Specified Drug-Use Survey of Alogliptin and Metformin Hydrochloride Combination Tablets "Survey on Long-term Use in Type 2 Diabetes Mellitus Patients With Renal or Hepatic Impairment or Advanced Age"
Conditions: Type 2 Diabetes Mellitus
Sponsor: Takeda

 
 
Title: Specified Drug-Use Survey of INISYNC Combination Tablets ͆ Survey on 
long-term use in type 2 diabetes mellitus patients with renal or hepatic impairment or 
advanced age” 
 
NCT Number: NCT03555565 
Protocol Approve Date: 01-JUN-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: 
z 
Named persons or organizations associated with the study. 
z 
Patient identifiers within the text, tables, or figures or in by-patient data listings. 
z 
Proprietary information, such as scales or coding systems, which are considered 
confidential information under prior agreements with license holder. 
z 
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 
INISYNC Combination Tablets  
“Survey on long-term use in  
type 2 diabetes mellitus patients with  
renal or hepatic impairment or advanced age” 
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

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
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Survey Sponsor  
Takeda Pharmaceutical Company Limited  
Protocol Number 
Alogliptin-Met-5003 
Version Number 
Version 5 
Date of Preparation 
June 1, 2019 
 
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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 ....................................................................................................................................... 3 
5.0 
Dosage and Administration ............................................................................................................................ 3 
6.0 
Planned Number of Survey Sites by Specialty Department ........................................................................... 3 
7.0 
Methods .......................................................................................................................................................... 3 
7.1 
Duration of Observation ............................................................................................................................. 3 
7.2 
Data Collection Method ............................................................................................................................. 3 
7.3 
Patient Enrollment Method ........................................................................................................................ 3 
7.4 
Case Report Form (Electronic) Completion and Electronic Signature ....................................................... 3 
8.0 
Planned Survey Period ................................................................................................................................... 4 
9.0 
Informed Consent ........................................................................................................................................... 4 
10.0 
Survey Variables ............................................................................................................................................. 4 
10.1 
Patient Enrollment ...................................................................................................................................... 4 
10.2 
Patient Background .................................................................................................................................... 5 
10.3 
Treatment Details ....................................................................................................................................... 6 
10.4 
Treatment Compliance Status for this Drug, and Daily Dosing Frequency and Number of Tablets for 
Concomitant Drugs ................................................................................................................................................ 6 
10.5 
Items of Tests and Observations ................................................................................................................. 6 
 
Vital Signs .......................................................................................................................................... 6 
 
Laboratory Tests ................................................................................................................................. 7 
 
Electrocardiogram .............................................................................................................................. 7 
 
Waist Circumference and Testing Related to Coronary Arteries and Arteriosclerosis ....................... 7 
 
Other Items of Observation ................................................................................................................ 7 
10.6 
Adverse Events ........................................................................................................................................... 8 
11.0 
Analytical Items and Methods ........................................................................................................................ 9 
11.1 
Disposition of Patients................................................................................................................................ 9 
11.2 
Patient Background .................................................................................................................................... 9 
11.3 
Treatment Details ..................................................................................................................................... 10 
11.4 
Treatment Compliance Status, and Daily Dosing Frequency and Number of Tablets for Concomitant 
Drugs  .................................................................................................................................................................. 10 
11.5 
Safety Data ............................................................................................................................................... 10 
 
Adverse Event Profile ...................................................................................................................... 10 
 
Factors Likely Affecting the Safety .................................................................................................. 10 
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11.6 
Efficacy data ............................................................................................................................................. 10 
 
HbA1c over time .............................................................................................................................. 10 
 
Fasting blood glucose over time ....................................................................................................... 10 
 
Fasting insulin over time .................................................................................................................. 10 
 
Factors likely affecting the efficacy ................................................................................................. 11 
 
Factors Likely Affecting Medication Adherence .............................................................................. 11 
11.7 
Special Patient Populations ...................................................................................................................... 11 
12.0 
Survey Informed Consent Form and Patient Consent .................................................................................. 11 
13.0 
Registration of Survey Information .............................................................................................................. 12 
14.0 
Administrative Structure .............................................................................................................................. 12 
15.0 
Trustees ........................................................................................................................................................ 12 
16.0 
Other Necessary Items .................................................................................................................................. 12 
16.1 
Amendments to the Protocol .................................................................................................................... 12 
16.2 
Actions to be Taken in Response to Detection of any Issues or Concerns ............................................... 12 
Appendix 1 
Observation Schedule ....................................................................................................................... 13 
Appendix 2 
Takeda Medically Significant AE List .............................................................................................. 14 
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1 
1.0
Background 
Drugs to treat type 2 diabetes mellitus are likely used over a long time in the routine clinical 
setting. Inisync Combination Tablets (hereinafter referred to as “this drug”) contain two active 
ingredients: alogliptin benzoate (brand name, Nesina Tablets) and metformin hydrochloride. 
Long-term combination use of these drugs in the routine clinical setting was previously 
investigated in a specified drug-use survey. However, clinical trial data were limited on the 
safety and efficacy of this drug in patients with renal impairment, patients with hepatic 
impairment and elderly patients, and therefore data in these patient populations are designated 
as part of “important missing information” in the risk management plan for this drug. Thus, 
with a focus particularly on these patient populations, the present specified drug-use survey 
(hereinafter referred to as “this survey”) has been planned to investigate the long-term safety 
and efficacy of this drug used in the routine clinical setting in type 2 diabetes mellitus patients
with renal or hepatic impairment or advanced age. 
 
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 
This survey aims to evaluate the long-term safety and efficacy of this drug in type 2 diabetes 
mellitus patients with renal impairment (mild), hepatic impairment (mild or moderate), or 
advanced age (t65 years) in the routine clinical setting. In addition, this survey will enroll as 
many as possible patients who were switched from alogliptin 25 mg and metformin 
hydrochloride 500 mg (ie, 250 mg twice daily) in combination as a prior medication, to 
examine the relationship between the efficacy and improvement in medication adherence by 
the switching to this combination product in those who were taking alogliptin benzoate and 
metformin hydrochloride in combination. 

3.0 
Planned Sample Size and Rationale 
3.1 Planned Sample Size 
600 subjects (including 300 subjects with hepatic impairment)
3.2 Rationale 
Among the important identified risks and important potential risks of this drug, the following 
were reported in the alogliptin + metformin QD group (alogliptin 25 mg plus metformin 
hydrochloride 500 mg once daily) of Study SYR-322-MET/CCT-001: infection-related 
adverse events (26.3%, 40/152 subjects), gastrointestinal symptom-related adverse events 
(9.9%, 15/152 subjects), lactic acidosis-related adverse events (1.3%, 2/152 subjects), and 
hepatic function disorder-related adverse events (0.7%, 1/152 subjects). Based on these data, 
the incidence in this survey can be assumed to be t0.7% for such events among the important 
identified risks and important potential risks of this drug. 
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Assuming a Poisson distribution for the number of such events occurring in this survey, and 
with a sample size of 300 each for patients with renal impairment, patients with hepatic 
impairment, and elderly patients, adverse events occurring with an incidence of t0.7% in one 
of the patient subpopulations can be detected in at least one patient with a probability of t87%. 
Thus, with this sample size, the events reported in Study SYR-322-MET/CCT-001 and 
designated as important identified risks and important potential risks of this drug would be 
evaluable to a reasonable extent. For events occurring with a lower incidence, overall safety 
assessment will be performed based on information not only from this survey but also from 
other sources including spontaneous reports and literature in particular. 
 
From the viewpoint of patient accrual, patients with hepatic impairment will be the most 
difficult subpopulation to be accrued in this survey, based on the accrual rates in a previously 
conducted specified drug-use survey of Nesina Tablets in type 2 diabetes mellitus patients 
with concomitant use of a biguanide, which also enrolled patients with renal impairment, 
patients with hepatic impairment, and elderly patients. Thus, in order to ensure that patients 
with hepatic impairment in particular are adequately enrolled in this survey, the accrual target 
is set to “300 patients with hepatic impairment”. When this target is reached, in light of the 
extent of overlapping of the subpopulations in the above-mentioned Nesina Tablets specified 
drug-use survey, approximately 300 patients with renal impairment and approximately 300 
elderly patients would have been accrued. 
 
Also, with a total sample size of t600 in this survey, improvement in patient convenience by 
switching to this combination product from alogliptin benzoate and metformin hydrochloride
in combination would be evaluable to a reasonable extent. 
4.0
Target Patient Population 
This survey will be conducted in patients with type 2 diabetes mellitus for whom combination 
therapy with alogliptin benzoate and metformin hydrochloride is appropriate in the opinion of 
a physician, and 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 one or more of the following: 
(1) Have renal impairment (mild) 
(2) Have hepatic impairment (mild or moderate) 
(3) Elderly (aged t65 years) 
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4.2 Exclusion Criteria 
Subjects who meet the following criterion will be excluded:
Patients with any contraindication for this drug
5.0
Dosage and Administration 
The usual adult dosage of this drug is 1 tablet (ie, 25 mg of alogliptin and 500 mg of 
metformin hydrochloride) once daily orally immediately before a meal or after a meal. The 
package insert for this drug should be referenced. 
6.0
Planned Number of Survey Sites by Specialty Department 
Approximately 120 sites, including department of internal medicine 
7.0
Methods 
7.1 Duration of Observation 
12 months 
7.2 Data Collection Method
Data will be collected using a web-based electronic data capture system (
). 
7.3 Patient Enrollment Method 
Patients will be enrolled using a centralized registration method via 
.
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 
 promptly after the end of observation at 12 months of treatment with this drug, 
and the survey 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 
 promptly 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 
, and the survey physician will enter an electronic signature. 
*: 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 
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entry to 
, 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 person in charge of Takeda Pharmaceutical Company Limited (hereinafter 
referred to as “Takeda personnel”). 
 
8.0 
Planned Survey Period 
Survey period: February 2017 to October 31, 2019  
Patient enrollment period: February 2017 to October 31, 2018 Note) 
Note) Even if this drug is prescribed by October 31, 2018, no patient enrollment (via 
) 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
Informed Consent 
Prior to enrollment of a patient in this survey, the survey physician will obtain written or 
verbal consent of the patient or the patient’s legally acceptable representative. Patients who 
provided consent will be assigned the subject identification numbers. 
10.0
Survey Variables 
The survey physician or designee will enter data on the following variables into 
. 
The survey schedule is shown in Appendix 1. 
10.1 Patient Enrollment 
1)Survey variables
Date of prescription of this drug, subject identification number, patient initials, sex, age, 
assessment against the inclusion criteria (ie, the patient has renal impairment*1 [mild], 
hepatic impairment*2 [mild or moderate], or advanced age [t65 years]), assessment against 
the exclusion criteria (ie, the patient does not have any contraindication for this drug), 
status of medication for type 2 diabetes mellitus immediately before use of this drug 
 
As a guide to severity assessment of renal impairment and hepatic impairment, the following tables 
should be referenced. 
 
 
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*1: Severity classification of renal impairment 
Severity of renal 
impairment 
eGFR 
(mL/min/1.73m2)  
Serum creatinine  
(mg/dL) * 
Creatinine clearance  
(Ccr, mL/min)  
Mild 
t60 to <90 
Male: >0.90 to d1.4 
Female: >0.77 to d1.2 
t50 to d80 
Moderate 
t30 to <60 
Male: >1.4 to d2.4 
Female: >1.2 to d2.0 
t30 to <50 
Severe or  
end-stage renal disease 
<30 
Male: >2.4 
Female: >2.0 
<30 
For end-stage renal disease, time of the measurement relative to a hemodialysis session is disregarded. 
 
*: Estimated values corresponding to the Ccr (for persons who are aged 60 years and weigh 65 kg)  
Adapted from the “Precautions related to Dosage and Administration” section of Nesina Tablets package insert (see 
Cockcroft DW, et al. Nephron 1976; 16: 31-41) 
 
*2: Severity classification of hepatic impairment 
Severity of 
hepatic 
impairment 
Mild 
Moderate 
Severe 
Total bilirubin 
(mg/dL)  
t1.6 to <3.0 
t3.0 to <10 
t10 
AST or ALT 
(U/L) 
t50 to <100 
t100 to <500 
t500 
ALP 
t1.25 × ULN to  
<2.5 × ULN 
t2.5 × ULN to  
<5 × ULN  
t5 × ULN  
Gamma-GTP 
t1.5 × ULN 
- 
- 
LDH 
t1.5 × ULN 
- 
- 
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 t6 
months 
ULN: Upper limit of normal of the study site 
 
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
10.2 Patient Background 
1) Survey variables 
Time of the diagnosis of type 2 diabetes mellitus, inpatient/outpatient category, 
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, status of occupation (presence or absence), status 
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of treatment compliance with alogliptin benzoate and metformin hydrochloride within 3 
months before the start of treatment with this drug*3 
*3: Assessed using a scale from 0% to 100% in increments of 5%. 
2) Time of data collection 
At initiation of treatment with this drug 
10.3 Treatment Details 
1) Survey variables 
Detailed use of this drug (therapy start date, therapy end date, and reason for 
discontinuation [if applicable]), detailed use of concomitant drugs*4 (for the treatment of 
diabetes mellitus) (presence or absence, if present, name of the drug, daily dose, and 
therapy dates), detailed use of concomitant drugs (for other conditions than diabetes 
mellitus) (presence or absence, if present, name of the drug, reason for use) 
*4: Including antidiabetic medication discontinued within 3 months before use of this drug 
(Also, alogliptin benzoate and metformin hydrochloride used before this drug will be 
investigated.) 
2) Time of data collection 
From initiation of treatment with this drug until 12 months later (or discontinuation of 
treatment) 
10.4 Treatment Compliance Status for this Drug, and Daily Dosing Frequency and Number of 
Tablets for Concomitant Drugs 
1) Survey variables 
The status of treatment compliance with this drug will be assessed using a scale from 0% to 
100% in increments of 5%. 
Also regarding concomitant drugs (for the treatment of diabetes mellitus or other 
conditions), the maximum number of doses administered per day and the maximum number 
of tablets administered per day will be investigated at each time of data collection. 
2)Time of data collection
At initiation of treatment with this drug (except treatment compliance status for this drug), 
and 1, 3, 6, 9, and 12 months later (or discontinuation of treatment) 
10.5 Items of Tests and Observations 
Data from tests and observations in the routine clinical setting, if performed at the respective 
time of data collection, will be entered. 
 
 Vital Signs 
1)Items of tests and observations
Pulse rate, blood pressure (systolic /diastolic), body weight
2)Time of data collection
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At initiation of treatment with this drug, and 1, 3, 6, 9, and 12 months later (or 
discontinuation of treatment), if performed 
 Laboratory Tests 
1)Test variables
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, LDH, total bilirubin, 
amylase, lipase, lactic acid 
2)Time of data collection
At initiation of treatment with this drug, and 1, 3, 6, 9, and 12 months later (or 
discontinuation of treatment), if performed 
 Electrocardiogram 
1)Test variable
Electrocardiogram (assessment)
2)Time of data collection
At initiation of treatment with this drug and 12 months later (or discontinuation of treatment), 
if performed
 
 Waist Circumference and Testing Related to Coronary Arteries and Arteriosclerosis 
1) Test variables 
Waist circumference*5, testing related to coronary arteries and arteriosclerosis*6 (eg, pulse 
wave velocity , blood pressure pulse wave test, cervical artery ultrasound, intravascular 
ultrasound) 
*5: 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. 
*6: 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 12 months later (or discontinuation of treatment), 
if performed 
 
 Other Items of Observation 
1) Observation item(s) 
Presence or absence of pregnancy during the observation (only in women)  
2) Time of data collection 
From initiation of treatment with this drug until 12 months later (or discontinuation of 
treatment) 
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10.6 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*7 (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. 
 
If onset of any of the following is reported as an adverse event, detailed information should 
be collected as needed: lactic acidosis, hypoglycemia, acute pancreatitis, hepatic function 
disorder or jaundice, severe skin disorder such as oculomucocutaneous syndrome 
(Stevens-Johnson syndrome) and erythema multiforme, rhabdomyolysis, intestinal 
obstruction, interstitial pneumonia, angioedema, gastrointestinal symptom, infection, 
malignant tumor, pemphigoid, cardiovascular event (eg, symptomatic coronary artery 
disease, cerebrovascular disorder, arteriosclerosis obliterans, cardiovascular death, sudden 
death). 
*7: 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 until 12 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. 
 
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10 
11.3 Treatment Details 
Detailed use of this drug and concomitant drugs will be summarized. 
 
11.4 Treatment Compliance Status, and Daily Dosing Frequency and Number of Tablets for 
Concomitant Drugs 
Treatment compliance status will be summarized for alogliptin benzoate and metformin 
hydrochloride within 3 months before use of this drug, and also for this drug at each time 
of data collection. Also regarding concomitant drugs (for the treatment of diabetes 
mellitus and other conditions), the maximum number of doses administered per day and 
the maximum number of tablets administered per day will be summarized. 
 
11.5 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). 
 
 Adverse Event Profile 
Adverse events occurring during the observation period will be summarized using 
frequency distribution by event type, time to onset, seriousness, causal relationship to this 
drug, etc. 
 Factors Likely Affecting the Safety 
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, presence or absence of renal impairment, presence or absence of hepatic 
impairment) and treatment details (eg, detailed use of this drug). 
11.6 Efficacy data 
The following data will be summarized using the efficacy analysis set. 
 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.  
 Fasting blood glucose over time 
The fasting blood glucose level and change (value at the respective time after initiation of 
treatment minus baseline value) at each time point of evaluation will be summarized.  
 
 Fasting insulin over time 
The fasting insulin level and change (value at the respective time after initiation of 
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11 
treatment minus baseline value) at each time point of evaluation will be summarized.  
 
 Factors likely affecting the efficacy 
A subgroup analysis will be performed on change in HbA1c etc., with stratification of 
patients according to background factors (eg, sex, age, presence or absence of renal 
impairment, presence or absence of hepatic impairment, baseline HbA1c level) and 
treatment details (eg, detailed use of this drug). In addition, among the patients with no 
change in the dose of alogliptin benzoate and metformin hydrochloride between before and 
after the switching to this drug, and no change in the dose of any antidiabetic medication 
during the treatment with this drug, the treatment compliance status between before and 
after the use of this drug and change in HbA1c will be summarized, and the relationship 
between medication adherence and change in HbA1c will be analyzed. In this analysis, in 
order to minimize influence of other factors than reductions in the number of tablets per 
day and the number of doses per day by switching to this drug among factors likely 
contributing to medication adherence, subgroup analyses according to such other factors etc. 
will be used to characterize the relationship between medication adherence and change in 
HbA1c as far as possible. 
 
 Factors Likely Affecting Medication Adherence 
Regarding change in the medication adherence, in order to minimize influence of other 
factors than reductions in the number of tablets administered per day and the number of 
doses per day by switching to this drug among factors likely contributing to medication 
adherence, subgroup analyses according to such other factors etc. will be used to 
characterize the influence of this drug on the medication adherence. 
11.7 Special Patient Populations 
For each of the subpopulations of patients with renal impairment, patients with hepatic 
impairment, and elderly patients in this survey, a similar analysis to Sections 10.1 to 10.8.3
will be performed. 
12.0
Survey Informed Consent Form and Patient Consent 
The survey informed consent form contains the description as to how the patients’ personal 
information and medical information are used in this survey. The informed consent form 
also describes the survey overview, the freedom of patients to withdraw from the survey at 
any time without providing a reason without any disadvantages in treatment. 
 
The survey physician will provide a potential survey subject (or legally acceptable 
representative) with explanation about this survey as provided in the informed consent 
form, and obtain verbal or written consent of the patient (or legally acceptable 
representative) to participate in this survey. For written consent, the patient (or legally 
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acceptable representative) will sign and date the informed consent form, and the survey 
physician will retain the original of the signed informed consent form. For verbal consent, 
the survey physician will document the verbal consent. 
 
13.0
Registration of Survey Information 
Before initiation of this survey, information on this survey will be registered with the 
following website. 
x Japan Pharmaceutical Information Center (JAPIC) Clinical Trials Information 
14.0
Administrative Structure 
See Attachment. 
15.0
Trustees 
See Attachment.

16.0 
Other Necessary Items 
16.1 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. 
16.2 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 2 
Takeda Medically Significant AE List 
 
General 
Malignancy 
Endotoxic shock 
Sepsis 
Transmission of an infectious agent by a 
medicinal product 
 
Blood and lymphatic System 
Bone marrow failure 
Disseminated Intravascular Coagulation  
Haemolytic anaemia 
Thrombotic Thrombocytopenic Purpura 
Cardiovascular System 
Cardiac arrest 
Cardiac failure 
Cardiomyopathy acute 
Malignant hypertension 
Myocardial infarction 
Ventricular arrhythmias 
Endocrine System 
Adrenal crisis  
Gastrointestinal System 
Acute pancreatitis 
GI haemorrhage 
GI perforation 
GI obstruction 
Necrotising colitis 
Peritonitis 
Hepatobiliary System 
Acute hepatic failure 
Fulminant hepatitis 
Urinary System 
Acute renal failure 
 
Immune system 
Anaphylaxis 
Progressive multifocal leukoencephalopathy 
(PML) 
Transplant rejection 
Musculoskeletal System 
Rhabdomyolysis 
Nervous System 
Cerebrovascular accident 
Coma 
Convulsive seizures 
Hyperthermia malignant 
Macular oedema 
Meningoencephalitis 
Neuroleptic malignant syndrome 
Suicidal behaviour 
Reproductive System 
Abortion 
Uterine perforation 
Respiratory System 
Acute respiratory failure 
Pulmonary hypertension 
Pulmonary thromboembolism 
Skin and subcutaneous tissue 
Toxic epidermal necrolysis 
Stevens-Johnson syndrome 
 
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

 
Protocol for Specified Drug-Use Survey of 
INISYNC Combination Tablets  
“Survey on long-term use in  
type 2 diabetes mellitus patients with  
renal or hepatic impairment or advanced age” 








Survey Sponsor  
Takeda Pharmaceutical Company Limited  
Protocol Number 
Alogliptin-Met-5003 
Version Number 
Version 4 
Date of Preparation 
November 27, 2017 
 
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Terms of Use

 
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 ....................................................................................................................................... 3 
5.0 
Dosage and Administration ............................................................................................................................ 3 
6.0 
Planned Number of Survey Sites by Specialty Department ........................................................................... 3 
7.0 
Methods .......................................................................................................................................................... 3 
7.1 
Duration of Observation ............................................................................................................................. 3 
7.2 
Data Collection Method ............................................................................................................................. 3 
7.3 
Patient Enrollment Method ........................................................................................................................ 3 
7.4 
Case Report Form (Electronic) Completion and Electronic Signature ....................................................... 3 
8.0 
Planned Survey Period ................................................................................................................................... 4 
9.0 
Informed Consent ........................................................................................................................................... 4 
10.0 
Survey Variables ............................................................................................................................................. 4 
10.1 
Patient Enrollment ...................................................................................................................................... 4 
10.2 
Patient Background .................................................................................................................................... 5 
10.3 
Treatment Details ....................................................................................................................................... 6 
10.4 
Treatment Compliance Status for this Drug, and Daily Dosing Frequency and Number of Tablets for 
Concomitant Drugs ................................................................................................................................................ 6 
10.5 
Items of Tests and Observations ................................................................................................................. 6 
 
Vital Signs .......................................................................................................................................... 6 
 
Laboratory Tests ................................................................................................................................. 7 
 
Electrocardiogram .............................................................................................................................. 7 
 
Waist Circumference and Testing Related to Coronary Arteries and Arteriosclerosis ....................... 7 
 
Other Items of Observation ................................................................................................................ 7 
10.6 
Adverse Events ........................................................................................................................................... 8 
11.0 
Analytical Items and Methods ........................................................................................................................ 9 
11.1 
Disposition of Patients................................................................................................................................ 9 
11.2 
Patient Background .................................................................................................................................... 9 
11.3 
Treatment Details ..................................................................................................................................... 10 
11.4 
Treatment Compliance Status, and Daily Dosing Frequency and Number of Tablets for Concomitant 
Drugs  .................................................................................................................................................................. 10 
11.5 
Safety Data ............................................................................................................................................... 10 
 
Adverse Event Profile ...................................................................................................................... 10 
 
Factors Likely Affecting the Safety .................................................................................................. 10 
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11.6 
Efficacy data ............................................................................................................................................. 10 
 
HbA1c over time .............................................................................................................................. 10 
 
Fasting blood glucose over time ....................................................................................................... 10 
 
Fasting insulin over time .................................................................................................................. 10 
 
Factors likely affecting the efficacy ................................................................................................. 11 
 
Factors Likely Affecting Medication Adherence .............................................................................. 11 
11.7 
Special Patient Populations ...................................................................................................................... 11 
12.0 
Survey Informed Consent Form and Patient Consent .................................................................................. 11 
13.0 
Registration of Survey Information .............................................................................................................. 12 
14.0 
Administrative Structure .............................................................................................................................. 12 
15.0 
Trustees ........................................................................................................................................................ 12 
16.0 
Other Necessary Items .................................................................................................................................. 12 
16.1 
Amendments to the Protocol .................................................................................................................... 12 
16.2 
Actions to be Taken in Response to Detection of any Issues or Concerns ............................................... 12 
Appendix 1 
Observation Schedule ....................................................................................................................... 13 
Appendix 2 
Takeda Medically Significant AE List .............................................................................................. 14 
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1 
1.0
Background 
Drugs to treat type 2 diabetes mellitus are likely used over a long time in the routine clinical 
setting. Inisync Combination Tablets (hereinafter referred to as “this drug”) contain two active 
ingredients: alogliptin benzoate (brand name, Nesina Tablets) and metformin hydrochloride. 
Long-term combination use of these drugs in the routine clinical setting was previously 
investigated in a specified drug-use survey. However, clinical trial data were limited on the 
safety and efficacy of this drug in patients with renal impairment, patients with hepatic 
impairment and elderly patients, and therefore data in these patient populations are designated 
as part of “important missing information” in the risk management plan for this drug. Thus, 
with a focus particularly on these patient populations, the present specified drug-use survey 
(hereinafter referred to as “this survey”) has been planned to investigate the long-term safety 
and efficacy of this drug used in the routine clinical setting in type 2 diabetes mellitus patients
with renal or hepatic impairment or advanced age. 
 
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 
This survey aims to evaluate the long-term safety and efficacy of this drug in type 2 diabetes 
mellitus patients with renal impairment (mild), hepatic impairment (mild or moderate), or 
advanced age (t65 years) in the routine clinical setting. In addition, this survey will enroll as 
many as possible patients who were switched from alogliptin 25 mg and metformin 
hydrochloride 500 mg (ie, 250 mg twice daily) in combination as a prior medication, to 
examine the relationship between the efficacy and improvement in medication adherence by 
the switching to this combination product in those who were taking alogliptin benzoate and 
metformin hydrochloride in combination. 

3.0 
Planned Sample Size and Rationale 
3.1 Planned Sample Size 
600 subjects (including 300 subjects with hepatic impairment)
3.2 Rationale 
Among the important identified risks and important potential risks of this drug, the following 
were reported in the alogliptin + metformin QD group (alogliptin 25 mg plus metformin 
hydrochloride 500 mg once daily) of Study SYR-322-MET/CCT-001: infection-related 
adverse events (26.3%, 40/152 subjects), gastrointestinal symptom-related adverse events 
(9.9%, 15/152 subjects), lactic acidosis-related adverse events (1.3%, 2/152 subjects), and 
hepatic function disorder-related adverse events (0.7%, 1/152 subjects). Based on these data, 
the incidence in this survey can be assumed to be t0.7% for such events among the important 
identified risks and important potential risks of this drug. 
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Assuming a Poisson distribution for the number of such events occurring in this survey, and 
with a sample size of 300 each for patients with renal impairment, patients with hepatic 
impairment, and elderly patients, adverse events occurring with an incidence of t0.7% in one 
of the patient subpopulations can be detected in at least one patient with a probability of t87%. 
Thus, with this sample size, the events reported in Study SYR-322-MET/CCT-001 and 
designated as important identified risks and important potential risks of this drug would be 
evaluable to a reasonable extent. For events occurring with a lower incidence, overall safety 
assessment will be performed based on information not only from this survey but also from 
other sources including spontaneous reports and literature in particular. 
 
From the viewpoint of patient accrual, patients with hepatic impairment will be the most 
difficult subpopulation to be accrued in this survey, based on the accrual rates in a previously 
conducted specified drug-use survey of Nesina Tablets in type 2 diabetes mellitus patients 
with concomitant use of a biguanide, which also enrolled patients with renal impairment, 
patients with hepatic impairment, and elderly patients. Thus, in order to ensure that patients 
with hepatic impairment in particular are adequately enrolled in this survey, the accrual target 
is set to “300 patients with hepatic impairment”. When this target is reached, in light of the 
extent of overlapping of the subpopulations in the above-mentioned Nesina Tablets specified 
drug-use survey, approximately 300 patients with renal impairment and approximately 300 
elderly patients would have been accrued. 
 
Also, with a total sample size of t600 in this survey, improvement in patient convenience by 
switching to this combination product from alogliptin benzoate and metformin hydrochloride
in combination would be evaluable to a reasonable extent. 
4.0
Target Patient Population 
This survey will be conducted in patients with type 2 diabetes mellitus for whom combination 
therapy with alogliptin benzoate and metformin hydrochloride is appropriate in the opinion of 
a physician, and 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 one or more of the following: 
(1) Have renal impairment (mild) 
(2) Have hepatic impairment (mild or moderate) 
(3) Elderly (aged t65 years) 
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4.2 Exclusion Criteria 
Subjects who meet the following criterion will be excluded:
Patients with any contraindication for this drug
5.0
Dosage and Administration 
The usual adult dosage of this drug is 1 tablet (ie, 25 mg of alogliptin and 500 mg of 
metformin hydrochloride) once daily orally immediately before a meal or after a meal. The 
package insert for this drug should be referenced. 
6.0
Planned Number of Survey Sites by Specialty Department 
Approximately 120 sites, including department of internal medicine 
7.0
Methods 
7.1 Duration of Observation 
12 months 
7.2 Data Collection Method
Data will be collected using a web-based electronic data capture system (
). 
7.3 Patient Enrollment Method 
Patients will be enrolled using a centralized registration method via 

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 
 promptly after the end of observation at 12 months of treatment with this drug, 
and the survey 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 
 promptly 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 
, and the survey physician will enter an electronic signature. 

*: 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 
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entry to 
, 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 
person in charge of Takeda Pharmaceutical Company Limited (hereinafter referred to as 
“Takeda personnel”). 
 
8.0 
Planned Survey Period 
Survey period: February 2017 to October 31, 2019  
Patient enrollment period: February 2017 to October 31, 2018 Note) 
Note) Even if this drug is prescribed by October 31, 2018, no patient enrollment (via 
) 
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
Informed Consent 
Prior to enrollment of a patient in this survey, the survey physician will obtain written or 
verbal consent of the patient or the patient’s legally acceptable representative. Patients who 
provided consent will be assigned the subject identification numbers. 
10.0
Survey Variables 
The survey physician or designee will enter data on the following variables into 
. The
survey schedule is shown in Appendix 1. 
10.1 Patient Enrollment 
1)Survey variables
Date of prescription of this drug, subject identification number, patient initials, sex, age, 
assessment against the inclusion criteria (ie, the patient has renal impairment*1 [mild], 
hepatic impairment*2 [mild or moderate], or advanced age [t65 years]), assessment against 
the exclusion criteria (ie, the patient does not have any contraindication for this drug), 
status of medication for type 2 diabetes mellitus immediately before use of this drug 
 
As a guide to severity assessment of renal impairment and hepatic impairment, the following tables 
should be referenced. 
 
 
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*1: Severity classification of renal impairment 
Severity of renal 
impairment 
eGFR 
(mL/min/1.73m2)  
Serum creatinine  
(mg/dL) * 
Creatinine clearance  
(Ccr, mL/min)  
Mild 
t60 to <90 
Male: >0.90 to d1.4 
Female: >0.77 to d1.2 
t50 to d80 
Moderate 
t30 to <60 
Male: >1.4 to d2.4 
Female: >1.2 to d2.0 
t30 to <50 
Severe or  
end-stage renal disease 
<30 
Male: >2.4 
Female: >2.0 
<30 
For end-stage renal disease, time of the measurement relative to a hemodialysis session is disregarded. 
 
*: Estimated values corresponding to the Ccr (for persons who are aged 60 years and weigh 65 kg)  
Adapted from the “Precautions related to Dosage and Administration” section of Nesina Tablets package insert (see 
Cockcroft DW, et al. Nephron 1976; 16: 31-41) 
 
*2: Severity classification of hepatic impairment 
Severity of 
hepatic 
impairment 
Mild 
Moderate 
Severe 
Total bilirubin 
(mg/dL)  
t1.6 to <3.0 
t3.0 to <10 
t10 
AST or ALT 
(U/L) 
t50 to <100 
t100 to <500 
t500 
ALP 
t1.25 × ULN to  
<2.5 × ULN 
t2.5 × ULN to  
<5 × ULN  
t5 × ULN  
Gamma-GTP 
t1.5 × ULN 
- 
- 
LDH 
t1.5 × ULN 
- 
- 
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 t6 
months 
ULN: Upper limit of normal of the study site 
 
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
10.2 Patient Background 
1) Survey variables 
Time of the diagnosis of type 2 diabetes mellitus, inpatient/outpatient category, 
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, status of occupation (presence or absence), status 
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of treatment compliance with alogliptin benzoate and metformin hydrochloride within 3 
months before the start of treatment with this drug*3 
*3: Assessed using a scale from 0% to 100% in increments of 5%. 
2) Time of data collection 
At initiation of treatment with this drug 
10.3 Treatment Details 
1) Survey variables 
Detailed use of this drug (therapy start date, therapy end date, and reason for 
discontinuation [if applicable]), detailed use of concomitant drugs*4 (for the treatment of 
diabetes mellitus) (presence or absence, if present, name of the drug, daily dose, and 
therapy dates), detailed use of concomitant drugs (for other conditions than diabetes 
mellitus) (presence or absence, if present, name of the drug, reason for use) 
*4: Including antidiabetic medication discontinued within 3 months before use of this drug 
(Also, alogliptin benzoate and metformin hydrochloride used before this drug will be 
investigated.) 
2) Time of data collection 
From initiation of treatment with this drug until 12 months later (or discontinuation of 
treatment) 
10.4 Treatment Compliance Status for this Drug, and Daily Dosing Frequency and Number of 
Tablets for Concomitant Drugs 
1) Survey variables 
The status of treatment compliance with this drug will be assessed using a scale from 0% to 
100% in increments of 5%. 
Also regarding concomitant drugs (for the treatment of diabetes mellitus or other 
conditions), the maximum number of doses administered per day and the maximum number 
of tablets administered per day will be investigated at each time of data collection. 
2)Time of data collection
At initiation of treatment with this drug (except treatment compliance status for this drug), 
and 1, 3, 6, 9, and 12 months later (or discontinuation of treatment) 
10.5 Items of Tests and Observations 
Data from tests and observations in the routine clinical setting, if performed at the respective 
time of data collection, will be entered. 
 
 Vital Signs 
1)Items of tests and observations
Pulse rate, blood pressure (systolic /diastolic), body weight
2)Time of data collection
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At initiation of treatment with this drug, and 1, 3, 6, 9, and 12 months later (or 
discontinuation of treatment), if performed 
 Laboratory Tests 
1)Test variables
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, LDH, total bilirubin, 
amylase, lipase, lactic acid 
2)Time of data collection
At initiation of treatment with this drug, and 1, 3, 6, 9, and 12 months later (or 
discontinuation of treatment), if performed 
 Electrocardiogram 
1)Test variable
Electrocardiogram (assessment)
2)Time of data collection
At initiation of treatment with this drug and 12 months later (or discontinuation of treatment), 
if performed
 
 Waist Circumference and Testing Related to Coronary Arteries and Arteriosclerosis 
1) Test variables 
Waist circumference*5, testing related to coronary arteries and arteriosclerosis*6 (eg, pulse 
wave velocity , blood pressure pulse wave test, cervical artery ultrasound, intravascular 
ultrasound) 
*5: 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. 
*6: 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 12 months later (or discontinuation of treatment), 
if performed 
 
 Other Items of Observation 
1) Observation item(s) 
Presence or absence of pregnancy during the observation (only in women)  
2) Time of data collection 
From initiation of treatment with this drug until 12 months later (or discontinuation of 
treatment) 
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10.6 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*7 (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. 
 
If onset of any of the following is reported as an adverse event, detailed information should 
be collected as needed: lactic acidosis, hypoglycemia, acute pancreatitis, hepatic function 
disorder or jaundice, severe skin disorder such as oculomucocutaneous syndrome 
(Stevens-Johnson syndrome) and erythema multiforme, rhabdomyolysis, intestinal 
obstruction, interstitial pneumonia, angioedema, gastrointestinal symptom, infection, 
malignant tumor, pemphigoid, cardiovascular event (eg, symptomatic coronary artery 
disease, cerebrovascular disorder, arteriosclerosis obliterans, cardiovascular death, sudden 
death). 
*7: 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 until 12 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. 
 
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10 
11.3 Treatment Details 
Detailed use of this drug and concomitant drugs will be summarized. 
 
11.4 Treatment Compliance Status, and Daily Dosing Frequency and Number of Tablets for 
Concomitant Drugs 
Treatment compliance status will be summarized for alogliptin benzoate and metformin 
hydrochloride within 3 months before use of this drug, and also for this drug at each time 
of data collection. Also regarding concomitant drugs (for the treatment of diabetes 
mellitus and other conditions), the maximum number of doses administered per day and 
the maximum number of tablets administered per day will be summarized. 
 
11.5 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). 
 
 Adverse Event Profile 
Adverse events occurring during the observation period will be summarized using 
frequency distribution by event type, time to onset, seriousness, causal relationship to this 
drug, etc. 
 Factors Likely Affecting the Safety 
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, presence or absence of renal impairment, presence or absence of hepatic 
impairment) and treatment details (eg, detailed use of this drug). 
11.6 Efficacy data 
The following data will be summarized using the efficacy analysis set. 
 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.  
 Fasting blood glucose over time 
The fasting blood glucose level and change (value at the respective time after initiation of 
treatment minus baseline value) at each time point of evaluation will be summarized.  
 
 Fasting insulin over time 
The fasting insulin level and change (value at the respective time after initiation of 
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11 
treatment minus baseline value) at each time point of evaluation will be summarized.  
 
 Factors likely affecting the efficacy 
A subgroup analysis will be performed on change in HbA1c etc., with stratification of 
patients according to background factors (eg, sex, age, presence or absence of renal 
impairment, presence or absence of hepatic impairment, baseline HbA1c level) and 
treatment details (eg, detailed use of this drug). In addition, among the patients with no 
change in the dose of alogliptin benzoate and metformin hydrochloride between before and 
after the switching to this drug, and no change in the dose of any antidiabetic medication 
during the treatment with this drug, the treatment compliance status between before and 
after the use of this drug and change in HbA1c will be summarized, and the relationship 
between medication adherence and change in HbA1c will be analyzed. In this analysis, in 
order to minimize influence of other factors than reductions in the number of tablets per 
day and the number of doses per day by switching to this drug among factors likely 
contributing to medication adherence, subgroup analyses according to such other factors etc. 
will be used to characterize the relationship between medication adherence and change in 
HbA1c as far as possible. 
 
 Factors Likely Affecting Medication Adherence 
Regarding change in the medication adherence, in order to minimize influence of other 
factors than reductions in the number of tablets administered per day and the number of 
doses per day by switching to this drug among factors likely contributing to medication 
adherence, subgroup analyses according to such other factors etc. will be used to 
characterize the influence of this drug on the medication adherence. 
11.7 Special Patient Populations 
For each of the subpopulations of patients with renal impairment, patients with hepatic 
impairment, and elderly patients in this survey, a similar analysis to Sections 10.1 to 10.8.3
will be performed. 
12.0
Survey Informed Consent Form and Patient Consent 
The survey informed consent form contains the description as to how the patients’ personal 
information and medical information are used in this survey. The informed consent form 
also describes the survey overview, the freedom of patients to withdraw from the survey at 
any time without providing a reason without any disadvantages in treatment. 
 
The survey physician will provide a potential survey subject (or legally acceptable 
representative) with explanation about this survey as provided in the informed consent 
form, and obtain verbal or written consent of the patient (or legally acceptable 
representative) to participate in this survey. For written consent, the patient (or legally 
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acceptable representative) will sign and date the informed consent form, and the survey 
physician will retain the original of the signed informed consent form. For verbal consent, 
the survey physician will document the verbal consent. 
 
13.0
Registration of Survey Information 
Before initiation of this survey, information on this survey will be registered with the 
following website. 
x Japan Pharmaceutical Information Center (JAPIC) Clinical Trials Information 
14.0
Administrative Structure 
See Attachment. 
15.0
Trustees 
See Attachment.

16.0 
Other Necessary Items 
16.1 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. 
16.2 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 2 
Takeda Medically Significant AE List 
 
General 
Malignancy 
Endotoxic shock 
Sepsis 
Transmission of an infectious agent by a 
medicinal product 
 
Blood and lymphatic System 
Bone marrow failure 
Disseminated Intravascular Coagulation  
Haemolytic anaemia 
Thrombotic Thrombocytopenic Purpura 
Cardiovascular System 
Cardiac arrest 
Cardiac failure 
Cardiomyopathy acute 
Malignant hypertension 
Myocardial infarction 
Ventricular arrhythmias 
Endocrine System 
Adrenal crisis  
Gastrointestinal System 
Acute pancreatitis 
GI haemorrhage 
GI perforation 
GI obstruction 
Necrotising colitis 
Peritonitis 
Hepatobiliary System 
Acute hepatic failure 
Fulminant hepatitis 
Urinary System 
Acute renal failure 
 
Immune system 
Anaphylaxis 
Progressive multifocal leukoencephalopathy 
(PML) 
Transplant rejection 
Musculoskeletal System 
Rhabdomyolysis 
Nervous System 
Cerebrovascular accident 
Coma 
Convulsive seizures 
Hyperthermia malignant 
Macular oedema 
Meningoencephalitis 
Neuroleptic malignant syndrome 
Suicidal behaviour 
Reproductive System 
Abortion 
Uterine perforation 
Respiratory System 
Acute respiratory failure 
Pulmonary hypertension 
Pulmonary thromboembolism 
Skin and subcutaneous tissue 
Toxic epidermal necrolysis 
Stevens-Johnson syndrome 
 
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

 
Protocol for Specified Drug-Use Survey of 
INISYNC Combination Tablets  
“Survey on long-term use in  
type 2 diabetes mellitus patients with  
renal or hepatic impairment or advanced age” 








Survey Sponsor  
Takeda Pharmaceutical Company Limited  
Protocol Number 
Alogliptin-Met-5003 
Version Number 
Version 3 
Date of Preparation 
January 12, 2017 
 
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Terms of Use

 
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 ....................................................................................................................................... 3 
5.0 
Dosage and Administration ............................................................................................................................ 3 
6.0 
Planned Number of Survey Sites by Specialty Department ........................................................................... 3 
7.0 
Methods .......................................................................................................................................................... 3 
7.1 
Duration of Observation ............................................................................................................................. 3 
7.2 
Data Collection Method ............................................................................................................................. 3 
7.3 
Patient Enrollment Method ........................................................................................................................ 3 
7.4 
Case Report Form (Electronic) Completion and Electronic Signature ....................................................... 3 
8.0 
Planned Survey Period ................................................................................................................................... 4 
9.0 
Informed Consent ........................................................................................................................................... 4 
10.0 
Survey Variables ............................................................................................................................................. 4 
10.1 
Patient Enrollment ...................................................................................................................................... 4 
10.2 
Patient Background .................................................................................................................................... 5 
10.3 
Treatment Details ....................................................................................................................................... 6 
10.4 
Treatment Compliance Status for this Drug, and Daily Dosing Frequency and Number of Tablets for 
Concomitant Drugs ................................................................................................................................................ 6 
10.5 
Items of Tests and Observations ................................................................................................................. 6 
 
Vital Signs .......................................................................................................................................... 6 
 
Laboratory Tests ................................................................................................................................. 7 
 
Electrocardiogram .............................................................................................................................. 7 
 
Waist Circumference and Testing Related to Coronary Arteries and Arteriosclerosis ....................... 7 
 
Other Items of Observation ................................................................................................................ 7 
10.6 
Adverse Events ........................................................................................................................................... 8 
11.0 
Analytical Items and Methods ........................................................................................................................ 9 
11.1 
Disposition of Patients................................................................................................................................ 9 
11.2 
Patient Background .................................................................................................................................... 9 
11.3 
Treatment Details ..................................................................................................................................... 10 
11.4 
Treatment Compliance Status, and Daily Dosing Frequency and Number of Tablets for Concomitant 
Drugs 10 
11.5 
Safety Data ............................................................................................................................................... 10 
 
Adverse Event Profile ...................................................................................................................... 10 
 
Factors Likely Affecting the Safety .................................................................................................. 10 
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11.6 
Efficacy data ............................................................................................................................................. 10 
 
HbA1c over time .............................................................................................................................. 10 
 
Fasting blood glucose over time ....................................................................................................... 10 
 
Fasting insulin over time .................................................................................................................. 10 
 
Factors likely affecting the efficacy ................................................................................................. 11 
 
Factors Likely Affecting Medication Adherence .............................................................................. 11 
11.7 
Special Patient Populations ...................................................................................................................... 11 
12.0 
Survey Informed Consent Form and Patient Consent .................................................................................. 11 
13.0 
Registration of Survey Information .............................................................................................................. 12 
14.0 
Administrative Structure .............................................................................................................................. 12 
15.0 
Trustees ........................................................................................................................................................ 12 
16.0 
Other Necessary Items .................................................................................................................................. 12 
16.1 
Amendments to the Protocol .................................................................................................................... 12 
16.2 
Actions to be Taken in Response to Detection of any Issues or Concerns ............................................... 12 
Appendix 1 
Observation Schedule ....................................................................................................................... 13 
Appendix 2 
Takeda Medically Significant AE List .............................................................................................. 14 
Property of Takeda: For non-commercial use only and subject 
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1 
1.0
Background 
Drugs to treat type 2 diabetes mellitus are likely used over a long time in the routine clinical 
setting. Inisync Combination Tablets (hereinafter referred to as “this drug”) contain two active 
ingredients: alogliptin benzoate (brand name, Nesina Tablets) and metformin hydrochloride. 
Long-term combination use of these drugs in the routine clinical setting was previously 
investigated in a specified drug-use survey. However, clinical trial data were limited on the 
safety and efficacy of this drug in patients with renal impairment, patients with hepatic 
impairment and elderly patients, and therefore data in these patient populations are designated 
as part of “important missing information” in the risk management plan for this drug. Thus, 
with a focus particularly on these patient populations, the present specified drug-use survey 
(hereinafter referred to as “this survey”) has been planned to investigate the long-term safety 
and efficacy of this drug used in the routine clinical setting in type 2 diabetes mellitus patients
with renal or hepatic impairment or advanced age. 
 
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 
This survey aims to evaluate the long-term safety and efficacy of this drug in type 2 diabetes 
mellitus patients with renal impairment (mild), hepatic impairment (mild or moderate), or 
advanced age (t65 years) in the routine clinical setting. In addition, this survey will enroll as 
many as possible patients who were switched from alogliptin 25 mg and metformin 
hydrochloride 500 mg (ie, 250 mg twice daily) in combination as a prior medication, to 
examine the relationship between the efficacy and improvement in medication adherence by 
the switching to this combination product in those who were taking alogliptin benzoate and 
metformin hydrochloride in combination. 

3.0 
Planned Sample Size and Rationale 
3.1 Planned Sample Size 
600 subjects (including 300 subjects with hepatic impairment)
3.2 Rationale 
Among the important identified risks and important potential risks of this drug, the following 
were reported in the alogliptin + metformin QD group (alogliptin 25 mg plus metformin 
hydrochloride 500 mg once daily) of Study SYR-322-MET/CCT-001: infection-related 
adverse events (26.3%, 40/152 subjects), gastrointestinal symptom-related adverse events 
(9.9%, 15/152 subjects), lactic acidosis-related adverse events (1.3%, 2/152 subjects), and 
hepatic function disorder-related adverse events (0.7%, 1/152 subjects). Based on these data, 
the incidence in this survey can be assumed to be t0.7% for such events among the important 
identified risks and important potential risks of this drug. 
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Assuming a Poisson distribution for the number of such events occurring in this survey, and 
with a sample size of 300 each for patients with renal impairment, patients with hepatic 
impairment, and elderly patients, adverse events occurring with an incidence of t0.7% in one 
of the patient subpopulations can be detected in at least one patient with a probability of t87%. 
Thus, with this sample size, the events reported in Study SYR-322-MET/CCT-001 and 
designated as important identified risks and important potential risks of this drug would be 
evaluable to a reasonable extent. For events occurring with a lower incidence, overall safety 
assessment will be performed based on information not only from this survey but also from 
other sources including spontaneous reports and literature in particular. 
 
From the viewpoint of patient accrual, patients with hepatic impairment will be the most 
difficult subpopulation to be accrued in this survey, based on the accrual rates in a previously 
conducted specified drug-use survey of Nesina Tablets in type 2 diabetes mellitus patients 
with concomitant use of a biguanide, which also enrolled patients with renal impairment, 
patients with hepatic impairment, and elderly patients. Thus, in order to ensure that patients 
with hepatic impairment in particular are adequately enrolled in this survey, the accrual target 
is set to “300 patients with hepatic impairment”. When this target is reached, in light of the 
extent of overlapping of the subpopulations in the above-mentioned Nesina Tablets specified 
drug-use survey, approximately 300 patients with renal impairment and approximately 300 
elderly patients would have been accrued. 
 
Also, with a total sample size of t600 in this survey, improvement in patient convenience by 
switching to this combination product from alogliptin benzoate and metformin hydrochloride
in combination would be evaluable to a reasonable extent. 
4.0
Target Patient Population 
This survey will be conducted in patients with type 2 diabetes mellitus for whom combination 
therapy with alogliptin benzoate and metformin hydrochloride is appropriate in the opinion of 
a physician, and 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 one or more of the following: 
(1) Have renal impairment (mild) 
(2) Have hepatic impairment (mild or moderate) 
(3) Elderly (aged t65 years) 
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4.2 Exclusion Criteria 
Subjects who meet the following criterion will be excluded:
Patients with any contraindication for this drug
5.0
Dosage and Administration 
The usual adult dosage of this drug is 1 tablet (ie, 25 mg of alogliptin and 500 mg of 
metformin hydrochloride) once daily orally immediately before a meal or after a meal. The 
package insert for this drug should be referenced. 
6.0
Planned Number of Survey Sites by Specialty Department 
Approximately 120 sites, including department of internal medicine 
7.0
Methods 
7.1 Duration of Observation 
12 months 
7.2 Data Collection Method
Data will be collected using a web-based electronic data capture system (
). 
7.3 Patient Enrollment Method 
Patients will be enrolled using a centralized registration method via 
.
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 
 promptly after the end of observation at 12 months of treatment with this drug, 
and the survey 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 
 promptly 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 
, and the survey physician will enter an electronic signature. 

*: 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 
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entry to 
, 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 
person in charge of Takeda Pharmaceutical Company Limited (hereinafter referred to as 
“Takeda personnel”). 
 
8.0 
Planned Survey Period 
Survey period: February 2017 to June 30, 2019  
Patient enrollment period: February 2017 to June 30, 2018 Note) 
Note) Even if this drug is prescribed by June 30, 2018, no patient enrollment (via 
) will 
be acceptable on or after July 1, 2018. 
If the total number of patients enrolled in this survey reached the planned sample size 
before June 30, 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
Informed Consent 
Prior to enrollment of a patient in this survey, the survey physician will obtain written or 
verbal consent of the patient or the patient’s legally acceptable representative. Patients who 
provided consent will be assigned the subject identification numbers. 
10.0
Survey Variables 
The survey physician or designee will enter data on the following variables into 
. The
survey schedule is shown in Appendix 1. 
10.1 Patient Enrollment 
1)Survey variables
Date of prescription of this drug, subject identification number, patient initials, sex, age, 
assessment against the inclusion criteria (ie, the patient has renal impairment*1 [mild], 
hepatic impairment*2 [mild or moderate], or advanced age [t65 years]), assessment against 
the exclusion criteria (ie, the patient does not have any contraindication for this drug), 
status of medication for type 2 diabetes mellitus immediately before use of this drug 
 
As a guide to severity assessment of renal impairment and hepatic impairment, the following tables 
should be referenced. 
 
 
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*1: Severity classification of renal impairment 
Severity of renal 
impairment 
eGFR 
(mL/min/1.73m2)  
Serum creatinine  
(mg/dL) * 
Creatinine clearance  
(Ccr, mL/min)  
Mild 
t60 to <90 
Male: >0.90 to d1.4 
Female: >0.77 to d1.2 
t50 to d80 
Moderate 
t30 to <60 
Male: >1.4 to d2.4 
Female: >1.2 to d2.0 
t30 to <50 
Severe or  
end-stage renal disease 
<30 
Male: >2.4 
Female: >2.0 
<30 
For end-stage renal disease, time of the measurement relative to a hemodialysis session is disregarded. 
 
*: Estimated values corresponding to the Ccr (for persons who are aged 60 years and weigh 65 kg)  
Adapted from the “Precautions related to Dosage and Administration” section of Nesina Tablets package insert (see 
Cockcroft DW, et al. Nephron 1976; 16: 31-41) 
 
*2: Severity classification of hepatic impairment 
Severity of 
hepatic 
impairment 
Mild 
Moderate 
Severe 
Total bilirubin 
(mg/dL)  
t1.6 to <3.0 
t3.0 to <10 
t10 
AST or ALT 
(U/L) 
t50 to <100 
t100 to <500 
t500 
ALP 
t1.25 × ULN to  
<2.5 × ULN 
t2.5 × ULN to  
<5 × ULN  
t5 × ULN  
Gamma-GTP 
t1.5 × ULN 
- 
- 
LDH 
t1.5 × ULN 
- 
- 
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 t6 
months 
ULN: Upper limit of normal of the study site 
 
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
10.2 Patient Background 
1) Survey variables 
Time of the diagnosis of type 2 diabetes mellitus, inpatient/outpatient category, 
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, status of occupation (presence or absence), status 
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of treatment compliance with alogliptin benzoate and metformin hydrochloride within 3 
months before the start of treatment with this drug*3 
*3: Assessed using a scale from 0% to 100% in increments of 5%. 
2) Time of data collection 
At initiation of treatment with this drug 
10.3 Treatment Details 
1) Survey variables 
Detailed use of this drug (therapy start date, therapy end date, and reason for 
discontinuation [if applicable]), detailed use of concomitant drugs*4 (for the treatment of 
diabetes mellitus) (presence or absence, if present, name of the drug, daily dose, and 
therapy dates), detailed use of concomitant drugs (for other conditions than diabetes 
mellitus) (presence or absence, if present, name of the drug, reason for use) 
*4: Including antidiabetic medication discontinued within 3 months before use of this drug 
(Also, alogliptin benzoate and metformin hydrochloride used before this drug will be 
investigated.) 
2) Time of data collection 
From initiation of treatment with this drug until 12 months later (or discontinuation of 
treatment) 
10.4 Treatment Compliance Status for this Drug, and Daily Dosing Frequency and Number of 
Tablets for Concomitant Drugs 
1) Survey variables 
The status of treatment compliance with this drug will be assessed using a scale from 0% to 
100% in increments of 5%. 
Also regarding concomitant drugs (for the treatment of diabetes mellitus or other 
conditions), the maximum number of doses administered per day and the maximum number 
of tablets administered per day will be investigated at each time of data collection. 
2)Time of data collection
At initiation of treatment with this drug (except treatment compliance status for this drug), 
and 1, 3, 6, 9, and 12 months later (or discontinuation of treatment) 
10.5 Items of Tests and Observations 
Data from tests and observations in the routine clinical setting, if performed at the respective 
time of data collection, will be entered. 
 
 Vital Signs 
1)Items of tests and observations
Pulse rate, blood pressure (systolic /diastolic), body weight
2)Time of data collection
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At initiation of treatment with this drug, and 1, 3, 6, 9, and 12 months later (or 
discontinuation of treatment), if performed 
 Laboratory Tests 
1)Test variables
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, LDH, total bilirubin, 
amylase, lipase, lactic acid 
2)Time of data collection
At initiation of treatment with this drug, and 1, 3, 6, 9, and 12 months later (or 
discontinuation of treatment), if performed 
 Electrocardiogram 
1)Test variable
Electrocardiogram (assessment)
2)Time of data collection
At initiation of treatment with this drug and 12 months later (or discontinuation of treatment), 
if performed
 
 Waist Circumference and Testing Related to Coronary Arteries and Arteriosclerosis 
1) Test variables 
Waist circumference*5, testing related to coronary arteries and arteriosclerosis*6 (eg, pulse 
wave velocity , blood pressure pulse wave test, cervical artery ultrasound, intravascular 
ultrasound) 
*5: 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. 
*6: 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 12 months later (or discontinuation of treatment), 
if performed 
 
 Other Items of Observation 
1) Observation item(s) 
Presence or absence of pregnancy during the observation (only in women)  
2) Time of data collection 
From initiation of treatment with this drug until 12 months later (or discontinuation of 
treatment) 
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10.6 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*7 (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. 
 
If onset of any of the following is reported as an adverse event, detailed information should 
be collected as needed: lactic acidosis, hypoglycemia, acute pancreatitis, hepatic function 
disorder or jaundice, severe skin disorder such as oculomucocutaneous syndrome 
(Stevens-Johnson syndrome) and erythema multiforme, rhabdomyolysis, intestinal 
obstruction, interstitial pneumonia, angioedema, gastrointestinal symptom, infection, 
malignant tumor, pemphigoid, cardiovascular event (eg, symptomatic coronary artery 
disease, cerebrovascular disorder, arteriosclerosis obliterans, cardiovascular death, sudden 
death). 
*7: 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 until 12 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. 
 
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10 
11.3 Treatment Details 
Detailed use of this drug and concomitant drugs will be summarized. 
 
11.4 Treatment Compliance Status, and Daily Dosing Frequency and Number of Tablets for 
Concomitant Drugs 
Treatment compliance status will be summarized for alogliptin benzoate and metformin 
hydrochloride within 3 months before use of this drug, and also for this drug at each time 
of data collection. Also regarding concomitant drugs (for the treatment of diabetes 
mellitus and other conditions), the maximum number of doses administered per day and 
the maximum number of tablets administered per day will be summarized. 
 
11.5 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). 
 
 Adverse Event Profile 
Adverse events occurring during the observation period will be summarized using 
frequency distribution by event type, time to onset, seriousness, causal relationship to this 
drug, etc. 
 Factors Likely Affecting the Safety 
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, presence or absence of renal impairment, presence or absence of hepatic 
impairment) and treatment details (eg, detailed use of this drug). 
11.6 Efficacy data 
The following data will be summarized using the efficacy analysis set. 
 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.  
 Fasting blood glucose over time 
The fasting blood glucose level and change (value at the respective time after initiation of 
treatment minus baseline value) at each time point of evaluation will be summarized.  
 
 Fasting insulin over time 
The fasting insulin level and change (value at the respective time after initiation of 
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11 
treatment minus baseline value) at each time point of evaluation will be summarized.  
 
 Factors likely affecting the efficacy 
A subgroup analysis will be performed on change in HbA1c etc., with stratification of 
patients according to background factors (eg, sex, age, presence or absence of renal 
impairment, presence or absence of hepatic impairment, baseline HbA1c level) and 
treatment details (eg, detailed use of this drug). In addition, among the patients with no 
change in the dose of alogliptin benzoate and metformin hydrochloride between before and 
after the switching to this drug, and no change in the dose of any antidiabetic medication 
during the treatment with this drug, the treatment compliance status between before and 
after the use of this drug and change in HbA1c will be summarized, and the relationship 
between medication adherence and change in HbA1c will be analyzed. In this analysis, in 
order to minimize influence of other factors than reductions in the number of tablets per 
day and the number of doses per day by switching to this drug among factors likely 
contributing to medication adherence, subgroup analyses according to such other factors etc. 
will be used to characterize the relationship between medication adherence and change in 
HbA1c as far as possible. 
 
 Factors Likely Affecting Medication Adherence 
Regarding change in the medication adherence, in order to minimize influence of other 
factors than reductions in the number of tablets administered per day and the number of 
doses per day by switching to this drug among factors likely contributing to medication 
adherence, subgroup analyses according to such other factors etc. will be used to 
characterize the influence of this drug on the medication adherence. 
11.7 Special Patient Populations 
For each of the subpopulations of patients with renal impairment, patients with hepatic 
impairment, and elderly patients in this survey, a similar analysis to Sections 10.1 to 10.8.3
will be performed. 
12.0
Survey Informed Consent Form and Patient Consent 
The survey informed consent form contains the description as to how the patients’ personal 
information and medical information are used in this survey. The informed consent form 
also describes the survey overview, the freedom of patients to withdraw from the survey at 
any time without providing a reason without any disadvantages in treatment. 
 
The survey physician will provide a potential survey subject (or legally acceptable 
representative) with explanation about this survey as provided in the informed consent 
form, and obtain verbal or written consent of the patient (or legally acceptable 
representative) to participate in this survey. For written consent, the patient (or legally 
Property of Takeda: 
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acceptable representative) will sign and date the informed consent form, and the survey 
physician will retain the original of the signed informed consent form. For verbal consent, 
the survey physician will document the verbal consent. 
 
13.0
Registration of Survey Information 
Before initiation of this survey, information on this survey will be registered with the 
following website. 
x Japan Pharmaceutical Information Center (JAPIC) Clinical Trials Information 
14.0
Administrative Structure 
See Attachment. 
15.0
Trustees 
See Attachment.

16.0 
Other Necessary Items 
16.1 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. 
16.2 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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Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

14 
Appendix 2 
Takeda Medically Significant AE List 
 
General 
Malignancy 
Endotoxic shock 
Sepsis 
Transmission of an infectious agent by a 
medicinal product 
 
Blood and lymphatic System 
Bone marrow failure 
Disseminated Intravascular Coagulation  
Haemolytic anaemia 
Thrombotic Thrombocytopenic Purpura 
Cardiovascular System 
Cardiac arrest 
Cardiac failure 
Cardiomyopathy acute 
Malignant hypertension 
Myocardial infarction 
Ventricular arrhythmias 
Endocrine System 
Adrenal crisis  
Gastrointestinal System 
Acute pancreatitis 
GI haemorrhage 
GI perforation 
GI obstruction 
Necrotising colitis 
Peritonitis 
Hepatobiliary System 
Acute hepatic failure 
Fulminant hepatitis 
Urinary System 
Acute renal failure 
 
Immune system 
Anaphylaxis 
Progressive multifocal leukoencephalopathy 
(PML) 
Transplant rejection 
Musculoskeletal System 
Rhabdomyolysis 
Nervous System 
Cerebrovascular accident 
Coma 
Convulsive seizures 
Hyperthermia malignant 
Macular oedema 
Meningoencephalitis 
Neuroleptic malignant syndrome 
Suicidal behaviour 
Reproductive System 
Abortion 
Uterine perforation 
Respiratory System 
Acute respiratory failure 
Pulmonary hypertension 
Pulmonary thromboembolism 
Skin and subcutaneous tissue 
Toxic epidermal necrolysis 
Stevens-Johnson syndrome 
 
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

 
Protocol for Specified Drug-Use Survey of 
INISYNC Combination Tablets  
“Survey on long-term use in  
type 2 diabetes mellitus patients with  
renal or hepatic impairment or advanced age” 








Survey Sponsor  
Takeda Pharmaceutical Company Limited  
Protocol Number 
Alogliptin-Met-5003 
Version Number 
Version 2 
Date of Preparation 
November 9, 2016 
 
Property of Takeda: For non-commercial 
ptin
ptin
sion 
ion 2
Novem
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use 
harm
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only and subject to the applicable 
ced a
ced 
Terms of Use

 
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 ....................................................................................................................................... 3 
5.0 
Dosage and Administration ............................................................................................................................ 3 
6.0 
Planned Number of Survey Sites by Specialty Department ........................................................................... 3 
7.0 
Methods .......................................................................................................................................................... 3 
7.1 
Duration of Observation ............................................................................................................................. 3 
7.2 
Data Collection Method ............................................................................................................................. 3 
7.3 
Patient Enrollment Method ........................................................................................................................ 3 
7.4 
Case Report Form (Electronic) Completion and Electronic Signature ....................................................... 3 
8.0 
Planned Survey Period ................................................................................................................................... 4 
9.0 
Informed Consent ........................................................................................................................................... 4 
10.0 
Survey Variables ............................................................................................................................................. 4 
10.1 
Patient Enrollment ...................................................................................................................................... 4 
10.2 
Patient Background .................................................................................................................................... 5 
10.3 
Treatment Details ....................................................................................................................................... 6 
10.4 
Treatment Compliance Status for this Drug, and Daily Dosing Frequency and Number of Tablets for 
Concomitant Drugs ................................................................................................................................................ 6 
10.5 
Items of Tests and Observations ................................................................................................................. 6 
 
Vital Signs .......................................................................................................................................... 6 
 
Laboratory Tests ................................................................................................................................. 7 
 
Electrocardiogram .............................................................................................................................. 7 
 
Waist Circumference and Testing Related to Coronary Arteries and Arteriosclerosis ....................... 7 
 
Other Items of Observation ................................................................................................................ 7 
10.6 
Adverse Events ........................................................................................................................................... 8 
11.0 
Analytical Items and Methods ........................................................................................................................ 9 
11.1 
Statistical Analysis Plan ............................................................................................................................. 9 
11.2 
Analysis Sets .............................................................................................................................................. 9 
11.3 
Disposition of Patients.............................................................................................................................. 10 
11.4 
Patient Background .................................................................................................................................. 10 
11.5 
Treatment Details ..................................................................................................................................... 10 
11.6 
Treatment Compliance Status, and Daily Dosing Frequency and Number of Tablets for Concomitant 
Drugs 10 
11.7 
Safety Data ............................................................................................................................................... 10 
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Adverse Event Profile ...................................................................................................................... 10 
 
Factors Likely Affecting the Safety .................................................................................................. 10 
11.8 
Efficacy data ............................................................................................................................................. 10 
 
HbA1c over time .............................................................................................................................. 10 
 
Fasting blood glucose over time ....................................................................................................... 11 
 
Fasting insulin over time .................................................................................................................. 11 
 
Factors likely affecting the efficacy ................................................................................................. 11 
 
Factors Likely Affecting Medication Adherence .............................................................................. 11 
11.9 
Special Patient Populations ...................................................................................................................... 11 
12.0 
Informed Consent Form and Patient Consent .............................................................................................. 11 
13.0 
Registration of Survey Information .............................................................................................................. 12 
14.0 
Administrative Structure .............................................................................................................................. 12 
14.1 
Chief Administrator .................................................................................................................................. 12 
15.0 
Trustees ........................................................................................................................................................ 12 
16.0 
Other Necessary Items .................................................................................................................................. 12 
16.1 
Amendments to the Protocol .................................................................................................................... 12 
16.2 
Actions to be Taken in Response to Detection of any Issues or Concerns ............................................... 12 
Appendix 1 
Observation Schedule ....................................................................................................................... 13 
Appendix 2 
Takeda Medically Significant AE List .............................................................................................. 14 
Property of Takeda: For non-commercial use only and 
....
.........
.....
subject 
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1.0
Background 
Drugs to treat type 2 diabetes mellitus are likely used over a long time in the routine clinical 
setting. Inisync Combination Tablets (hereinafter referred to as “this drug”) contain two active 
ingredients: alogliptin benzoate (brand name, Nesina Tablets) and metformin hydrochloride. 
Long-term combination use of these drugs in the routine clinical setting was previously 
investigated in a specified drug-use survey. However, clinical trial data were limited on the 
safety and efficacy of this drug in patients with renal impairment, patients with hepatic 
impairment and elderly patients, and therefore data in these patient populations are designated 
as part of “important missing information” in the risk management plan for this drug. Thus, 
with a focus particularly on these patient populations, the present specified drug-use survey 
(hereinafter referred to as “this survey”) has been planned to investigate the long-term safety 
and efficacy of this drug used in the routine clinical setting in type 2 diabetes mellitus patients
with renal or hepatic impairment or advanced age. 
 
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 
This survey aims to evaluate the long-term safety and efficacy of this drug in type 2 diabetes 
mellitus patients with renal impairment (mild), hepatic impairment (mild or moderate), or 
advanced age (t65 years) in the routine clinical setting. In addition, this survey will enroll as 
many as possible patients who were switched from alogliptin 25 mg and metformin 
hydrochloride 500 mg (ie, 250 mg twice daily) in combination as a prior medication, to 
examine the relationship between the efficacy and improvement in medication adherence by 
the switching to this combination product in those who were taking alogliptin benzoate and 
metformin hydrochloride in combination. 

3.0 
Planned Sample Size and Rationale 
3.1 Planned Sample Size 
600 subjects (including 300 subjects with hepatic impairment)
3.2 Rationale 
Among the important identified risks and important potential risks of this drug, the following 
were reported in the alogliptin + metformin QD group (alogliptin 25 mg plus metformin 
hydrochloride 500 mg once daily) of Study SYR-322-MET/CCT-001: infection-related 
adverse events (26.3%, 40/152 subjects), gastrointestinal symptom-related adverse events 
(9.9%, 15/152 subjects), lactic acidosis-related adverse events (1.3%, 2/152 subjects), and 
hepatic function disorder-related adverse events (0.7%, 1/152 subjects). Based on these data, 
the incidence in this survey can be assumed to be t0.7% for such events among the important 
identified risks and important potential risks of this drug. 
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Assuming a Poisson distribution for the number of such events occurring in this survey, and 
with a sample size of 300 each for patients with renal impairment, patients with hepatic 
impairment, and elderly patients, adverse events occurring with an incidence of t0.7% in one 
of the patient subpopulations can be detected in at least one patient with a probability of t87%. 
Thus, with this sample size, the events reported in Study SYR-322-MET/CCT-001 and 
designated as important identified risks and important potential risks of this drug would be 
evaluable to a reasonable extent. For events occurring with a lower incidence, overall safety 
assessment will be performed based on information not only from this survey but also from 
other sources including spontaneous reports and literature in particular. 
 
From the viewpoint of patient accrual, patients with hepatic impairment will be the most 
difficult subpopulation to be accrued in this survey, based on the accrual rates in a previously 
conducted specified drug-use survey of Nesina Tablets in type 2 diabetes mellitus patients 
with concomitant use of a biguanide, which also enrolled patients with renal impairment, 
patients with hepatic impairment, and elderly patients. Thus, in order to ensure that patients 
with hepatic impairment in particular are adequately enrolled in this survey, the accrual target 
is set to “300 patients with hepatic impairment”. When this target is reached, in light of the 
extent of overlapping of the subpopulations in the above-mentioned Nesina Tablets specified 
drug-use survey, approximately 300 patients with renal impairment and approximately 300 
elderly patients would have been accrued. 
 
Also, with a total sample size of t600 in this survey, improvement in patient convenience by 
switching to this combination product from alogliptin benzoate and metformin hydrochloride
in combination would be evaluable to a reasonable extent. 
4.0
Target Patient Population 
This survey will be conducted in patients with type 2 diabetes mellitus for whom combination 
therapy with alogliptin benzoate and metformin hydrochloride is appropriate in the opinion of 
a physician, and 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 one or more of the following: 
(1) Have renal impairment (mild) 
(2) Have hepatic impairment (mild or moderate) 
(3) Elderly (aged t65 years) 
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4.2 Exclusion Criteria 
Subjects who meet the following criterion will be excluded:
Patients with any contraindication for this drug
5.0
Dosage and Administration 
The usual adult dosage of this drug is 1 tablet (ie, 25 mg of alogliptin and 500 mg of 
metformin hydrochloride) once daily orally immediately before a meal or after a meal. The 
package insert for this drug should be referenced. 
6.0
Planned Number of Survey Sites by Specialty Department 
Approximately 120 sites, including department of internal medicine 
7.0
Methods 
7.1 Duration of Observation 
12 months 
7.2 Data Collection Method
Data will be collected using a web-based electronic data capture system (
). 
7.3 Patient Enrollment Method 
Patients will be enrolled using a centralized registration method via 
.
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 
 promptly after the end of observation at 12 months of treatment with this drug, 
and the survey 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 
 promptly 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 
, and the survey physician will enter an electronic signature. 

*: 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 
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entry to 
, 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 
person in charge of Takeda Pharmaceutical Company Limited (hereinafter referred to as 
“Takeda personnel”). 
 
8.0 
Planned Survey Period 
Survey period: February 2017 to June 30, 2019  
Patient enrollment period: February 2017 to June 30, 2018 Note) 
Note) Even if this drug is prescribed by June 30, 2018, no patient enrollment (via 
) will 
be acceptable on or after July 1, 2018. 
If the total number of patients enrolled in this survey reached the planned sample size 
before June 30, 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
Informed Consent 
Prior to enrollment of a patient in this survey, the survey physician will obtain written consent 
of the patient or the patient’s legally acceptable representative. Patients who provided consent 
will be assigned the subject identification numbers. 
10.0
Survey Variables 
The survey physician or designee will enter data on the following variables into 
. The
survey schedule is shown in Appendix 1. 
10.1 Patient Enrollment 
1)Survey variables
Date of prescription of this drug, subject identification number, patient initials, sex, age, 
assessment against the inclusion criteria (ie, the patient has renal impairment*1 [mild], 
hepatic impairment*2 [mild or moderate], or advanced age [t65 years]), assessment against 
the exclusion criteria (ie, the patient does not have any contraindication for this drug), 
status of medication with alogliptin benzoate and metformin hydrochloride (presence or 
absence of concomitant use as alogliptin 25 mg and metformin hydrochloride 500 mg [250 
mg BID]) immediately before use of this drug 
 
As a guide to severity assessment of renal impairment and hepatic impairment, the following tables 
should be referenced. 
 
 
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*1: Severity classification of renal impairment 
Severity of renal 
impairment 
eGFR 
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Serum creatinine  
(mg/dL) * 
Creatinine clearance  
(Ccr, mL/min)  
Mild 
t60 to <90 
Male: >0.90 to d1.4 
Female: >0.77 to d1.2 
t50 to d80 
Moderate 
t30 to <60 
Male: >1.4 to d2.4 
Female: >1.2 to d2.0 
t30 to <50 
Severe or  
end-stage renal disease 
<30 
Male: >2.4 
Female: >2.0 
<30 
For end-stage renal disease, time of the measurement relative to a hemodialysis session is disregarded. 
 
*: Estimated values corresponding to the Ccr (for persons who are aged 60 years and weigh 65 kg)  
Adapted from the “Precautions related to Dosage and Administration” section of Nesina Tablets package insert (see 
Cockcroft DW, et al. Nephron 1976; 16: 31-41) 
 
*2: Severity classification of hepatic impairment 
Severity of 
hepatic 
impairment 
Mild 
Moderate 
Severe 
Total bilirubin 
(mg/dL)  
t1.6 to <3.0 
t3.0 to <10 
t10 
AST or ALT 
(U/L) 
t50 to <100 
t100 to <500 
t500 
ALP 
t1.25 × ULN to  
<2.5 × ULN 
t2.5 × ULN to  
<5 × ULN  
t5 × ULN  
Gamma-GTP 
t1.5 × ULN 
- 
- 
LDH 
t1.5 × ULN 
- 
- 
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 t6 
months 
ULN: Upper limit of normal of the study site 
 
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
10.2 Patient Background 
1) Survey variables 
Time of the diagnosis of type 2 diabetes mellitus, inpatient/outpatient category, 
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, status of occupation (presence or absence), status 
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of treatment compliance with alogliptin benzoate and metformin hydrochloride within 3 
months before the start of treatment with this drug*3 
*3: Assessed using a scale from 0% to 100% in increments of 5%. 
2) Time of data collection 
At initiation of treatment with this drug 
10.3 Treatment Details 
1) Survey variables 
Detailed use of this drug (therapy start date, therapy end date, and reason for 
discontinuation [if applicable]), detailed use of concomitant drugs*4 (for the treatment of 
diabetes mellitus) (presence or absence, if present, name of the drug, daily dose, and 
therapy dates), detailed use of concomitant drugs (for other conditions than diabetes 
mellitus) (presence or absence, if present, name of the drug, reason for use) 
*4: Including antidiabetic medication discontinued within 3 months before use of this drug 
(Also, alogliptin benzoate and metformin hydrochloride used before this drug will be 
investigated.) 
2) Time of data collection 
From initiation of treatment with this drug until 12 months later (or discontinuation of 
treatment) 
10.4 Treatment Compliance Status for this Drug, and Daily Dosing Frequency and Number of 
Tablets for Concomitant Drugs 
1) Survey variables 
The status of treatment compliance with this drug will be assessed using a scale from 0% to 
100% in increments of 5%. 
Also regarding concomitant drugs (for the treatment of diabetes mellitus or other 
conditions), the maximum number of doses administered per day and the maximum number 
of tablets administered per day will be investigated at each time of data collection. 
2)Time of data collection
At initiation of treatment with this drug (except treatment compliance status for this drug), 
and 1, 3, 6, 9, and 12 months later (or discontinuation of treatment) 
10.5 Items of Tests and Observations 
Data from tests and observations in the routine clinical setting, if performed at the respective 
time of data collection, will be entered. 
 
 Vital Signs 
1)Items of tests and observations
Pulse rate, blood pressure (systolic /diastolic), body weight
2)Time of data collection
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At initiation of treatment with this drug, and 1, 3, 6, 9, and 12 months later (or 
discontinuation of treatment), if performed 
 Laboratory Tests 
1)Test variables
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, LDH, total bilirubin, 
amylase, lipase, lactic acid 
2)Time of data collection
At initiation of treatment with this drug, and 1, 3, 6, 9, and 12 months later (or 
discontinuation of treatment), if performed 
 Electrocardiogram 
1)Test variable
Electrocardiogram (assessment)
2)Time of data collection
At initiation of treatment with this drug and 12 months later (or discontinuation of treatment), 
if performed
 
 Waist Circumference and Testing Related to Coronary Arteries and Arteriosclerosis 
1) Test variables 
Waist circumference*5, testing related to coronary arteries and arteriosclerosis*6 (eg, pulse 
wave velocity , blood pressure pulse wave test, cervical artery ultrasound, intravascular 
ultrasound) 
*5: 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. 
*6: 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 12 months later (or discontinuation of treatment), 
if performed 
 
 Other Items of Observation 
1) Observation item(s) 
Presence or absence of pregnancy during the observation (only in women)  
2) Time of data collection 
From initiation of treatment with this drug until 12 months later (or discontinuation of 
treatment) 
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10.6 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*7 (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. 
 
If onset of any of the following is reported as an adverse event, detailed information should 
be collected as needed: lactic acidosis, hypoglycemia, acute pancreatitis, hepatic function 
disorder or jaundice, severe skin disorder such as oculomucocutaneous syndrome 
(Stevens-Johnson syndrome) and erythema multiforme, rhabdomyolysis, intestinal 
obstruction, interstitial pneumonia, angioedema, gastrointestinal symptom, infection, 
malignant tumor, pemphigoid, cardiovascular event (eg, symptomatic coronary artery 
disease, cerebrovascular disorder, arteriosclerosis obliterans, cardiovascular death, sudden 
death). 
*7: 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 until 12 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. 
 
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10 
11.3 Disposition of Patients 
Number of patients enrolled in the survey, number of patients with collected case report forms, 
numbers of patients evaluated for the safety and efficacy, number of patients excluded from 
analyses and reasons for exclusion, etc. will be summarized. 
11.4 Patient Background 
Patient background data such as sex, age, duration of type 2 diabetes mellitus, and concurrent 
diseases will be summarized. 
11.5 Treatment Details 
Detailed use of this drug and concomitant drugs will be summarized. 
 
11.6 Treatment Compliance Status, and Daily Dosing Frequency and Number of Tablets for 
Concomitant Drugs 
Treatment compliance status will be summarized for alogliptin benzoate and metformin 
hydrochloride within 3 months before use of this drug, and also for this drug at each time 
of data collection. Also regarding concomitant drugs (for the treatment of diabetes 
mellitus and other conditions), the maximum number of doses administered per day and 
the maximum number of tablets administered per day will be summarized. 
 
11.7 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). 
 
 Adverse Event Profile 
Adverse events occurring during the observation period will be summarized using 
frequency distribution by event type, time to onset, seriousness, causal relationship to this 
drug, etc. 
 Factors Likely Affecting the Safety 
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, presence or absence of renal impairment, presence or absence of hepatic 
impairment) and treatment details (eg, detailed use of this drug). 
11.8 Efficacy data 
The following data will be summarized using the efficacy analysis set. 
 HbA1c over time 
The HbA1c level and change (value at the respective time after initiation of treatment 
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minus baseline value) at each time point of evaluation will be summarized.  
 Fasting blood glucose over time 
The fasting blood glucose level and change (value at the respective time after initiation of 
treatment minus baseline value) at each time point of evaluation will be summarized.  
 
 Fasting insulin over time 
The fasting insulin level and change (value at the respective time after initiation of 
treatment minus baseline value) at each time point of evaluation will be summarized.  
 
 Factors likely affecting the efficacy 
A subgroup analysis will be performed on change in HbA1c etc., with stratification of 
patients according to background factors (eg, sex, age, presence or absence of renal 
impairment, presence or absence of hepatic impairment, baseline HbA1c level) and 
treatment details (eg, detailed use of this drug). In addition, among the patients with no 
change in the dose of alogliptin benzoate and metformin hydrochloride between before and 
after the switching to this drug, and no change in the dose of any antidiabetic medication 
during the treatment with this drug, the treatment compliance status between before and 
after the use of this drug and change in HbA1c will be summarized, and the relationship 
between medication adherence and change in HbA1c will be analyzed. In this analysis, in 
order to minimize influence of other factors than reductions in the number of tablets per 
day and the number of doses per day by switching to this drug among factors likely 
contributing to medication adherence, subgroup analyses according to such other factors etc. 
will be used to characterize the relationship between medication adherence and change in 
HbA1c as far as possible. 
 
 Factors Likely Affecting Medication Adherence 
Regarding change in the medication adherence, in order to minimize influence of other 
factors than reductions in the number of tablets administered per day and the number of 
doses per day by switching to this drug among factors likely contributing to medication 
adherence, subgroup analyses according to such other factors etc. will be used to 
characterize the influence of this drug on the medication adherence. 
11.9 Special Patient Populations 
For each of the subpopulations of patients with renal impairment, patients with hepatic 
impairment, and elderly patients in this survey, a similar analysis to Sections 10.1 to 10.8.3
will be performed. 
12.0
Informed Consent Form and Patient Consent 
The informed consent form contains the description as to how the patients’ personal 
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information and medical information are used in this survey. The informed consent form 
also describes the survey overview, the freedom of patients to withdraw from the survey at 
any time without providing a reason without any disadvantages in treatment. 
 
The survey physician will provide a potential survey subject (or legally acceptable 
representative) with explanation about this survey as provided in the informed consent 
form. If of the patient (or legally acceptable representative) agrees to participate in this 
survey, he/she (or legally acceptable representative) will sign and date the informed 
consent form. The survey physician will retain the original of the signed informed consent 
form. 
 
13.0
Registration of Survey Information 
Before initiation of this survey, information on this survey will be registered with the 
following website. 
x Japan Pharmaceutical Information Center (JAPIC) Clinical Trials Information 
14.0
Administrative Structure 
14.1 Chief Administrator 
Post-marketing Survey Chief Administrator 
Takeda Pharmaceutical Company Limited 
15.0
Trustees 
16.0
Other Necessary Items 
16.1 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. 
16.2 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. 
PPD
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Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

14 
Appendix 2 
Takeda Medically Significant AE List 
 
General 
Malignancy 
Endotoxic shock 
Sepsis 
Transmission of an infectious agent by a 
medicinal product 
 
Blood and lymphatic System 
Bone marrow failure 
Disseminated Intravascular Coagulation  
Haemolytic anaemia 
Thrombotic Thrombocytopenic Purpura 
Cardiovascular System 
Cardiac arrest 
Cardiac failure 
Cardiomyopathy acute 
Malignant hypertension 
Myocardial infarction 
Ventricular arrhythmias 
Endocrine System 
Adrenal crisis  
Gastrointestinal System 
Acute pancreatitis 
GI haemorrhage 
GI perforation 
GI obstruction 
Necrotising colitis 
Peritonitis 
Hepatobiliary System 
Acute hepatic failure 
Fulminant hepatitis 
Urinary System 
Acute renal failure 
 
Immune system 
Anaphylaxis 
Progressive multifocal leukoencephalopathy 
(PML) 
Transplant rejection 
Musculoskeletal System 
Rhabdomyolysis 
Nervous System 
Cerebrovascular accident 
Coma 
Convulsive seizures 
Hyperthermia malignant 
Macular oedema 
Meningoencephalitis 
Neuroleptic malignant syndrome 
Suicidal behaviour 
Reproductive System 
Abortion 
Uterine perforation 
Respiratory System 
Acute respiratory failure 
Pulmonary hypertension 
Pulmonary thromboembolism 
Skin and subcutaneous tissue 
Toxic epidermal necrolysis 
Stevens-Johnson syndrome 
 
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

 
Protocol for Specified Drug-Use Survey of 
INISYNC Combination Tablets  
“Survey on long-term use in  
type 2 diabetes mellitus patients with  
renal or hepatic impairment or advanced age” 








Survey Sponsor  
Takeda Pharmaceutical Company Limited  
Protocol Number 
Alogliptin-Met-5003 
Version Number 
Version 1 
Date of Preparation 
October 11, 2016 
 
Property of Takeda: For non-commercial 
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Terms of Use

 
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 ....................................................................................................................................... 3 
5.0 
Dosage and Administration ............................................................................................................................ 3 
6.0 
Planned Number of Survey Sites by Specialty Department ........................................................................... 3 
7.0 
Methods .......................................................................................................................................................... 3 
7.1 
Duration of Observation ............................................................................................................................. 3 
7.2 
Data Collection Method ............................................................................................................................. 3 
7.3 
Patient Enrollment Method ........................................................................................................................ 3 
7.4 
Case Report Form (Electronic) Completion and Electronic Signature ....................................................... 3 
8.0 
Planned Survey Period ................................................................................................................................... 4 
9.0 
Informed Consent ........................................................................................................................................... 4 
10.0 
Survey Variables ............................................................................................................................................. 4 
10.1 
Patient Enrollment ...................................................................................................................................... 4 
10.2 
Patient Background .................................................................................................................................... 5 
10.3 
Treatment Details ....................................................................................................................................... 6 
10.4 
Treatment Compliance Status for this Drug, and Daily Dosing Frequency and Number of Tablets for 
Concomitant Drugs ................................................................................................................................................ 6 
10.5 
Items of Tests and Observations ................................................................................................................. 6 
 
Vital Signs .......................................................................................................................................... 6 
 
Laboratory Tests ................................................................................................................................. 7 
 
Electrocardiogram .............................................................................................................................. 7 
 
Waist Circumference and Testing Related to Coronary Arteries and Arteriosclerosis ....................... 7 
 
Other Items of Observation ................................................................................................................ 7 
10.6 
Adverse Events ........................................................................................................................................... 8 
11.0 
Analytical Items and Methods ........................................................................................................................ 9 
11.1 
Statistical Analysis Plan ............................................................................................................................. 9 
11.2 
Analysis Sets .............................................................................................................................................. 9 
11.3 
Disposition of Patients.............................................................................................................................. 10 
11.4 
Patient Background .................................................................................................................................. 10 
11.5 
Treatment Details ..................................................................................................................................... 10 
11.6 
Treatment Compliance Status, and Daily Dosing Frequency and Number of Tablets for Concomitant 
Drugs 10 
11.7 
Safety Data ............................................................................................................................................... 10 
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Adverse Event Profile ...................................................................................................................... 10 
 
Factors Likely Affecting the Safety .................................................................................................. 10 
11.8 
Efficacy data ............................................................................................................................................. 10 
 
HbA1c over time .............................................................................................................................. 10 
 
Fasting blood glucose over time ....................................................................................................... 11 
 
Fasting insulin over time .................................................................................................................. 11 
 
Factors likely affecting the efficacy ................................................................................................. 11 
 
Factors Likely Affecting Medication Adherence .............................................................................. 11 
11.9 
Special Patient Populations ...................................................................................................................... 11 
12.0 
Informed Consent Form and Patient Consent .............................................................................................. 11 
13.0 
Registration of Survey Information .............................................................................................................. 12 
14.0 
Administrative Structure .............................................................................................................................. 12 
14.1 
Chief Administrator .................................................................................................................................. 12 
15.0 
Trustees ........................................................................................................................................................ 12 
16.0 
Other Necessary Items .................................................................................................................................. 12 
16.1 
Amendments to the Protocol .................................................................................................................... 12 
16.2 
Actions to be Taken in Response to Detection of any Issues or Concerns ............................................... 12 
Appendix 1 
Observation Schedule ....................................................................................................................... 14 
Appendix 2 
Takeda Medically Significant AE List .............................................................................................. 15 
Property of Takeda: For non-commercial use only and 
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1 
1.0
Background 
Drugs to treat type 2 diabetes mellitus are likely used over a long time in the routine clinical 
setting. Inisync Combination Tablets (hereinafter referred to as “this drug”) contain two active 
ingredients: alogliptin benzoate (brand name, Nesina Tablets) and metformin hydrochloride. 
Long-term combination use of these drugs in the routine clinical setting was previously 
investigated in a specified drug-use survey. However, clinical trial data were limited on the 
safety and efficacy of this drug in patients with renal impairment, patients with hepatic 
impairment and elderly patients, and therefore data in these patient populations are designated 
as part of “important missing information” in the risk management plan for this drug. Thus, 
with a focus particularly on these patient populations, the present specified drug-use survey 
(hereinafter referred to as “this survey”) has been planned to investigate the long-term safety 
and efficacy of this drug used in the routine clinical setting in type 2 diabetes mellitus patients
with renal or hepatic impairment or advanced age. 
 
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 
This survey aims to evaluate the long-term safety and efficacy of this drug in type 2 diabetes 
mellitus patients with renal impairment (mild), hepatic impairment (mild or moderate), or 
advanced age (t65 years) in the routine clinical setting. In addition, this survey will enroll as 
many as possible patients who were switched from alogliptin 25 mg and metformin 
hydrochloride 500 mg (ie, 250 mg twice daily) in combination as a prior medication, to 
examine the relationship between the efficacy and improvement in medication adherence by 
the switching to this combination product in those who were taking alogliptin benzoate and 
metformin hydrochloride in combination. 

3.0 
Planned Sample Size and Rationale 
3.1 Planned Sample Size 
600 subjects (including 300 subjects with hepatic impairment)
3.2 Rationale 
Among the important identified risks and important potential risks of this drug, the following 
were reported in the alogliptin + metformin QD group (alogliptin 25 mg plus metformin 
hydrochloride 500 mg once daily) of Study SYR-322-MET/CCT-001: infection-related 
adverse events (26.3%, 40/152 subjects), gastrointestinal symptom-related adverse events 
(9.9%, 15/152 subjects), lactic acidosis-related adverse events (1.3%, 2/152 subjects), and 
hepatic function disorder-related adverse events (0.7%, 1/152 subjects). Based on these data, 
the incidence in this survey can be assumed to be t0.7% for such events among the important 
identified risks and important potential risks of this drug. 
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Assuming a Poisson distribution for the number of such events occurring in this survey, and 
with a sample size of 300 each for patients with renal impairment, patients with hepatic 
impairment, and elderly patients, adverse events occurring with an incidence of t0.7% in one 
of the patient subpopulations can be detected in at least one patient with a probability of t87%. 
Thus, with this sample size, the events reported in Study SYR-322-MET/CCT-001 and 
designated as important identified risks and important potential risks of this drug would be 
evaluable to a reasonable extent. For events occurring with a lower incidence, overall safety 
assessment will be performed based on information not only from this survey but also from 
other sources including spontaneous reports and literature in particular. 
 
From the viewpoint of patient accrual, patients with hepatic impairment will be the most 
difficult subpopulation to be accrued in this survey, based on the accrual rates in a previously 
conducted specified drug-use survey of Nesina Tablets in type 2 diabetes mellitus patients 
with concomitant use of a biguanide, which also enrolled patients with renal impairment, 
patients with hepatic impairment, and elderly patients. Thus, in order to ensure that patients 
with hepatic impairment in particular are adequately enrolled in this survey, the accrual target 
is set to “300 patients with hepatic impairment”. When this target is reached, in light of the 
extent of overlapping of the subpopulations in the above-mentioned Nesina Tablets specified 
drug-use survey, approximately 300 patients with renal impairment and approximately 300 
elderly patients would have been accrued. 
 
Also, with a total sample size of t600 in this survey, improvement in patient convenience by 
switching to this combination product from alogliptin benzoate and metformin hydrochloride
in combination would be evaluable to a reasonable extent. 
4.0
Target Patient Population 
This survey will be conducted in patients with type 2 diabetes mellitus for whom combination 
therapy with alogliptin benzoate and metformin hydrochloride is appropriate in the opinion of 
a physician, and 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 one or more of the following: 
(1) Have renal impairment (mild) 
(2) Have hepatic impairment (mild or moderate) 
(3) Elderly (aged t65 years) 
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4.2 Exclusion Criteria 
Subjects who meet the following criterion will be excluded:
Patients with any contraindication for this drug
5.0
Dosage and Administration 
The usual adult dosage of this drug is 1 tablet (ie, 25 mg of alogliptin and 500 mg of 
metformin hydrochloride) once daily orally immediately before a meal or after a meal. The 
package insert for this drug should be referenced. 
6.0
Planned Number of Survey Sites by Specialty Department 
Approximately 120 sites, including department of internal medicine 
7.0
Methods 
7.1 Duration of Observation 
12 months 
7.2 Data Collection Method
Data will be collected using a web-based electronic data capture system (
). 
7.3 Patient Enrollment Method 
Patients will be enrolled using a centralized registration method via 
.
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 
 promptly after the end of observation at 12 months of treatment with this drug, 
and the survey 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 
 promptly 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 
, and the survey physician will enter an electronic signature. 

*: 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 
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4 
entry to 
, 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 
person in charge of Takeda Pharmaceutical Company Limited (hereinafter referred to as 
“Takeda personnel”). 
 
8.0 
Planned Survey Period 
Survey period: February 2017 to June 30, 2019  
Patient enrollment period: February 2017 to June 30, 2018 Note) 
Note) Even if this drug is prescribed by June 30, 2018, no patient enrollment (via 
) will 
be acceptable on or after July 1, 2018. 
If the total number of patients enrolled in this survey reached the planned sample size 
before June 30, 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
Informed Consent 
Prior to enrollment of a patient in this survey, the survey physician will obtain written consent 
of the patient or the patient’s legally acceptable representative. Patients who provided consent 
will be assigned the subject identification numbers. 
10.0
Survey Variables 
The survey physician or designee will enter data on the following variables into
. The
survey schedule is shown in Appendix 1. 
10.1 Patient Enrollment 
1)Survey variables
Date of prescription of this drug, subject identification number, patient initials, sex, age, 
assessment against the inclusion criteria (ie, the patient has renal impairment*1 [mild], 
hepatic impairment*2 [mild or moderate], or advanced age [t65 years]), assessment against 
the exclusion criteria (ie, the patient does not have any contraindication for this drug), 
status of medication with alogliptin benzoate and metformin hydrochloride (presence or 
absence of concomitant use as alogliptin 25 mg and metformin hydrochloride 500 mg [250 
mg BID]) immediately before use of this drug 
 
As a guide to severity assessment of renal impairment and hepatic impairment, the following tables 
should be referenced. 
 
 
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*1: Severity classification of renal impairment 
Severity of renal 
impairment 
eGFR 
(mL/min/1.73m2)  
Serum creatinine  
(mg/dL) * 
Creatinine clearance  
(Ccr, mL/min)  
Mild 
t60 to <90 
Male: >0.90 to d1.4 
Female: >0.77 to d1.2 
t50 to d80 
Moderate 
t30 to <60 
Male: >1.4 to d2.4 
Female: >1.2 to d2.0 
t30 to <50 
Severe or  
end-stage renal disease 
<30 
Male: >2.4 
Female: >2.0 
<30 
For end-stage renal disease, time of the measurement relative to a hemodialysis session is disregarded. 
 
*: Estimated values corresponding to the Ccr (for persons who are aged 60 years and weigh 65 kg)  
Adapted from the “Precautions related to Dosage and Administration” section of Nesina Tablets package insert (see 
Cockcroft DW, et al. Nephron 1976; 16: 31-41) 
 
*2: Severity classification of hepatic impairment 
Severity of 
hepatic 
impairment 
Mild 
Moderate 
Severe 
Total bilirubin 
(mg/dL)  
t1.6 to <3.0 
t3.0 to <10 
t10 
AST or ALT 
(U/L) 
t50 to <100 
t100 to <500 
t500 
ALP 
t1.25 × ULN to  
<2.5 × ULN 
t2.5 × ULN to  
<5 × ULN  
t5 × ULN  
Gamma-GTP 
t1.5 × ULN 
- 
- 
LDH 
t1.5 × ULN 
- 
- 
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 t6 
months 
ULN: Upper limit of normal of the study site 
 
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
10.2 Patient Background 
1) Survey variables 
Time of the diagnosis of type 2 diabetes mellitus, inpatient/outpatient category, 
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, status of occupation (presence or absence), status 
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of treatment compliance with alogliptin benzoate and metformin hydrochloride within 3 
months before the start of treatment with this drug*3 
*3: Assessed using a scale from 0% to 100% in increments of 5%. 
2) Time of data collection 
At initiation of treatment with this drug 
10.3 Treatment Details 
1) Survey variables 
Detailed use of this drug (therapy start date, therapy end date, and reason for 
discontinuation [if applicable]), detailed use of concomitant drugs*4 (for the treatment of 
diabetes mellitus) (presence or absence, if present, name of the drug, daily dose, and 
therapy dates), detailed use of concomitant drugs (for other conditions than diabetes 
mellitus) (presence or absence, if present, name of the drug, reason for use) 
*4: Including antidiabetic medication discontinued within 3 months before use of this drug 
(Also, alogliptin benzoate and metformin hydrochloride used before this drug will be 
investigated.) 
2) Time of data collection 
From initiation of treatment with this drug until 12 months later (or discontinuation of 
treatment) 
10.4 Treatment Compliance Status for this Drug, and Daily Dosing Frequency and Number of 
Tablets for Concomitant Drugs 
1) Survey variables 
The status of treatment compliance with this drug will be assessed using a scale from 0% to 
100% in increments of 5%. 
Also regarding concomitant drugs (for the treatment of diabetes mellitus or other 
conditions), the maximum number of doses administered per day and the maximum number 
of tablets administered per day will be investigated at each time of data collection. 
2)Time of data collection
At initiation of treatment with this drug (except treatment compliance status for this drug), 
and 1, 3, 6, 9, and 12 months later (or discontinuation of treatment) 
10.5 Items of Tests and Observations 
Data from tests and observations in the routine clinical setting, if performed at the respective 
time of data collection, will be entered. 
 
 Vital Signs 
1)Items of tests and observations
Pulse rate, blood pressure (systolic /diastolic), body weight
2)Time of data collection
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At initiation of treatment with this drug, and 1, 3, 6, 9, and 12 months later (or 
discontinuation of treatment), if performed 
 Laboratory Tests 
1)Test variables
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, LDH, total bilirubin, 
amylase, lipase, lactic acid 
2)Time of data collection
At initiation of treatment with this drug, and 1, 3, 6, 9, and 12 months later (or 
discontinuation of treatment), if performed 
 Electrocardiogram 
1)Test variable
Electrocardiogram (assessment)
2)Time of data collection
At initiation of treatment with this drug and 12 months later (or discontinuation of treatment), 
if performed
 
 Waist Circumference and Testing Related to Coronary Arteries and Arteriosclerosis 
1) Test variables 
Waist circumference*5, testing related to coronary arteries and arteriosclerosis*6 (eg, pulse 
wave velocity , blood pressure pulse wave test, cervical artery ultrasound, intravascular 
ultrasound) 
*5: 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. 
*6: 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 12 months later (or discontinuation of treatment), 
if performed 
 
 Other Items of Observation 
1) Observation item(s) 
Presence or absence of pregnancy during the observation (only in women)  
2) Time of data collection 
From initiation of treatment with this drug until 12 months later (or discontinuation of 
treatment) 
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10.6 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*7 (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. 
 
If onset of any of the following is reported as an adverse event, detailed information should 
be collected as needed: lactic acidosis, hypoglycemia, acute pancreatitis, hepatic function 
disorder or jaundice, severe skin disorder such as oculomucocutaneous syndrome 
(Stevens-Johnson syndrome) and erythema multiforme, rhabdomyolysis, intestinal 
obstruction, interstitial pneumonia, angioedema, gastrointestinal symptom, infection, 
malignant tumor, cardiovascular event (eg, symptomatic coronary artery disease, 
cerebrovascular disorder, arteriosclerosis obliterans, cardiovascular death, sudden death). 
*7: 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 until 12 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. 
 
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11.3 Disposition of Patients 
Number of patients enrolled in the survey, number of patients with collected case report forms, 
numbers of patients evaluated for the safety and efficacy, number of patients excluded from 
analyses and reasons for exclusion, etc. will be summarized. 
11.4 Patient Background 
Patient background data such as sex, age, duration of type 2 diabetes mellitus, and concurrent 
diseases will be summarized. 
11.5 Treatment Details 
Detailed use of this drug and concomitant drugs will be summarized. 
 
11.6 Treatment Compliance Status, and Daily Dosing Frequency and Number of Tablets for 
Concomitant Drugs 
Treatment compliance status will be summarized for alogliptin benzoate and metformin 
hydrochloride within 3 months before use of this drug, and also for this drug at each time 
of data collection. Also regarding concomitant drugs (for the treatment of diabetes 
mellitus and other conditions), the maximum number of doses administered per day and 
the maximum number of tablets administered per day will be summarized. 
 
11.7 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). 
 
 Adverse Event Profile 
Adverse events occurring during the observation period will be summarized using 
frequency distribution by event type, time to onset, seriousness, causal relationship to this 
drug, etc. 
 Factors Likely Affecting the Safety 
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, presence or absence of renal impairment, presence or absence of hepatic 
impairment) and treatment details (eg, detailed use of this drug). 
11.8 Efficacy data 
The following data will be summarized using the efficacy analysis set. 
 HbA1c over time 
The HbA1c level and change (value at the respective time after initiation of treatment 
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minus baseline value) at each time point of evaluation will be summarized.  
 Fasting blood glucose over time 
The fasting blood glucose level and change (value at the respective time after initiation of 
treatment minus baseline value) at each time point of evaluation will be summarized.  
 
 Fasting insulin over time 
The fasting insulin level and change (value at the respective time after initiation of 
treatment minus baseline value) at each time point of evaluation will be summarized.  
 
 Factors likely affecting the efficacy 
A subgroup analysis will be performed on change in HbA1c etc., with stratification of 
patients according to background factors (eg, sex, age, presence or absence of renal 
impairment, presence or absence of hepatic impairment, baseline HbA1c level) and 
treatment details (eg, detailed use of this drug). In addition, among the patients with no 
change in the dose of alogliptin benzoate and metformin hydrochloride between before and 
after the switching to this drug, and no change in the dose of any antidiabetic medication 
during the treatment with this drug, the treatment compliance status between before and 
after the use of this drug and change in HbA1c will be summarized, and the relationship 
between medication adherence and change in HbA1c will be analyzed. In this analysis, in 
order to minimize influence of other factors than reductions in the number of tablets per 
day and the number of doses per day by switching to this drug among factors likely 
contributing to medication adherence, subgroup analyses according to such other factors etc. 
will be used to characterize the relationship between medication adherence and change in 
HbA1c as far as possible. 
 
 Factors Likely Affecting Medication Adherence 
Regarding change in the medication adherence, in order to minimize influence of other 
factors than reductions in the number of tablets administered per day and the number of 
doses per day by switching to this drug among factors likely contributing to medication 
adherence, subgroup analyses according to such other factors etc. will be used to 
characterize the influence of this drug on the medication adherence. 
11.9 Special Patient Populations 
For each of the subpopulations of patients with renal impairment, patients with hepatic 
impairment, and elderly patients in this survey, a similar analysis to Sections 10.1 to 10.8.3
will be performed. 
12.0
Informed Consent Form and Patient Consent 
The informed consent form contains the description as to how the patients’ personal 
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information and medical information are used in this survey. The informed consent form 
also describes the survey overview, the freedom of patients to withdraw from the survey at 
any time without providing a reason without any disadvantages in treatment. 
 
The survey physician will provide a potential survey subject (or legally acceptable 
representative) with explanation about this survey as provided in the informed consent 
form. If of the patient (or legally acceptable representative) agrees to participate in this 
survey, he/she (or legally acceptable representative) will sign and date the informed 
consent form. The survey physician will retain the original of the signed informed consent 
form. 
 
13.0
Registration of Survey Information 
Before initiation of this survey, information on this survey will be registered with the 
following website. 
x Japan Pharmaceutical Information Center (JAPIC) Clinical Trials Information 
14.0
Administrative Structure 
14.1 Chief Administrator 
Post-marketing Survey Chief Administrator 
Takeda Pharmaceutical Company Limited 
15.0
Trustees 
16.0
Other Necessary Items 
16.1 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. 
16.2 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. 
PPD
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15 
Appendix 2 
Takeda Medically Significant AE List 
 
General 
Malignancy 
Endotoxic shock 
Sepsis 
Transmission of an infectious agent by a 
medicinal product 
 
Blood and lymphatic System 
Bone marrow failure 
Disseminated Intravascular Coagulation  
Haemolytic anaemia 
Thrombotic Thrombocytopenic Purpura 
Cardiovascular System 
Cardiac arrest 
Cardiac failure 
Cardiomyopathy acute 
Malignant hypertension 
Myocardial infarction 
Ventricular arrhythmias 
Endocrine System 
Adrenal crisis  
Gastrointestinal System 
Acute pancreatitis 
GI haemorrhage 
GI perforation 
GI obstruction 
Necrotising colitis 
Peritonitis 
Hepatobiliary System 
Acute hepatic failure 
Fulminant hepatitis 
Urinary System 
Acute renal failure 
 
Immune system 
Anaphylaxis 
Progressive multifocal leukoencephalopathy 
(PML) 
Transplant rejection 
Musculoskeletal System 
Rhabdomyolysis 
Nervous System 
Cerebrovascular accident 
Coma 
Convulsive seizures 
Hyperthermia malignant 
Macular oedema 
Meningoencephalitis 
Neuroleptic malignant syndrome 
Suicidal behaviour 
Reproductive System 
Abortion 
Uterine perforation 
Respiratory System 
Acute respiratory failure 
Pulmonary hypertension 
Pulmonary thromboembolism 
Skin and subcutaneous tissue 
Toxic epidermal necrolysis 
Stevens-Johnson syndrome 
 
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