 
 
Dosage in patients with moderate or more severe renal impairment: 
 
Serum creatinine 
(mg/dL)* 
Creatinine 
clearance 
(Ccr; mL/min) 
Dose 
Patients with moderate 
renal impairment 
Males: 1.4–2.4 
Females: 1.2–2.0 
30–50 
50 mg Q1W 
SRI/ 
ESRF 
Males: >2.4 
Females: >2.0 
<30 
25 mg Q1W 
In patients with ESRF, the temporal relationship between Zafatek 25 mg treatment and hemodialysis will 
not be taken into consideration. 
*: Ccr equivalent for person aged 60 years with body weight of 65 kg 
(2) The investigator will instruct the patients as follows: 
 1) To take Zafatek 25 mg once a week on the same day each week. 
 2) To take any missed doses at the prescribed dosage as soon as the patient realizes he/she has missed the 
dose, and to take all subsequent scheduled doses on the scheduled day. 
 
 
7.0 
PLANNED NUMBER OF SURVEILLANCE SITES BY DEPARTMENT 
By department, approximately 30 medical institutions (herein “surveillance sites”) are 
scheduled to be enrolled in the present SDUS, including internal medicine, nephrology and 
dialysis departments. 
 
8.0 
METHODS 
8.1 
Observation Period 
12 months 
 
8.2 
Surveillance Site Recruitment and Contracting 
Takeda Pharmaceutical Company Limited (herein “Takeda Pharmaceutical”) will conclude a 
written agreement with medical institutions (herein “the surveillance sites”) to conduct this 
Surveillance. 
 
8.3 
Patient Consent 
Prior to enrollment, the surveillance site investigator (herein “the investigator”) will seek the 
Precautions Concerning Dosage and Administration: 
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informed consent of the patient (or their legally-authorized representative) to provide 
information for use in the present SDUS by way of a written or verbal explanation of the 
Surveillance. Patients (or their legally-authorized representative) who agree to participate in the 
Surveillance following the written explanation will be asked to sign and date the Informed 
Consent Form (ICF). The investigator will then retain the original signed ICF. For patients who 
agree to participate in the Surveillance following the verbal explanation, the investigator will 
create a record of their verbal consent. 
The written explanation will contain an outline of the Surveillance, the procedure for handling 
the patient’s personal information and personal health information throughout the Surveillance, 
and the fact that the patient could stop participating in the Surveillance at any time and for any 
reason without penalty. 
The investigator will then assign an identification number (“patient ID number”) to the patients 
who provide their informed consent. 
 
8.4 
Patient Enrollment Method 
Patients will be enrolled according to a central enrollment procedure using a web-based 
electronic data capture system (Rave EDC). The investigator or investigator’s representative 
(herein “the IR”) will be required to enter the enrollment details (see section 10.1) of all patients 
who are prescribed Zafatek 25 mg on or after the start date of the surveillance site’s agreement 
with Takeda Pharmaceutical into the Rave EDC system by 14 days after their first dose of 
Zafatek 25 mg (wherein the prescribing date is defined as “Day 0” and the day after the 
prescribing date is defined as “Day 1”), after which the investigator will attach his/her electronic 
signature. 
 
8.5 
Completion and Submission of Case Report Forms 
Surveillance data will be collected using the Rave EDC system. 
After performing the scheduled assessments and observations on all enrolled patients (see 
sections 10.2 through 10.6 and Appendix 1 for details), the investigator or the IR*1 will promptly 
enter the surveillance data in the Rave EDC system and the investigator will then attach his/her 
electronic signature. If the investigator or the IR cannot confirm whether or not the patient has 
taken a prescribed dose of Zafatek 25 mg, the unconfirmed dosing will be recorded in the Rave 
EDC system (while the other relevant data elements can be left blank). 
 However, in patients in whom Zafatek 25 mg treatment is discontinued due to AE onset, the 
investigator will follow the patient after discontinuation wherever feasible until the event is 
either resolved or resolving, after which the investigator or the IR will enter the assessment and 
observation data in the Rave EDC system and the investigator will attach his/her electronic 
signature. 
*1: The investigator’s representative (“the IR”) is defined as personnel employed at the 
surveillance site (including the contracted Clinical Research Coordinator (CRC) and other 
personnel contracted by the surveillance site). The Principal Investigator of the Surveillance 
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(“the PI”; a single physician for the entire surveillance site or for each department who is 
assigned when the SDUS agreement is concluded with Takeda Pharmaceutical) is 
responsible for creating and signing/sealing a record of the designated IRs and submitting 
it to Takeda Pharmaceutical. 
 
9.0 
PLANNED DURATION OF SURVEILLANCE 
Surveillance period: 1 March 2020 to 31 January 2023*2 
Patient enrollment period: 1 March 2020 to 30 September 2021*3 
 
*2: At completion of re-examination of all patient Case Report Forms (CRFs). 
*3: Patients will not be enrolled (i.e., registered in the Rave EDC system) from 1 October 2021 
onwards even if they have received Zafatek 25 mg on or before 30 September 2021. 
 
Furthermore, enrollment will be closed before the end of the enrollment period if the actual 
number of patients enrolled in the Surveillance reaches the planned sample size before 30 
September 2021. If the enrollment period is shortened for this reason, the Surveillance 
period will be changed accordingly. 
 
10.0 
SURVEILLANCE DATA ELEMENTS 
The investigator or the IR will enter the following surveillance data in the Rave EDC system. 
The schedule of assessments and observations in the present SDUS is shown in Appendix 1. 
10.1 Patient Enrollment 
1) Surveillance data elements 
Zafatek 25 mg prescribing date, patient ID number, sex, age (at Zafatek 25 mg prescribing 
date), assessment of enrollment eligibility based on inclusion and exclusion criteria 
2) Surveillance timing 
At patient enrollment 
 
10.2 Patient Demographics and Baseline Characteristics 
1) Surveillance data elements 
Date of T2DM diagnosis, healthcare category (at start of Zafatek 25 mg treatment), height, 
history of smoking, history of alcohol consumption, hypersensitivity (Y/N and description), 
concurrent illness (Y/N and description), previous medical history (Y/N and description) 
2) Surveillance timing 
At start of Zafatek 25 mg treatment 
 
 
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10.3 Treatment Details 
1) Surveillance data elements 
Zafatek 25 mg treatment details (amount per dose, dosing period, reason for any 
discontinuation), concomitant medication (anti-diabetic medication)*4 treatment details (Y/N, 
drug name, route of administration, daily dose, dosing period), concomitant medication 
(other than anti-diabetic medication) treatment details (Y/N, drug name, reason for use), 
dialysis treatment details (Y/N, type [hemodialysis/peritoneal dialysis/other], dialysis period) 
*4: Includes any anti-diabetic drugs that were discontinued within the 3 months prior to 
initiation of Zafatek 25 mg treatment 
 
2) Surveillance timing 
The period from the start of Zafatek 25 mg treatment (Day 0) until 12 months of treatment 
(Day 360) (or until treatment discontinuation) 
 
10.4 Compliance with Zafatek 25 mg Treatment and Dietary/Exercise Therapy 
1) Surveillance data elements 
Zafatek 25 mg treatment compliance status, description of and reason(s) for any treatment 
non-compliance, dietary/exercise therapy compliance status 
Criteria for Assessing Zafatek 25 mg Treatment Compliance 
1. Patient took the drug once weekly as prescribed at least 90% of the time 
2. Patient took the drug once weekly as prescribed at least 70% of the time 
3. Patient took the drug once weekly as prescribed at least 50% of the time 
4. Patient took the drug once weekly as prescribed less than 50% of the time 
5. Patient did not take the drug 
6. Patient’s treatment compliance is unknown 
 
Description of and Reasons for Treatment Non-Compliance (only required for weeks in 
which the patient did not take the drug once weekly as prescribed) 
a. Patient took the drug twice or more in one week. 
Reasons: 
A1. Patient took the drug twice in one week to make up for a previously-missed 
dose. 
A2. Patient inadvertently took the drug twice or more in one week due to 
forgetting the dosing day, etc. 
A3. Patient took the drug twice or more in one week due to mistaking the dosing 
frequency for daily dosing. 
A4. Patient inadvertently took the drug twice or more in one week after taking it 
together with a separate daily medication. 
A5. Other reason (provide details) 
b. Patient took a dose exceeding the prescribed single dose. 
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Enter a description of and reason for the excessive dose in the Rave EDC system. 
c. Patient did not take a weekly dose. 
Reasons: 
A1. Patient forgot to take the drug. 
A2. Patient could not take the drug due to work or other circumstances. 
A3. Other reason (provide details) 
Criteria for Assessing Compliance with Dietary/Exercise Therapy 
1. Patient followed with the therapy regimen at least 90% of the time (i.e., followed 
the regimen properly and as directed) 
2. Patient followed with the therapy regimen at least 70% of the time (i.e., followed 
the regimen generally and as directed) 
3. Patient followed with the therapy regimen at least 50% of the time (i.e., followed 
the regimen as directed at least half of the time) 
4. Patient followed with the therapy regimen less than 50% of the time (i.e., did not 
follow the regimen as directed more than half of the time) 
5. Patient did not follow the therapy regimen 
6. Patient’s compliance with the therapy regimen is unknown 
 
2) Surveillance timing 
At start of Zafatek 25 mg treatment (Day 0; compliance with dietary/exercise therapy only) 
and at 1 month (Day 30), 3 months (Day 90), 6 months (Day 180), 9 months (Day 270) and 
12 months (Day 360) of treatment (or at treatment discontinuation) 
 
10.5 Assessments and Observations 
Data on each of the following assessments and observations performed at each scheduled 
timepoint will be entered in the Rave EDC system. 
 Vital Signs 
1) Assessments and observations 
Pulse rate, blood pressure (systolic/diastolic), body weight 
2) Surveillance timing 
Measurement timepoints at start of Zafatek 25 mg treatment (Day 0) and at 1 month (Day 
30), 3 months (Day 90), 6 months (Day 180), 9 months (Day 270) and 12 months (Day 
360) of treatment (or at treatment discontinuation) 
 
 Laboratory Tests 
1) Tests/Assays 
Glycated hemoglobin (HbA1c) (National Glycohemoglobin Standardization Program 
[NGSP] values; same hereinafter), glycoalbumin, fasting blood glucose, fasting triglyceride, 
total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) 
cholesterol, serum creatinine, blood urea nitrogen (BUN), urine albumin (urine albumin-
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creatinine ratio [uACR]), aspartate aminotransferase (AST), alanine aminotransferase (ALT), 
gamma-glutamyl transpeptidase (γ-GTP), alkaline phosphatase (ALP), total bilirubin, 
amylase, lipase 
2) Surveillance timing 
Test/assay timepoints at start of Zafatek 25 mg treatment (Day 0) and at 1 month (Day 30), 
3 months (Day 90), 6 months (Day 180), 9 months (Day 270) and 12 months (Day 360) of 
treatment (or at treatment discontinuation) 
 
 Electrocardiography 
1) Tests/Assays 
ECG (findings and assessments) 
2) Surveillance timing 
Test/assay timepoints at start of Zafatek 25 mg treatment (Day 0) and at 1 month (Day 30), 
3 months (Day 90), 6 months (Day 180), 9 months (Day 270) and 12 months (Day 360) of 
treatment (or at treatment discontinuation) 
 
 Other Observations 
1) Observations 
Pregnancy status (Y/N) during the observation period (female patients only), withdrawal of 
consent 
If a patient is found to be pregnant during the observation period, the investigator is required 
to immediately contact Takeda Pharmaceutical. Pursuant to a request by Takeda 
Pharmaceutical, the investigator will then provide details of the pregnancy using the attached 
Pregnancy Form. Where possible, the submitted form will include information up to 
childbirth such as premature delivery or other outcomes. 
2) Surveillance timing 
The period from the start of Zafatek 25 mg treatment (Day 0) until 12 months of treatment 
(Day 360) (or until treatment discontinuation) 
 
10.6 Adverse Events 
1) Surveillance data elements 
Presence or absence (Y/N) of adverse event (herein “AE”; see Table 1), AE term, date of 
onset, seriousness and reason for assessment as serious (see Table 2), reason for discontinuing 
Zafatek 25 mg, date of outcome assessment, outcome, causal relationship with Zafatek 
25 mg*5 (see Table 3) 
If the AE outcome is “not recovered/not resolved” or “unknown” or if the causal relationship 
is deemed “not evaluable,” the patient will be followed to the extent possible. 
If a patient experiences an AE corresponding to the risks identified in the Safety 
Specification—specifically, hypoglycemia or infection—detailed information on the time of 
onset, seriousness and other relevant case data will be collected to the extent possible. 
*5 : If the causal relationship with Zafatek 25 mg is deemed ‘not related,’ the investigator will record the 
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rationale for this assessment. Alternatively, if the causal relationship is deemed ‘not evaluable,’ the 
investigator will provide the reason for this assessment. 
 
 
N.B.) Points to consider when assessing AEs: 
Abnormal worsening of the target disease (i.e., worsening beyond the expected natural course of the 
disease) should be assessed as an AE. 
 
2) Surveillance timing 
The period from the start of Zafatek 25 mg treatment (Day 0) until 12 months of treatment 
(Day 360) (or until treatment discontinuation) 
 
 
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Table 1 Definition of Adverse Events 
An adverse event (AE) is defined as any untoward medical occurrence in a patient administered a 
pharmaceutical product during the course of a clinical investigation, and that does not necessarily have 
a clear causal relationship with this pharmaceutical product. 
An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of a pharmaceutical product, whether 
or not considered related to the pharmaceutical product. 
 
Table 2 Criteria for Assessing Seriousness 
AEs that meet any of the following criteria will be assessed as serious: 
1. Results in death (death) 
2. Is life-threatening (risk of death) 
The term “life-threatening” in the definition of serious 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 were more severe. 
3. Requires inpatient hospitalization or prolongation of existing hospitalization 
(hospitalization/prolonged hospitalization) 
4. Results in persistent or significant disability/incapacity (disability) 
5. Leads to a congenital anomaly/birth defect (congenital anomaly) 
6. Is an important medical event that may not be immediately life-threatening or result in death or 
hospitalization but may jeopardize the patient or may require intervention to prevent outcomes 
such as those listed in items 1 to 5 above. 
 
 
* Any reported AE that is listed in the “Takeda Medically Significant AE List” will be handled as serious. 
 
Table 3 Criteria for Assessing Causal Relationship of Adverse Events with Zafatek 25 mg 
Assessment 
Assessment Criteria 
Related 
A causal relationship cannot be ruled out because there is a temporal correlation 
between event onset and drug administration (including the course of the event 
after treatment is discontinued) or because it is at least plausible that the event 
was caused by the drug despite the possible involvement of other factors such 
as the underlying disease, concurrent illness or concomitant medication or 
procedures. 
Not Related 
There is no temporal correlation with the drug or there is sufficient evidence to 
suggest that the event was caused by other factors such as the underlying 
disease, concurrent illness, or concomitant medication or procedures. 
Not Evaluable 
There is insufficient information on the temporal relationship (including the 
course of the event after treatment is discontinued), underlying disease, 
concurrent illness, or concomitant medication or procedures to evaluate the 
causal relationship. 
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11.0 
ANALYSES AND METHODS 
11.1 Statistical Analysis Plan 
A Statistical Analysis Plan (SAP) will be prepared prior to data lock. The SAP will contain 
definitions of the surveillance data elements and will describe the methods for statistical analysis. 
 
11.2 Analysis Sets 
The present SDUS is designed using the “Safety Analysis Set” as the analysis population. 
 
11.3 Patient Disposition 
Patient disposition will be tabulated for the number of enrolled patients, the number of patients 
for whom electronic CRFs (eCRFs) are submitted/collected, the number of patients in the Safety 
Analysis Set, the number of patients excluded from analysis and the reason(s) for their exclusion. 
 
11.4 Patient Demographics and Baseline Characteristics 
Demographics and baseline characteristics will be tabulated for sex, age, disease duration, 
concurrent illness and other relevant variables. 
 
11.5 Treatment Details 
Details of the Zafatek 25 mg treatment, treatment compliance, and use of concomitant 
medications will be tabulated. 
 
11.6 Safety 
The following data will be tabulated for the Safety Analysis Set. AEs will be summarized by 
Preferred Term (PT) and System Organ Class (SOC) using the Japanese translation of Medical 
Dictionary for Regulatory Activities (MedDRA/J). 
 Adverse Event Incidence Data 
AE incidences during the observation period will be tabulated by category, time of onset, 
seriousness, causal relationship with Zafatek 25 mg and other relevant variables. 
 
 Factors Potentially Affecting Safety 
Adverse drug reaction (ADR) incidences during the observation period will be tabulated by 
strata consisting of patient demographics and baseline characteristics (e.g., sex, age, 
concurrent illness [Y/N]) and by Zafatek 25 mg treatment details, concomitant medication 
(Y/N) and dialysis treatment (Y/N). 
 
 Time Courses of Laboratory and Other Test Values 
Laboratory and other test values and absolute changes from baseline in these values (i.e., the 
test value at each test timepoint after starting Zafatek 25 mg minus the test value at the start 
of Zafatek 25 mg treatment) will be tabulated for each timepoint of the HbA1c, glycoalbumin, 
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13 
 
fasting blood glucose and lipid tests and the kidney function tests. 
 
11.7 Patients with Special Backgrounds 
Safety data will be tabulated by strata for elderly patients and patients with hepatic impairment. 
 
12.0 
REGISTRATION OF SURVEILLANCE INFORMATION 
Takeda Pharmaceutical will register information about the present SDUS on the following 
publicly-accessible websites prior to commencing the surveillance. 
· 
JAPIC Clinical Trials Information website, Japan Pharmaceutical Information Center (JAPIC) 
· 
ClinicalTrials.gov clinical trials registry, U.S. National Institutes of Health (NIH) 
 
13.0 
SURVEILLANCE ADMINISTRATIVE STRUCTURE 
13.1 Administrative Structure for Postmarketing Surveillance 
See attachment document. 
 
14.0 
CONTRACT RESEARCH ORGANIZATIONS 
14.1 
PRA Health Sciences Co., Ltd. 
Address 
 
: 4-1-3 Kyutaromachi, Chuo-ku, Osaka-shi, Osaka 
Contracted operations 
: Data management, electronic data capture (EDC) system 
development and management, retention/archiving of records, 
postmarketing surveillance support operations 
 
14.2 
EPS Corporation 
Address 
 
: 2-23 Shimomiyabicho, Shinjuku-ku, Tokyo 
Contracted operations : Statistical analysis 
 
14.3 
PharField Corporation 
Address 
 
: 2-8-20 Saga, Koto-ku, Tokyo 
Contracted operations : Monitoring operations 
 
15.0 
POSSIBLE FOLLOW-UP PROCEDURES BASED ON SURVEILLANCE FINDINGS 
AND ADOPTION CRITERIA 
The Pharmaceutical Risk Management Plan (RMP) containing the following information will 
be revised at the relevant milestones in the present SDUS. 
· 
If any new information or findings are obtained in relation to the Safety Specification, the 
need for any changes to the Package Insert’s Risk Minimization Plan will be investigated. 
· 
The need for any changes to the present SDUS Protocol, including any new items in the 
Safety Specification, will be investigated. 
 
16.0 
SCHEDULED MILESTONES FOR EVALUATION OF SDUS CONDUCT & RESULTS 
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14 
 
AND PMDA REPORTING, AND RATIONALE THEREFOR 
Milestone: At release of Periodic Safety Update Reports (PSURs); Rationale: To 
comprehensively investigate safety information. 
Milestone: At creation of Final Report at 8 months after completion of the present SDUS; 
Rationale: To perform final tabulation of all enrolled patient data after data lock, and to then 
prepare and submit the Final Report. 
 
17.0 
OTHER NECESSARY MATTERS 
17.1 Amendments to the Protocol 
The Protocol for the present SDUS will be revised and amended during the Surveillance where 
required based on information obtained on the Surveillance progress, the occurrence of any 
ADRs or serious ADRs that are not expected based on the Zafatek Package Insert’s “Precautions 
Concerning Use,” any increases in the incidence of identified ADRs, and the appropriateness of 
surveillance data elements. If approval is granted for a partial change to Zafatek’s authorized 
Dosage and Administration or Indications, the need for corresponding amendments to the 
Protocol will be investigated and, if deemed necessary, the Protocol will be amended 
accordingly during the Surveillance. 
 
17.2 Handling of Issues and Uncertainties 
If any issues are identified in relation to the safety of Zafatek 25 mg, the appropriate action will 
be taken based on a detailed analysis of the relevant data. 
 
 
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15 
 
 
Appendix 1 Schedule of Assessments and Observations 
 
Surveillance Timing 
 
 
 
 
 
 
 
 
Surveillance Data Elements 
Observation Period 
At patient 
enrollment 
At start of 
Zafatek 
25 mg 
treatment 
(baseline) 
1 month 
3 months 
6 months 
9 months 12 months 
At discon-
tinuation of 
Zafatek 
25 mg 
treatment 
Day 
- 
0 
30 
90 
180 
270 
360 
- 
Window (min–max) 
- 
-30–0 
1–60 
61–136 
137–226 
227–316 
317–456 
- 
Informed consent 
○ 
 
 
 
 
 
 
 
Patient 
Enrollment 
Zafatek 25 mg prescribing date 
○ 
 
 
 
 
 
 
 
Patient ID No. 
○ 
 
 
 
 
 
 
 
Sex 
○ 
 
 
 
 
 
 
 
Age 
○ 
 
 
 
 
 
 
 
Assessment of enrollment eligibility 
○ 
 
 
 
 
 
 
 
Patient Demographics and 
Baseline Characteristics 
Date of T2DM diagnosis 
 
○ 
 
 
 
 
 
 
Healthcare category 
 
○ 
 
 
 
 
 
 
Hypersensitivity 
 
○ 
 
 
 
 
 
 
Concurrent illnesses 
 
○ 
 
 
 
 
 
 
Previous medical history 
 
○ 
 
 
 
 
 
 
Height 
 
○ 
 
 
 
 
 
 
Smoking history 
 
○ 
 
 
 
 
 
 
Alcohol consumption history 
 
○ 
 
 
 
 
 
 
Treatment Details 
Zafatek 25 mg treatment 
 
 
○ 
Concomitant medications (anti-diabetic & other 
medications) 
 
 
○ 
Dialysis treatment 
 
○ 
 
○ 
Zafatek 25 mg treatment compliance status, 
description of and reason(s) for any treatment 
 
 
○ 
○ 
○ 
○ 
○ 
○ 
Dietary/exercise therapy compliance 
 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
Assessments & 
Observations 
Pulse rate, blood pressure, body weight 
 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
Laboratory Tests 
 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
Electrocardiography 
 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
Pregnancy (Y/N) (female patients only) 
 
 
○ 
Adverse Events 
 
 
○ 
 
○      : Performed at scheduled timepoint 
○ 
: Perform throughout indicated period 
 
Data from assessments and observations performed in routine clinical practice will be recorded in the Rave EDC system. Data from 
assessments and observations performed at discontinuation of treatment will be recorded in the Rave EDC system during the 
specified time window. 
 
 
 
○ 
○ 
○ 
○ 
○ 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

Document History 
 
Version 
Date 
Comments 
original version 
2019/12/23 
New document 
2nd version 
2020/6/12 
A change in the company name of a CRO following a change in 
the surveillance administrative structure 
3rd version 
2021/1/15 
The addition of a CRO 
4th version 
2021/6/8 
Extension of the surveillance period and patient enrollment 
period 
5th version 
2021/9/6 
A change in the planned sample size 
6th version 
2022/5/11 
Addition of the Organization Structure as a Protocol attachment 
 
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