Specified Drug-Use Survey of Trelagliptin Tablets "Survey on Long-term Use in Patients With Type 2 Diabetes Mellitus"
Conditions: Type 2 Diabetes Mellitus
Sponsor: Takeda

 
 
Title: Specified Drug-Use Survey of Zafatek Tablets “Survey on long-term use in 
patients with type 2 diabetes mellitus” 
 
NCT Number: NCT03555591 
Protocol Approve Date: 25-Dec-2020 
 
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. 

Protocol for Specified Drug-Use Survey of 
Zafatek Tablets 
“Survey on long-term use in patients with 
type 2 diabetes mellitus” 
Survey Sponsor 
Takeda Pharmaceutical Company Limited 
Protocol Number 
Trelagliptin-5001 
Version Number 
Version 9 
Date of Preparation December 25, 2020 
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Table of Contents 
1.0 
Background .................................................................................................................................................... 1 
2.0 
Objectives ....................................................................................................................................................... 1 
3.0 
Planned Sample Size and Rationale ............................................................................................................... 1 
3.1 
Planned Sample Size .............................................................................................................................. 1 
3.2 
Rationale................................................................................................................................................. 1 
4.0 
Target Patient Population ............................................................................................................................... 2 
4.1 
Inclusion Criteria .................................................................................................................................... 2 
4.2 
Exclusion Criteria ................................................................................................................................... 2 
5.0 
Dosage and Administration ............................................................................................................................ 2 
6.0 
Planned Number of Survey Sites by Specialty Department ........................................................................... 3 
7.0 
Methods .......................................................................................................................................................... 3 
7.1 
Duration of observation .......................................................................................................................... 3 
7.2 
Request for the Survey and Contract with the Medical Institution ........................................................ 3 
7.3 
Patient Enrollment Method .................................................................................................................... 3 
7.4 
Case Report Form (Electronic) Completion and Electronic Signature................................................... 3 
7.5 
Actions Taken for Serious Adverse Events ............................................................................................ 4 
8.0 
Planned Survey Period ................................................................................................................................... 4 
9.0 
Survey Variables ............................................................................................................................................. 4 
9.1 
Patient Enrollment .................................................................................................................................. 4 
9.2 
Patient Background ................................................................................................................................ 5 
9.3 
Treatment Details etc. ............................................................................................................................. 5 
9.3.1 Treatment Details ...................................................................................................................................... 5 
9.3.2 Treatment Compliance Status, Treatment Noncompliance Details and Reasons, and Diet/Exercise 
Therapy Compliance Status................................................................................................................................ 6 
9.4 
Items of Tests and Observations ............................................................................................................. 7 
9.4.1 Vital Signs ................................................................................................................................................. 7 
9.4.2 Laboratory Tests ........................................................................................................................................ 7 
9.4.3 Electrocardiogram ..................................................................................................................................... 7 
9.4.4 Waist Circumference and Testing Related to Coronary Arteries and Arteriosclerosis .............................. 8 
9.4.5 Other Items of Observation ....................................................................................................................... 8 
9.5 
Adverse Events ....................................................................................................................................... 8 
10.0 
Analytical Items and Methods ...................................................................................................................... 10 
10.1 
Statistical Analysis Plan ....................................................................................................................... 10 
10.2 
Analysis Populations ............................................................................................................................ 10 
10.3 
Disposition of Patients.......................................................................................................................... 10 
10.4 
Patient Background .............................................................................................................................. 11 
10.5 
Treatment Details etc. ........................................................................................................................... 11 
10.6 
Safety Data ........................................................................................................................................... 11 
10.6.1 Adverse Event Profile ............................................................................................................................ 11 
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10.6.2 Factors Likely Affecting the Safety ....................................................................................................... 11 
10.7 
Efficacy Data ........................................................................................................................................ 11 
10.7.1 HbA1c Over Time ................................................................................................................................. 11 
10.7.2 Laboratory Test Values Over Time ........................................................................................................ 11 
10.7.3 Factors Likely Affecting the Efficacy ................................................................................................... 12 
10.8 
Special Patient Populations .................................................................................................................. 12 
10.9 
Interim Analysis ................................................................................................................................... 12 
11.0 
Registration of Survey Information .............................................................................................................. 12 
12.0 
Administrative Structure .............................................................................................................................. 12 
12.1 
Survey Manager ................................................................................................................................... 12 
13.0 
Trustees ........................................................................................................................................................ 12 
14.0 
Other Necessary Items ................................................................................................................................. 13 
14.1 
Amendments to the Protocol ................................................................................................................ 13 
14.2 
Actions to be taken in Response to Detection of any Issues or Concerns ............................................ 13 
 
Appendix Observation Schedule  .................................................................................................................... 14 
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1.0 Background 
Zafatek Tablets (hereinafter referred to as “this drug”) is a dipeptidyl peptidase-4 (DPP-4) inhibitor. 
It contains trelagliptin succinate, and is orally administered once weekly for the treatment of type 
2 diabetes mellitus. Since oral drugs to treat type 2 diabetes mellitus are usually used over a long 
time, the long-term use data in the routine clinical setting should be collected. 
 
The present specified drug-use survey on “long-term use in patients with type 2 diabetes mellitus” 
(hereinafter referred to as “this survey”) has been thus planned to investigate the long-term (3-
year) safety and efficacy of this drug used in the routine clinical setting in type 2 diabetes mellitus 
patients. 
 
This survey will be conducted in compliance with the Ministerial Ordinance on Good Post-
Marketing Study Practice (GPSP) and relevant regulatory requirements. 
 
2.0 Objectives 
To evaluate the long-term safety and efficacy of this drug in patients with type 2 diabetes mellitus 
in the routine clinical setting in Japan. 
 
3.0 Planned Sample Size and Rationale 
3.1 Planned Sample Size 
3,000 subjects 
 
3.2 Rationale 
Drugs to treat type 2 diabetes mellitus are likely used over a long time in the routine clinical setting. 
To investigate the long-term safety and efficacy of this drug used in the routine clinical setting, 
the observation period has been set to 3 years and the planned sample size has been set to 3000. 
With this sample size of 3000, adverse drug reactions occurring with an incidence of ≥0.1% can 
be detected with a probability of 95%. 
 
Among the currently ongoing specified drug-use surveys of another DPP-4 inhibitor Nesina 
Tablets of “Survey on Nesina alone or with an alpha-GI”, “Survey on Nesina with a 
thiazolidinedione”, “Survey on Nesina with a sulfonylurea”, and “Survey on Nesina with a 
biguanide”, the safety analysis set as of April 15, 2015 consisted of 6734 subjects, of whom 52.5% 
were elderly, 54.4% had renal impairment, and 17.8% had hepatic impairment. Based on these 
data, the sample size of 3000 in this survey would allow data collection from approximately 1600 
elderly patients, approximately 1600 patients with renal impairment, and approximately 500 
patients with hepatic impairment. This sample size is not based on statistical power calculation. 
 
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4.0 Target Patient Population 
This survey will be conducted in patients with type 2 diabetes mellitus who fulfill the following 
inclusion criteria and who do not meet the following exclusion criteria. The PRECAUTIONS 
section of the package insert for this drug should also be referenced.  
 
4.1 Inclusion Criteria 
Subjects should meet the following criterion: 
Type 2 diabetes mellitus patients* 
*: With or without use of antidiabetic medication 
 
4.2 Exclusion Criteria 
Subjects who meet any of the following criteria will be excluded: 
(1) Have severe ketosis, diabetic coma or precoma, or type 1 diabetes mellitus 
(2) Have severe infection, perioperative status, or serious trauma 
(3) Have severe renal impairment or on dialysis due to end-stage renal disease 
(4) Have a history of hypersensitivity to any ingredients of this drug 
 
5.0 Dosage and Administration 
The usual adult dosage of trelagliptin is 100 mg once weekly orally. The PRECAUTIONS section 
of the package insert for this drug should also be referenced. 
 
<Precautions related to Dosage and Administration> 
(1) Patients with moderate renal impairment will have increased blood concentrations of this 
drug because of delayed excretion, and thus require dose reduction, using the table below 
as a guide.  
 
Dose in patients with moderate renal impairment 
Serum creatinine  
(mg/dL)* 
Creatinine clearance  
(Ccr, mL/min)  
Dose 
Male: >1.4 to ≤ 2.4 
Female: >1.2 to ≤ 2.0 
≥30 to <50 
50 mg once weekly 
*: Estimated values corresponding to the Ccr (for persons who are aged 60 years and weigh 65 kg)  
 
(2) Patients must be instructed that:  
1) Since this drug is designed for once-weekly oral dosing, this drug should be taken on the 
same day of every week.  
2) If a missed dose is noticed, only this dose should be taken as soon as it is remembered, 
and the subsequent doses should be taken as originally scheduled.  
 
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6.0 Planned Number of Survey Sites by Specialty Department 
Approximately 300 sites, including department of internal medicine 
 
7.0 Methods 
7.1 Duration of observation 
36 months 
 
7.2 Request for the Survey and Contract with the Medical Institution 
This survey will use a web-based electronic data capture system (PostMaNet). To request the 
conduct of the survey, the person in charge at Takeda Pharmaceutical Company Limited 
(hereinafter referred to as “Takeda personnel”) will explain to a potential survey physician and 
designee* about the survey objectives and contents, as well as the PostMaNet usage methods and 
handling of electronic signature and user IDs and passwords, using the “Request for cooperation 
in the specified drug-use survey”, “Survey implementation outline”, “Data entry screen images” 
and “PostMaNet User Manual (Quick Guide)”. A written contract with the medical institution will 
then be signed, while the Takeda personnel will ask to perform the survey within the survey period 
specified on the contract. 
 
*: The survey physician’s designee must be a person who belongs to the medical institution (this 
includes a dispatched CRC or any other person with a signed consignment contract with the 
medical institution). Before the survey physician’s designee can perform data entry to 
PostMaNet, the principal survey physician (ie, a person designated under contract at each survey 
site [medical institution or department] who is responsible for the conduct of the survey at the 
survey site) will prepare a written record (any format) of the designation and the date of 
designation and, after signing (or affixing name with seal), submit it to the Takeda personnel. 
 
7.3 Patient Enrollment Method 
Patients will be enrolled using a centralized registration method via PostMaNet. For patients 
prescribed this drug on or after the first day of the contract period for the medical institution, the 
survey physician will enter the patient data required for enrollment (see Section 9.1) into 
PostMaNet by 14 days after the prescription of this drug (with the day of prescription counted as 
“0 days” and the day following prescription counted as “1 day after prescription”), and enter an 
electronic signature. 
 
7.4 Case Report Form (Electronic) Completion and Electronic Signature 
The survey physician or designee will enter data on patient background, treatment details, etc. into 
PostMaNet, roughly within 1 month after the end of required observations at 12 months and 36 
months after the start of treatment with this drug (or discontinuation of treatment), and the survey 
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physician will enter an electronic signature. If administration of this drug could not be confirmed, 
the fact of this should be entered (no other data are required). 
 
For patients who discontinued treatment with this drug for certain reasons during the course of the 
observation period, the survey physician or designee will enter data on patient background, 
treatment details, etc. into PostMaNet roughly within 1 month after the end of required 
observations, and the survey physician will enter an electronic signature. However, for patients 
who discontinued treatment with this drug because of onset of an adverse event, even after the 
discontinuation of this drug the survey physician will continue observation as far as possible up 
to resolution or improvement of the adverse event. The survey physician or designee will then 
enter the observation result into PostMaNet, and the survey physician will enter an electronic 
signature. 
 
7.5 Actions Taken for Serious Adverse Events 
When any serious adverse event occurred during the observation period, the survey physician will 
immediately report it to the Takeda personnel. If requested by the Takeda personnel, the survey 
physician will also provide detailed information separately. 
 
8.0 Planned Survey Period 
Survey period: May 2016 to October 31, 2021  
Patient enrollment period: May 2016 to October 31, 2018* 
 
*: Even if this drug is prescribed by October 31, 2018, no patient enrollment (via PostMaNet) will 
be acceptable on or after November 1, 2018. 
If the total number of patients enrolled in this survey reached the planned sample size before 
October 31, 2018, patient enrolment will be closed before the end of the patient enrollment period. 
If the patient enrollment period is shortened, the survey period will also be changed according 
to the shortened enrollment period. 
 
9.0 Survey Variables 
The survey physician or designee will enter data on the following variables into PostMaNet. The 
survey schedule is shown in Appendix. 
 
9.1 Patient Enrollment 
1) Survey variables 
Date of prescription of this drug, subject identification number, patient initials, sex, date of 
birth, assessment against the inclusion criteria, assessment against the exclusion criteria, any 
serum creatinine data within 1 month before the start of treatment with this drug (presence or 
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absence and, if present, the specific data), severity of renal impairment and its basis (if without 
any serum creatinine data within 1 month before the start of treatment with this drug), any 
total bilirubin, AST or ALT data within 1 month before the start of treatment with this drug 
(presence or absence and, if present, the specific data), severity of hepatic impairment* and 
its basis (if without total bilirubin, AST or ALT data within 1 month before the start of 
treatment with this drug), presence or absence of concurrent or past history of pancreatitis or 
gallbladder stone 
 
Severity of 
hepatic 
impairment 
Mild 
Moderate 
Severe 
Total bilirubin 
(mg/dL) 
≥1.6 to <3.0 
≥3.0 to <10 
≥10 
AST or ALT 
(U/L) 
≥50 to <100 
≥100 to <500 
≥500 
Manifestations 
- 
Jaundice, hepatomegaly,  
pain in the right 
hypochondrium, hepatic 
steatosis 
Bleeding tendency, 
disturbed consciousness 
and other signs of hepatic 
failure (fulminant 
hepatitis), liver cirrhosis, 
liver tumor,  
persistent jaundice over 
≥6 months 
Adapted from Criteria for Seriousness/Severity Grading of Adverse Drug Reactions (Notification No. 80 of the Safety 
Division, Pharmaceutical Affairs Bureau, Ministry of Health and Welfare, dated June 29, 1992)  
 
2) Time of data collection 
At enrollment of the patient 
 
9.2 Patient Background 
1) Survey variables 
Time of the diagnosis of type 2 diabetes mellitus, inpatient/outpatient category (at initiation of 
treatment with this drug), hypersensitive diathesis (presence or absence, and details), 
concurrent diseases (presence or absence, and details), medical history (presence or absence, 
and details), height, history of smoking, history of alcohol consumption 
2) Time of data collection 
At initiation of treatment with this drug 
 
9.3 Treatment Details etc. 
9.3.1 Treatment Details 
1) Survey variables 
Detailed use of this drug (dose, therapy dates, and reason for discontinuation), detailed use of 
concomitant drugs* (for the treatment of diabetes mellitus) (presence or absence, name of the 
drug, route of administration, daily dose, and therapy dates), detailed use of concomitant drugs 
(for other conditions than diabetes mellitus) (presence or absence, name of the drug, reason 
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for use, route of administration, daily dose, and therapy dates) 
*Including antidiabetic medication discontinued within 3 months before use of this drug 
2) Time of data collection 
From initiation of treatment with this drug to 36 months later (or discontinuation of treatment) 
 
9.3.2 Treatment Compliance Status, Treatment Noncompliance Details and Reasons, and 
Diet/Exercise Therapy Compliance Status 
1) Survey variables 
Status of treatment compliance with this drug*, treatment noncompliance details and reasons**, 
diet/exercise therapy compliance status*** 
 
*Treatment compliance status will be categorized as follows: 
1. ≥90% of the doses were taken once weekly as prescribed. 
2. ≥70% of the doses were taken once weekly as prescribed. 
3. ≥50% of the doses were taken once weekly as prescribed. 
4. <50% of the doses were taken once weekly as prescribed. 
5. No doses were taken. 
6. Unknown treatment compliance status 
 
**Treatment noncompliance details and reasons (Only for patients who did not follow the 
once-weekly dosing schedule in any week) 
a. Two doses were taken in any week. 
<Reason> 
A1: A missed dose was noticed and taken, and consequently two doses were taken 
in that week. 
A2: Inadvertently two or more doses were taken in any week, for example because 
the scheduled dosing day in the week has slipped the mind. 
A3: Inadvertently the dosing frequency was misunderstood as daily, and 
consequently two or more doses were taken in any week. 
A4: Inadvertently this drug and daily medications were taken together, and 
consequently two or more doses of this drug were taken in any week. 
A5: Other (Specify details.) 
b. A larger dose than prescribed was taken. 
The specific details and reason should be entered into PostMaNet. 
c. There was any week in which no dose of this drug was taken. 
<Reason> 
A1: The dose was forgotten. 
A2: The dose could not be taken because of conflicting work schedule etc. 
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A3: Other (Specify details.) 
 
***Diet/exercise therapy compliance status will be categorized as follows:  
1. ≥90% were performed (The prescribed regimen was nearly completely followed.) 
2. ≥70% were performed (The prescribed regimen was followed most of the time.) 
3. ≥50% were performed (The prescribed regimen was followed at least 50% of the time.) 
4. <50% were performed (The prescribed regimen was followed less than 50% of the time) 
5. Not performed 
6. Unknown compliance status 
 
2) Time of data collection 
At initiation of treatment with this drug (only the diet/exercise therapy compliance status), and 
1, 3, 6, 12, 18, 24, 30, and 36 months later (or discontinuation of treatment) 
 
9.4 Items of Tests and Observations 
9.4.1 Vital Signs 
1) Items of tests and observations 
Pulse rate, blood pressure (systolic /diastolic), body weight 
2) Time of data collection  
At initiation of treatment with this drug, and 1, 3, 6, 12, 18, 24, 30, and 36 months later (or 
discontinuation of treatment), if measured 
 
9.4.2 Laboratory Tests 
1) Test variables 
HbA1c (NGSP value [same applies below]), fasting blood glucose, fasting insulin, fasting 
glucagon, fasting triglyceride, total cholesterol, HDL cholesterol, LDL cholesterol, serum 
creatinine, BUN, urinary albumin (urine albumin/creatinine ratio), AST, ALT, gamma-GTP, 
ALP, total bilirubin, amylase, lipase 
2) Time of data collection 
At initiation of treatment with this drug, and 1, 3, 6, 12, 18, 24, 30, and 36 months later (or 
discontinuation of treatment), if performed 
 
9.4.3 Electrocardiogram 
1) Test variables  
Electrocardiogram (assessment and findings)  
2) Time of data collection 
At initiation of treatment with this drug, and 1, 3, 6, 12, 24, and 36 months later (or 
discontinuation of treatment), if performed  
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9.4.4 Waist Circumference and Testing Related to Coronary Arteries and Arteriosclerosis 
1) Test variables 
Waist circumference*, testing related to coronary arteries and arteriosclerosis** (eg, pulse 
wave velocity [PWV]), blood pressure pulse wave test [cardio-ankle vascular index; CAVI], 
cervical artery ultrasound, intravascular ultrasound [IVUS]) 
*: Measured at the patient’s umbilicus level in a standing position at gentle exhalation. However, in patients 
with marked fat accumulation with downward deviation of the umbilicus, the waist circumference will be 
measured at the level of the midpoint between the lowest rib and the anterior superior iliac spine. 
**: Any testing method is allowed, but in principle the same method should be used throughout the individual 
time points of evaluation. The testing may be omitted if no testing device is available. 
2) Time of data collection 
At initiation of treatment with this drug, and 6, 12, 24, and 36 months later (or discontinuation 
of treatment), if performed 
 
 
9.4.5 Other Items of Observation 
1) Observation item(s) 
Presence or absence of pregnancy during the observation (only in women) 
Any pregnancy found during the observation period should be immediately notified to the 
Takeda personnel. In response to a request by the Takeda personnel, the survey physician will 
provide detailed information (as far as possible up to the outcome of pregnancy, eg premature 
labour) using a Pregnancy Sheet separately. 
2) Time of data collection 
From initiation of treatment with this drug to 36 months later (or discontinuation of treatment) 
 
9.5 Adverse Events 
1) Survey variables 
Presence or absence of adverse events (see Table 1), adverse event term, date of onset, 
seriousness and reason for the assessment as serious (see Table 2), reason for discontinuation 
of this drug, outcome assessment date, outcome, causal relationship to this drug* (see Table 3) 
 
If the event outcome is “Not resolved” or “Unknown”, and if the causal relationship is 
“Unassessable”, the event should be followed as far as possible. 
 
Detailed event information should be collected as much as possible for any reported adverse 
events of hypoglycemia, skin disorder, acute pancreatitis, proarrhythmia with prolonged 
QT/QTc interval, intestinal obstruction, infection, malignant tumor, and cardiovascular event 
(eg, symptomatic coronary artery disease, cerebrovascular disorder, arteriosclerosis obliterans, 
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cardiovascular death, sudden death); as well as any adverse events reported in patients with 
renal impairment, patients with hepatic impairment, elderly patients, patients on concomitant 
insulin, and patients given overdosage of this drug. 
*: If the causal relationship to this drug is “Not related”, the basis for the assessment should be collected. 
If the causal relationship to this drug is “Unassessable”, the reason should be collected. 
Note) Special guidance about reporting of adverse events: 
Abnormal worsening of the target disease, eg, outside the predictable range of the natural course of 
the disease, is regarded as an adverse event. 
 
2) Time of data collection 
From initiation of treatment with this drug to 36 months later (or discontinuation of treatment) 
 
Table 1 
Definition of an Adverse Event 
An adverse event (AE) is defined as any untoward medical occurrence in a patient administered a 
pharmaceutical product and which does not necessarily have a causal relationship with this treatment.  
An adverse event can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, 
whether or not the event is considered causally related to the use of the product. 
Note that the following events will also be handled as adverse events: 
- Any manifestation in an infant breastfed by the mother taking this drug  
- Any untoward manifestation in a child given this drug 
- Any manifestation due to vocational exposure to this drug 
- Any manifestation due to a counterfeit product of a prescription drug marketed by Takeda 
- Any untoward manifestation in a patient given this drug revealed by a lawsuit or any other legal action 
 
Table 2 
Criteria for Serious Adverse Events 
An adverse event is assessed as “serious” if it results in any of the following outcomes:  
1. results in death (Death), 
2. is life-threatening (Life-threatening), 
3. requires hospitalization or prolongation of existing hospitalization (Hospitalization/Prolongation of 
hospitalization), 
4. results in persistent or significant disability/incapacity (Disability), 
5. leads to a congenital anomaly or birth defect (Congenital anomaly), or 
6. is any other important medical event that does not 1 to 5 above. 
Serious adverse events include events described in the “Takeda Medically Significant AE List”. 
 
Takeda Medically Significant AE List 
- Acute respiratory failure/Acute respiratory distress 
syndrome (ARDS) 
- Anaphylactic shock 
- Torsade de pointes / Ventricular fibrillation / 
- Acute renal failure 
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Ventricular tachycardia 
- Malignant hypertension 
- Pulmonary hypertension 
- Convulsive seizure (including convulsion and 
epilepsy) 
- Pulmonary fibrosis (including interstitial 
pneumonia) 
- Agranulocytosis 
- Neuroleptic malignant syndrome/ Malignant 
hyperthermia 
- Aplastic anaemia 
- Spontaneous abortion / Stillbirth and fetal death 
- Toxic epidermal necrolysis / Oculomucocutaneous 
syndrome (Stevens-Johnson syndrome) 
- Confirmed or suspected transmission of 
infectious agent by a medicinal product 
- Hepatic necrosis 
- Confirmed or suspected endotoxin shock 
- Acute hepatic failure 
 
 
Table 3 
Assessment of the Causal Relationship Between an Adverse Event and this Drug 
Causality 
classification 
Definition 
Related 
An adverse event that follows a temporal sequence from administration of 
this drug (including the course after withdrawal of the drug), or for which 
there is at least reasonable possibility of involvement of this drug and its 
causal role cannot be ruled out, although factors other than the drug, such as 
the primary disease, concurrent diseases, concomitant drugs or concurrent 
treatments, may also be responsible. 
Not related 
An adverse event that does not follow a temporal sequence from administration 
of this drug or that can reasonably be explained by other factors, such as the 
primary disease, concurrent diseases, concomitant drugs or concurrent 
treatments.  
Unassessable 
The causality cannot be assessed because of insufficiency of required 
information, such as temporal sequence of the event onset relative to 
administration of this drug (including the course after withdrawal of the drug), 
primary disease, concurrent diseases, concomitant drugs, and concurrent 
treatments. 
 
10.0 Analytical Items and Methods 
10.1 Statistical Analysis Plan 
A statistical analysis plan will be prepared before the database lock. The statistical analysis plan 
will describe the definitions of evaluation items and details of analytical methods.  
 
10.2 Analysis Populations 
Two analysis populations of the “safety analysis set” and “efficacy analysis set” will be defined.  
 
10.3 Disposition of Patients 
Number of patients enrolled in the survey, number of patients with collected case report forms 
(electronic), numbers of patients evaluated for the safety and efficacy, number of patients excluded 
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from analyses and reasons for exclusion, etc. will be summarized. 
 
10.4 Patient Background 
Patient background data such as sex, age, duration of disease, hypersensitive diathesis, and 
concurrent diseases will be summarized. 
 
10.5 Treatment Details etc. 
Detailed use of this drug, treatment compliance status, detailed use of concomitant drugs, etc. will 
be summarized. 
 
10.6 Safety Data 
The following data will be summarized using the safety analysis set. Adverse events will be coded 
using the MedDRA/J, and summarized by Preferred Term (PT) and System Organ Class (SOC). 
 
10.6.1 Adverse Event Profile 
Adverse events occurring during the observation period will be summarized using frequency 
distribution by event type, causal relationship to this drug, etc. 
 
10.6.2 Factors Likely Affecting the Safety 
Adverse events and adverse drug reactions occurring during the observation period will be 
summarized using frequency distribution, with stratification of patients according to 
background factors (eg, sex, age) and treatment details (eg, detailed use of this drug, detailed 
use of concomitant drugs). 
 
10.7 Efficacy Data 
The following data will be summarized using the efficacy analysis set. 
 
10.7.1 HbA1c Over Time 
The HbA1c level and change (value at the respective time after initiation of treatment minus 
baseline value) at each time point of evaluation will be summarized. In addition, the glycemic 
control goal achievement rate at each time point of evaluation will be summarized. 
 
10.7.2 Laboratory Test Values Over Time 
For fasting blood glucose, fasting insulin, HOMA-β*, etc., the level and change at each time 
point of evaluation (value at the respective time after initiation of treatment minus baseline 
value) will be summarized. 
* HOMA-β: (fasting insulin × 360)/(fasting blood glucose − 63) 
 
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10.7.3 Factors Likely Affecting the Efficacy 
The change in HbA1c etc. will be summarized with stratification of patients according to 
background factors (eg, sex, age, baseline HbA1c level) and treatment details (eg, detailed use 
of this drug, detailed use of concomitant drugs). 
 
10.8 Special Patient Populations 
The safety and efficacy in patients with renal impairment, patients with hepatic impairment and 
elderly patients will be summarized with stratification of patients. 
 
10.9 Interim Analysis 
For early assessment and analysis of safety data from this survey, and publication of the results as 
necessary, an interim analysis will be performed based on the entered data up to 12 months of 
treatment, when the duration of observation has reached 1 year in all subjects. 
 
11.0 Registration of Survey Information 
Before initiation of this survey, information on this survey will be registered with the following 
website. 
• Japan Pharmaceutical Information Center (JAPIC) Clinical Trials Information 
 
12.0 Administrative Structure 
12.1 Survey Manager 
Post-marketing surveillance manager, Takeda Pharmaceutical Company Limited 
 
13.0 Trustees 
(1) AC Medical Inc. 
Address: 1-12-38 Esaka-cho, Suita City, Osaka 
Activities: Supportive activities in the PostMaNet construction 
 
(2) Fujitsu Japan Corporation 
Address: 2-2-2 Nakanoshima, Kita-ku, Osaka 
Activities: PostMaNet construction and operation 
 
 
(3) Cognizant Japan KK 
Address: PMO Hanzomon, 2-1 Kojimachi, Chiyoda-ku, Tokyo 
Activities: Data management 
 
(4) PRA Health Sciences K.K. 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

 
13 
Address: 4-1-3 Kyutaromachi, Chuo-ku, Osaka 
Activities: Supportive activities in data management, record archiving, adverse event report 
conversion to PDF, and dissemination of information 
 
(5) EPS Corporation 
Address: 2-23 Shimomiyabicho, Shinjuku-ku, Tokyo 
Activities: Statistical analysis activities 
 
（6）PharField Corporation 
Address: 2-8-20 Saga, Koto-ku, Tokyo 
Activities: Monitoring progress management and monitoring activities 
 
14.0 Other Necessary Items 
14.1 Amendments to the Protocol 
During the survey period, monitoring will be performed regarding the progress of the survey, 
occurrence of adverse drug reactions unexpected from the PRECAUTIONS and serious adverse 
drug reactions, any increase in the incidence of particular adverse drug reactions, validity of the 
survey variables, etc., and the protocol will be reviewed and amended as necessary. If any partial 
change to the DOSAGE AND ADMINISTRATION, INDICATIONS, etc. is approved during the 
survey period, whether or not the protocol should be amended will be examined, and the protocol 
will be amended as necessary. 
 
14.2 Actions to be taken in Response to Detection of any Issues or Concerns 
Whenever an issue is found regarding the safety or efficacy, the data will be investigated in detail, 
and necessary actions will be determined. 
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14 
Appendix 
Observation Schedule 
              Time of data collection  
 
Survey variables  
Observation period 
Enrollment 
Start of 
treatment 
1 month 
3 months 
6 months 
12 
months 
18 
months 
24 
months 
30 
months  
36 
months 
Discontin
uation of 
treatment
Patient enrollment 
Date of prescription of this drug 
○ 
 
 
 
 
 
 
 
 
 
 
Subject identification number 
○ 
 
 
 
 
 
 
 
 
 
 
Patient initials 
○ 
 
 
 
 
 
 
 
 
 
 
Sex 
○ 
 
 
 
 
 
 
 
 
 
 
Date of birth 
○ 
 
 
 
 
 
 
 
 
 
 
Assessment against inclusion/exclusion 
criteria 
○ 
 
 
 
 
 
 
 
 
 
 
Serum creatinine within 1 month before use 
of this drug (presence or absence and, if 
present, specific data) 
○ 
 
 
 
 
 
 
 
 
 
 
Severity of renal impairment and its basis (if 
without any serum creatinine within 1 
month before use of this drug) 
○ 
 
 
 
 
 
 
 
 
 
 
Total bilirubin, AST or ALT within 1 month 
before use of this drug (presence or absence 
and, if present, specific data) 
○ 
 
 
 
 
 
 
 
 
 
 
Severity of hepatic impairment and its basis 
(if without total bilirubin, AST or ALT 
within 1 month before use of this drug) 
○ 
 
 
 
 
 
 
 
 
 
 
Presence or absence of concurrent or past 
history of pancreatitis or gallbladder stone 
○ 
 
 
 
 
 
 
 
 
 
 
Patient background 
Time of the diagnosis of type 2 diabetes 
mellitus 
 
○ 
 
 
 
 
 
 
 
 
 
Inpatient/outpatient category 
 
○ 
 
 
 
 
 
 
 
 
 
Hypersensitive diathesis 
 
○ 
 
 
 
 
 
 
 
 
 
Concurrent diseases 
 
○ 
 
 
 
 
 
 
 
 
 
Medical history 
 
○ 
 
 
 
 
 
 
 
 
 
Height 
 
○ 
 
 
 
 
 
 
 
 
 
History of smoking 
 
○ 
 
 
 
 
 
 
 
 
 
History of alcohol consumption 
 
○ 
 
 
 
 
 
 
 
 
 
Treatment details etc. 
Detailed use of this drug 
 
○ 
Detailed use of concomitant drugs (for 
diabetes mellitus) 
 
 
○ 
Detailed use of concomitant drugs (for other 
conditions than diabetes mellitus) 
 
 
○ 
Treatment compliance status, treatment 
noncompliance details and reasons 
 
 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
Diet/exercise therapy compliance status 
 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
Assessments 
Pulse rate, blood pressure, body weight 
 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
Laboratory tests  
HbA1c, fasting blood glucose, fasting 
insulin, fasting glucagon, fasting triglyceride
total cholesterol, HDL cholesterol, LDL 
cholesterol, serum creatinine, BUN, urinary 
albumin (urine albumin/creatinine ratio), 
AST, ALT, gamma-GTP, ALP, total bilirubin,
amylase, lipase 
 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
Electrocardiogram 
 
○ 
○ 
○ 
○ 
○ 
 
○ 
 
○ 
○ 
Waist circumference 
 
○ 
 
 
○ 
○ 
 
○ 
 
○ 
○ 
Testing related to coronary arteries and 
arteriosclerosis 
 
○ 
 
 
○ 
○ 
 
○ 
 
○ 
○ 
Any pregnancy (women only)  
 
 
○ 
Adverse event monitoring  
 
 
○ 
○ 
: Performed 
 ○ 
: Performed throughout the period 
* Including antidiabetic medication discontinued within 3 months before use of this drug 
○ 
○* 
○ 
○ 
○ 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use