Alogliptin (Nesina) Tablets Specified Drug-use Survey "Type 2 Diabetes Mellitus: Combination Therapy With Hypoglycemic Drug (Insulin Preparation or Rapid-acting Insulin Secretagogues, Etc)"
Conditions: Type 2 Diabetes Mellitus
Sponsor: Takeda

 
 
Title: Nesina Tablets Specified Drug-use Survey "Type 2 Diabetes Mellitus: 
Combination Therapy With Hypoglycemic Drug (Insulin Preparation or Rapid-acting 
Insulin Secretagogues, Etc)" 
 
NCT Number: NCT02221284 
Protocol Approve Date: 02-Jun-2017 
 
Certain information within this Protocol has been redacted (ie, specific content is 
masked irreversibly from view with a black/blue bar) to protect either personally 
identifiable information or company confidential information. 
 
This may include, but is not limited to, redaction of the following: 
 
Named persons or organizations associated with the study. 
 
Patient identifiers within the text, tables, or figures or in by-patient data listings. 
 
Proprietary information, such as scales or coding systems, which are considered 
confidential information under prior agreements with license holder. 
 
Other information as needed to protect confidentiality of Takeda or partners, 
personal information, or to otherwise protect the integrity of the clinical study. 
 
If needed, certain appendices that contain a large volume of personally identifiable 
information or company confidential information may be removed in their entirety if it 
is considered that they do not add substantially to the interpretation of the data (eg, 
appendix of investigator’s curriculum vitae). 
 
Note; This document was translated into English as the language on original version 
was Japanese. 

 
 
 
 
Protocol for 
Nesina Tablets Specified Drug-use Survey "Type 2 
Diabetes Mellitus: Combination Therapy With 
Hypoglycemic Drug (Insulin Preparation or 
Rapid-acting Insulin Secretagogues, Etc)" 
 
 
 
 
 
 
 
 
 
 
Version 
Sixth version 
Creation date 
June 2, 2017 
Sponsor 
Takeda Pharmaceutical Company Limited. 
 
 
 
 

 
 
 
Table of Contents 
1.0 
Background .................................................................................................................................................... 1 
2.0 
Objectives ....................................................................................................................................................... 1 
3.0 
Number of Planned Participants and the Rationales ...................................................................................... 1 
3.1 
Number of Planned Participants ............................................................................................................. 1 
3.2 
Rationales ............................................................................................................................................... 1 
4.0 
Patients for Survey ......................................................................................................................................... 2 
4.1 
Inclusion Criteria .................................................................................................................................... 2 
4.2 
Exclusion Criteria ................................................................................................................................... 2 
5.0 
Dosage and Administration ............................................................................................................................ 2 
6.0 
Number of Scheduled Sites by Department ................................................................................................... 3 
7.0 
Methods .......................................................................................................................................................... 3 
7.1 
Observation period ................................................................................................................................. 3 
7.2 
Request for Sites and Agreement ........................................................................................................... 3 
7.3 
Patient Enrollment Methods patients...................................................................................................... 3 
7.4 
Creation and Submission of Survey Sheet ............................................................................................. 3 
7.5 
Measures for Development of Serious Adverse Events ......................................................................... 4 
8.0 
Scheduled Period ............................................................................................................................................ 4 
9.0 
Matters to be Surveyed ................................................................................................................................... 4 
9.1 
Description Details in Patient Enrollment Sheet .................................................................................... 4 
9.2 
Description Items in Survey Sheet ......................................................................................................... 4 
9.2.1 
Front Cover of Survey Sheet .............................................................................................................. 4 
9.2.2 
Patient Demographics ......................................................................................................................... 4 
9.2.3 
Details of Treatment ........................................................................................................................... 5 
9.2.4 
Compliance with Nesina and Compliance with Diet/Exercise Therapy ............................................. 5 
9.2.5 
Laboratory/Observation Parameters ................................................................................................... 6 
9.2.5.1 
Vital Signs ...................................................................................................................................... 6 
9.2.5.2 
Laboratory Values ........................................................................................................................... 6 
9.2.5.3 
Electrocardiography ....................................................................................................................... 6 
9.2.5.4 
Tests for Waist Circumference, Coronary Arteriosclerosis, and Arteriosclerosis ........................... 6 
9.2.5.5 
Other Parameters ............................................................................................................................ 7 
9.2.6 
Adverse Event .................................................................................................................................... 7 
10.0 
Analysis Parameters and Methods ................................................................................................................. 9 
10.1 
Patient Component Parameters .............................................................................................................. 9 
10.2 
Patient Demographics............................................................................................................................. 9 
10.3 
Details of Treatment ............................................................................................................................... 9 
10.4 
Safety Parameters ................................................................................................................................... 9 
10.4.1 
Occurrence of Adverse Events ........................................................................................................... 9 
10.4. 2 
Factors Probably Affecting Safety ................................................................................................ 10 
10.5 
Efficacy Parameters .............................................................................................................................. 10 

 
 
 
10.5.1 
Change in HbA1c ............................................................................................................................. 10 
10.5.2 
Changes in Laboratory Test Values .................................................................................................. 10 
10.5.3 
Factors Probably Affecting Efficacy ................................................................................................ 10 
10.6 
Parameters in Patients with Special Demographics ............................................................................. 10 
11.0 
Registration of Survey Data ......................................................................................................................... 10 
12.0 
Organizations ............................................................................................................................................... 10 
12.1 
Manager ................................................................................................................................................ 10 
12.2 
Central Enrollment Center .................................................................................................................... 11 
13.0 
CRO.............................................................................................................................................................. 11 
14.0 
Other Necessary Matters .............................................................................................................................. 11 
14.1 
Protocol Revision ................................................................................................................................. 11 
14.2 
Measures for Issues or Questions ......................................................................................................... 11 
 
Appendix Observation Schedule  ............................................................................................................................ 12 

 
1 
 
1.0 
Background 
Nesina tablets (hereinafter, Nesina) are dipeptidyl peptidase-4inhibitors (hereinafter, 
DPP-4inhibitors) and oral hypoglycemic drugs mainly characterized by glucose level-dependent 
insulin secretion promotion via a GLP-1 increase and pancreas protection. Since oral 
hypoglycemic drugs have been generally used for a long period in patients and since multiple 
hypoglycemic drugs may be used simultaneously, it is important that long-term results of oral 
hypoglycemic drugs should be obtained from a daily clinical practice. The Specified Drug-use 
Survey of Nesina has been conducted in type 2 diabetes mellitus patients who have had an 
inadequate response to diet/exercise therapies only or diet/exercise therapies plus α-glucosidase 
inhibitors, thiazolidines, sulfonylureas, or biguanides. In the future, the specified drug-use 
survey of complication with Nesina and insulin preparations and insulin secretagogues is also 
expected to be conducted. 
Therefore, the Nesina Tablets Specified Drug-use Survey "Type 2 Diabetic Patients Receiving 
Combination Therapy With a Hypoglycemic Agent (e.g., Insulin Preparations or Rapid-acting 
Insulin Secretagogues)” (hereinafter, this survey) is planned aiming to evaluate the safety and 
efficacy of Nesina when administered for 1 year in type 2 diabetic patients who have had an 
inadequate response to hypoglycemic agents (e.g., insulin preparations, rapid-acting insulin 
secretagogues) in addition to dietary/exercise therapy in daily medical practice. 
This survey is conducted according to the relevant regulatory requirements including the GPSP 
ordinance. 
 
2.0 
Objectives 
This survey is designed to evaluate the safety and efficacy of long-term use of alogliptin tablets 
(Nesina Tablets) in type 2 diabetic patients who have had an inadequate response to 
hypoglycemic agents (e.g., insulin preparations or rapid-acting insulin secretagogues)* in 
addition to dietary/exercise therapy in daily medical practice. 
*Hypoglycemic agents which have not been used in the past Nesina Specified Drug-use Survey (i.e., other 
than α-glucosidase inhibitors, thiazolidines, sulfonylureas, and biguanides) 
 
3.0 
Number of Planned Participants and the Rationales 
3.1 
Number of Planned Participants 
1,000 participants 
 
3.2 
Rationales 
The Specified Drug-use Survey of Nesina has been conducted in type 2 diabetes mellitus 
patients who have had an inadequate response to diet/exercise therapies only or diet/exercise 
therapies plus α-glucosidase inhibitors, thiazolidines, sulfonylureas, or biguanides. In the future, 
the specified drug-use survey of complication with Nesina and insulin preparations and insulin 

 
2 
 
secretagogues is also expected to be conducted. 
Therefore, the planned participants was established as 1,000 to collect as many as participants 
who receive a long-term complication therapy with Nesina and these hypoglycemic agents (e.g., 
insulin preparations, rapid-acting insulin secretagogues). 
In the pooled tabulation of participants in the past Nesina Specified Drug-use Survey (as of 
November 30, 2013; Safety Analysis Set, 10,025 participants), the proportion of participants was 
as follows: elderly, 58.0%; renal impairment participants, 15.1%; and hepatic impairment 
participants, 13.3%. By establishment of the planned participants of 1,000 in this survey, data 
will be collected from approximately 600 elderly participants, approximately 150 renal 
impairment participants, and approximately 100 hepatic impairment participants. This 
establishment is not based on the statistical evidence. 
 
4.0 
Patients for Survey 
Patients with type 2 diabetes mellitus. However, participants must meet the inclusion criteria and 
none of the exclusion criteria, described below. Refer to the Precaution in the package insert. 
4.1 
Inclusion Criteria 
Patients who meet the following criterion are included in this survey: 
Patients who have had an inadequate response to the following medications/therapies: 
 
Use of one hypoglycemic agent such as insulin preparations and rapid-acting insulin 
secretagogues, excluding other types of hypoglycemic agents (e.g., α-glucosidase inhibitors, 
thiazolidines, sulfonylureas, biguanides)*, in addition to dietary/exercise therapy 
*For use of Nesina Tablets in combination with these agents, a specified drug-use survey is currently 
ongoing. 
 
4.2 
Exclusion Criteria 
Patients who meet any of the following criteria are excluded from this survey:  
Patients with contraindications for Nesina Tablets 
(1) 
Those with severe ketosis, in a state of diabetic coma or precoma, or with type 1 
diabetes mellitus [Quickly rectifying hyperglycemia with administration of intravenous 
fluid or insulin is essential in these patients; therefore, administration of Nesina Tablets 
is not appropriate.] 
(2) 
Those with severe infections, before or after surgery, or with serious trauma [Controlling 
blood glucose with an injection of insulin is desirable for these patients; therefore, 
administration of Nesina Tablets is not appropriate.] 
(3) 
Those with a history of hypersensitivity to any of the ingredients of Nesina Tablets 
 
5.0 
Dosage and Administration 
For adults, 25 mg of alogliptin is usually administered orally once daily. Refer to the Precaution 

 
3 
 
in the package insert. For renal impairment patients, refer to the Precaution with Respect to 
Dosage and Administration in the package insert. 
 
6.0 
Number of Scheduled Sites by Department 
Internal medicine or other department: Approximately 200 sites 
 
7.0 
Methods 
7.1 
Observation period 
12 months 
 
7.2 
Request for Sites and Agreement 
The survey is conducted using the paper survey sheet. Before asking survey, the parson in charge 
of medical information in Takeda Pharmaceutical Company Limited. (Hereinafter, Takeda MRs) 
will fully explain to the Investigator about the objectives, details, and methods of this survey, 
based on “Request for Cooperation of Specified Drug-use Survey,” “Summary for Survey,” 
“Patient Enrollment Sheet (sample),” and “Survey Sheet (sample)” and will finalize written 
agreement with survey sites to ask requests for surveillance within the specified period. 
 
7.3 
Patient Enrollment Methods patients 
This survey is conducted by Fax using Central Enrollment System. The Investigator will enroll 
patients for whom Nesina was prescribed after the start date of agreement with a survey site, by 
faxing to the Central Enrollment Center (refer to Section 12.2) the “Patient Enrollment Sheet” 
including the information regarding patient enrollment (refer to Section 9.1) before 14 days after 
the Nesina prescription date (define the prescription date as “0 day” and one day after the 
prescription date as “1 day”). Patients for whom Nesina prescription is scheduled cannot be 
enrolled earlier. The participant who assessed as ineligible for the survey for any reason cannot 
be enrolled in the survey. The Investigator will enroll a new participant using the “Patient 
Enrollment Sheet” supplied by the Takeda MR. The Takeda MR will supply for the Investigator 
the survey sheet issued after the Central Enrollment Center enrolled the participant. 
 
7.4 
Creation and Submission of Survey Sheet 
The Investigator will create the survey sheet for all enrolled participants and submit it to the 
Takeda around within 1 month after the end of the observation period. If Nesina administration 
cannot be confirmed, specify it (do not specify other columns). 
For participants who early discontinue treatment with Nesina during the observation period for 
any reason, the Investigator will create the survey sheet for him/her and submit it to the Takeda 
around within 1 month after the end of necessary observation. However, for participants who 
early discontinue treatment with Nesina due to an adverse event, the Investigator will continue 

 
4 
 
observation even after treatment discontinuation, wherever possible, until the adverse event 
resolve or is resolving and will create the survey sheet and submit it to the Takeda. 
 
7.5 
Measures for Development of Serious Adverse Events 
In case of development of a serious adverse event in the observation period, the Investigator will 
immediately contact the parson in charge in Takeda Pharmaceutical Company Limited. (person 
in charge in Takeda). If the person in charge in Takeda requests additional detailed information, 
the Investigator will provide it. 
 
8.0 
Scheduled Period 
Survey period: June 2014 to June 30, 2017 
Patient enrollment period: June 2014 to June 30, 2016* 
*Even if Nesina is prescribed before June 30 2016, the patients cannot be enrolled (fax of the Patient 
Enrollment Sheet) after July 1 2016. 
In case that the enrolled participants reach the scheduled number of participants in the survey before June 30 
2016, the enrollment will close earlier than the scheduled patient enrollment period. If patient enrollment 
period is shorten, the survey period will be also changed according to the shorten period. 
 
9.0 
Matters to be Surveyed 
The Investigator will describe the data described below in the Patient Enrollment Sheet and the 
survey sheet. The schedule of this survey is shown in the Appendix. 
9.1 
Description Details in Patient Enrollment Sheet 
1) Matters to be surveyed 
Name of survey site, name of the investigator who describe in the Patient Enrollment Sheet, 
Nesina prescription date, Patient ID Number, patient initial, sex, birth date, inclusion criteria 
assessment, and exclusion criteria assessment 
2) Survey period 
At patient enrollment 
 
9.2 
Description Items in Survey Sheet 
9.2.1 Front Cover of Survey Sheet 
Last description date in the survey sheet and name of the Investigator who described the survey 
sheet 
 
9.2.2 Patient Demographics 
1) Matters to be surveyed 
Diagnosis period of type 2 diabetes mellitus, category of clinical practice, disposition of 
hypersensitivity (yes/no and detail), concurrent disease (yes/no and detail), past medical 

 
5 
 
history (yes/no and detail), height, smoking history, drinking history, presence or absence of 
serum creatinine within 1 month after the start of Nesina treatment, serum creatinine level (if 
serum creatinine present), and severity of renal impairment and rationale for the assessment 
(if serum creatinine absent). 
2) Survey period 
At the start of Nesina treatment 
 
9.2.3 
Details of Treatment 
1) Matters to be surveyed 
Details of Nesina treatment (daily dose, administration period, and reason for 
discontinuation), and status of concomitant medications (hypoglycemic agents*) (yes/no, 
drug name, daily dose, route of administration, administration period, and objective of 
administration) 
*Hypoglycemic agents which are discontinued within 3 months prior to Nesina treatment are included. 
2) Survey period 
Period from the start of Nesina treatment to 12 months after treatment (or treatment 
discontinuation) 
 
9.2.4 
Compliance with Nesina and Compliance with Diet/Exercise Therapy 
1) Matters to be surveyed 
Compliance with Nesina* and compliance with diet/exercise therapy** 
 
 
*Criteria for assessment of compliance with Nesina 
1. ≥ 90% (A participant won’t miss administration, or even if he/she missed 
administration, the frequency is twice or three times a month.) 
2. ≥ 70% (A participant missed administration once or twice weekly.) 
3. ≥ 50% (A participant missed administration three times a week.) 
4. < 50% (A participant missed administration four times or more a week.) 
 
**Criteria for assessment of compliance with diet/exercise therapy 
1. ≥ 90% (A participant complied as instructed.) 
2. ≥ 70% (A participant mostly complied as instructed.) 
3. ≥ 50% (A participant did not complied well as instructed.) 
4. < 50% (A participant did not mostly complied as instructed.) 
5. Not performed 
6. Unknown 
 

 
6 
 
2) Survey period 
At the start of Nesina treatment (compliance with diet/exercise therapy only), 1 month, 3 
months, 6 months, and 12 months after the start of treatment (or treatment discontinuation) 
 
9.2.5 
Laboratory/Observation Parameters 
9.2.5.1 Vital Signs 
1) Laboratory/observation parameters 
Pulse rate, blood pressure (systolic/diastolic), and weight 
2) Survey period 
Each time point at the start of Nesina treatment, 1 month, 3 months, 6 months, and 12 months 
after the start of treatment (or treatment discontinuation) 
 
9.2.5.2 Laboratory Values 
1) Laboratory parameters 
HbA1c (NGSP value, same hereafter), fasting glucose, fasting insulin, fasting glucagon, 
fasting triglyceride, total cholesterol, HDL-cholesterol, LDL-cholesterol, serum creatinine, 
BUN, urinary albumin (corrected by creatinine), AST, ALT, γ-GTP, ALP, total bilirubin, 
amylase, and lipase 
2) Survey period 
Each time point at the start of Nesina treatment, 1 month, 3 months, 6 months, and 12 months 
after the start of treatment (or treatment discontinuation) 
 
9.2.5.3 Electrocardiography 
1) Observation Parameters 
Electrocardiograms (assessment and findings) 
2) Survey period 
Each time point from the start of Nesina treatment to 12 months after treatment (or treatment 
discontinuation) 
 
9.2.5.4 Tests for Waist Circumference, Coronary Arteriosclerosis, and Arteriosclerosis 
1) Observation Parameters 
Tests for waist circumference,* coronary arteriosclerosis and arteriosclerosis** (e.g., pulse 
wave velocity, cardio-ankle vascular index, intima-media thickness, intra-vascular 
ultrasound) 
*Measure the waist diameter during light expiration at standing position and at the level of the navel. If the 
lower deviation of the navel occurs because of significant abdominal fat accumulation, measure the waist 
diameter at the level of the midpoint between the inferior rib border and anterior superior iliac spine. 
**Any methods can be used. In principle, however, use the same methods for each test. If there are no 

 
7 
 
devices for measurement, the tests can be omitted. 
2) Survey period 
Each time point from the start of Nesina treatment to 12 months after treatment (or treatment 
discontinuation) 
 
9.2.5.5 Other Parameters 
1) Observation parameters 
Pregnancy during the observation period (yes or no) (females only) 
In case of pregnancy in the observation period, the Investigator will immediately contact the 
person in charge in Takeda. The Investigator will provide detailed information (including the 
information until the delivery, as possible, such as preterm delivery) using the separate 
pregnancy sheet after the request from the person in charge in Takeda. 
2) Survey period 
Period from the start of Nesina treatment to 12 months after treatment (or treatment 
discontinuation) 
 
9.2.6 
Adverse Event 
1) Matters to be surveyed 
Presence or absence of adverse events (refer to Table 1), term of adverse events, onset date, 
seriousness and the reason (refer to Table 2), presence or absence of Nesina discontinuation, 
outcome assessment date, outcome, and causal relationship to Nesina* (refer to Table 3). 
If the outcome is assessed as Not resolved or Unknown and if the causal relationship cannot 
be assessed, the participant will be followed up, wherever possible. 
The detailed information (e.g., clinical course, laboratory tests for diagnosis) will be collected 
as possible for development of hypoglycemia, acute pancreatitis, renal impairment / jaundice, 
skin disorder including oculomucocutaneous syndrome (Stevens-Johnson syndrome) and 
erythema multiforme, rhabdomyolysis, intestinal obstruction, interstitial pneumonia, 
angioedema, infection, malignant tumor, pemphigoid, and cardiovascular system-related 
event (e.g., symptomatic coronary artery disease, cerebrovascular disorder, arteriosclerosis 
obliterans, cardiovascular death, sudden death) 
*If the causal relationship to Nesina is assessed as Not related, collect the rationales for assessment. If the 
relationship is assessed as Not assessable, collected the reason for Not assessable. 
 
Note) Matters that should be considered for adverse events 
Abnormal exacerbation of the target disease, i.e., worsening beyond expected natural 
clinical course, is defined as an adverse event; however, the expected worsening is not 
defined as an adverse vent. 
2) Survey period 

 
8 
 
Period from the start of Nesina treatment to 12 months after treatment (or treatment 
discontinuation) 
 
Table 1 Definition of adverse event 
An adverse event (AE) is defined as any unfavorable event that develops after a pharmaceutical 
product is administered and which does not necessarily have a causal relationship with treatment.  
An adverse event can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding, for example), symptom, or disease temporally associated with the use of a 
medicinal product, whether or not considered related to the medicinal product. 
The following events will be handled as adverse events: 
• Symptoms present in infants breastfed by a Nesina taking mother 
• Symptoms present in children who received the relevant drug 
• Symptoms due to occupational exposure to the relevant drug 
• Symptoms due to counterfeit medications of the legitimate medicinal products manufactured by 
Takeda 
• Unfavorable symptoms present in the patient who received the relevant drug, known by a lawsuit or 
other legal actions 
 
Table 2 Criteria for severity assessment 
An event which meet any of the following criteria will be assessed as “Serious:” 
1. Results in death (death). 
2. Is life-threatening (potential death threat). 
3. Requires inpatient hospitalization or prolongation of existing hospitalization (admission / prolonged 
hospitalization). 
4. Results in persistent or significant disability/incapacity (disability). 
5. Is a congenital anomaly/birth defect (congenital anomaly). 
6. Other significant medical conditions which do not meet the above criteria 1 to 5. Events listed in the 
“Takeda Medically Significant AE List are included in this section criteria. 
 
Takeda Medically Significant AE List 
• Acute respiratory failure / acute respiratory 
distress syndrome (ARDS) 
• Anaphylactic shock 
• Torsade de pointes / ventricular fibrillation / 
ventricular tachycardia 
• Acute renal failure 
• Malignant hypertension 
• Pulmonary hypertension 
• Convulsive seizure (including convulsion and 
epilepsy) 
• Pulmonary fibrosis (including interstitial 
pneumonia) 
• Agranulocytosis 
• Malignant syndrome / malignant hyperthermia 
• Aplastic anemia 
• Spontaneous abortion / stillbirth and fetal death 
• Toxic epidermal necrolysis / 
• Spread of infection via drug or suspected spread 

 
9 
 
oculomucocutaneous syndrome 
(Stevens-Johnson syndrome) 
• Hepatic necrosis 
• Acute hepatic failure 
• Endotoxic shock or suspected endotoxic shock 
Table 3 Criteria for causality assessment between adverse events and Nesina 
Assessment 
Assessment criterion 
Related 
Temporally correlation (including the post-treatment clinical course) present. Or an 
adverse event that may have been caused by the primary disease, concurrent disease, 
concomitant medication, or other factor including concomitant procedures, but also 
suggested to be caused by the relevant drug. 
Not related 
No temporally correlation with the relevant drug. Or an adverse event presumably 
caused by the primary disease, concurrent disease, concomitant medication, or other 
factor. 
Not 
assessable 
Lack of information for assessment of temporal correlation (including the post-treatment 
clinical course), the primary disease, concurrent disease, concomitant medication, other 
factor, etc. 
 
10.0 
Analysis Parameters and Methods 
10.1 Patient Component Parameters 
The following will be tabulated: number of enrolled participants, number of survey sheet 
collected participants, number of the Safety Analysis Set, number of the Efficacy Analysis Set, 
and number of patients excluded from analysis and the reason for exclusion, etc. 
 
10.2 Patient Demographics 
Patient demographics including sex, age, disease period, hypersensitivity predisposition, and 
concurrent disease will be tabulated. 
 
10.3 Details of Treatment 
The following will be tabulated: status of Nesina treatment, status of concomitant medications, 
and compliance with Nesina treatment, etc. 
 
10.4 Safety Parameters 
The items described below will be tabulated in the Safety Analysis Set. Adverse events will be 
coded using the MedDRA/J and summarized by Preferred Term (PT) and System Organ Class 
(SOC). 
10.4.1 Occurrence of Adverse Events 
For adverse events reported in the observation period, the type and causal relationship to 
Nesina will be tabulated. 

 
10 
 
 
10.4. 2 Factors Probably Affecting Safety 
For adverse drug reactions reported in the observation period, the frequency of patient 
demographics (e.g., sex, age), details of treatment (e.g., status of Nesina, and status of 
concomitant medications) will be stratified. 
 
10.5 Efficacy Parameters 
The following will be tabulated in the Efficacy Analysis Set: 
10.5.1 Change in HbA1c 
HbA1c test values and the corresponding change from baseline at each testing time point (i.e., 
test value at each testing time point − test value at baseline) will be tabulated. In addition, the 
objective glycemic control achievement rate at each testing time point will be tabulated. 
 
10.5.2 Changes in Laboratory Test Values 
Test values (fasting blood glucose level, fasting insulin level, HOMA-R,* and HOMA-β*) 
and the corresponding changes from baseline at each testing time point (i.e., test value at each 
testing time point − test value at baseline) will be tabulated. 
*HOMA-R: Fasting insulin × Fasting glucose / 405 
**HOMA-β: (Fasting insulin × 360) / (Fasting glucose − 63) 
 
10.5.3 Factors Probably Affecting Efficacy 
For the changes in HbA1c and glycemic control achievement rate at 12 months after the start 
of treatment, the following will be stratified: patient demographics (e.g., sex, age, HbA1c at 
the start of Nesina treatment) and details of treatment (e.g., status of Nesina treatment, status 
of concomitant medications). 
 
10.6 Parameters in Patients with Special Demographics 
The safety and efficacy of Nesina will be stratified in elderly patients or patients with 
hepatic/renal impairment. 
 
11.0 
Registration of Survey Data 
Takeda Pharmaceutical Company Limited. will register the survey information in the following 
open websites before the start of this survey. 
• Japan Pharmaceutical Information Center-Clinical Trials Information 
• Clinical trial registration system of National Institute of Health (US): ClinicalTrials.gov 
 
12.0 
Organizations 
12.1 Manager 
Takeda Pharmaceutical Company Limited. 

 
11 
 
 
 
12.2 Central Enrollment Center 
 
13.0 
CRO 
 
14.0 
Other Necessary Matters 
14.1 Protocol Revision 
During the survey period, the protocol can be reviewed and revised, if the following are 
necessary to be changed after monitored: the survey progress, adverse drug reactions / serious 
adverse drug reactions unexpected from the Precautions, increased frequency of specified 
adverse drug reactions (yes or no), and parameter appropriateness. During the survey period, if 
partly changes of dosage and administration and indications are approved, the protocol revision 
will be also considered and performed as necessary. 
 
14.2 Measures for Issues or Questions 
If any question about the safety or efficacy is arisen, data will be investigated and the relevant 
persons will take measures for the question. 
 
 
PPD
PPD
PPD

 
12 
 
Appendix 
Observation Schedule 
 
Survey period 
 
 
Parameter 
Observation period 
At patient 
enrollment 
 
 
At start of 
treatment 
 
1 months after 
treatment 
 
3 months after 
treatment 
 
6 months after 
treatment 
 
12 months after 
treatment 
 
At treatment 
discontinuation 
 
Patient enrollment 
Nesina prescription date 
○ 
 
 
 
 
 
 
Patient ID Number 
○ 
Patients initial 
○ 
Sex 
○ 
Birth date 
○ 
Assessment of inclusion criteria / exclusion criteria 
○ 
 
 
 
 
 
 
At patient demographics 
Diagnosis period of type 2 diabetes mellitus 
○ 
 
 
 
Category of clinical practice 
○ 
 
 
 
 
Hypersensitivity predisposition 
○ 
 
 
 
 
Concurrent disease 
○ 
 
 
 
 
Past medical history 
○ 
 
 
 
 
Height 
○ 
 
 
 
Smoking history 
 
○ 
 
 
 
 
Drinking history 
 
○ 
 
 
 
 
Presence or absence of serum creatinine within 1 
month after the start of Nesina treatment, serum 
creatinine level (if serum creatinine present), and 
severity of renal impairment and rationale for the 
assessment (if serum creatinine absent). 
 
○ 
 
 
 
 
 
Details 
of 
treatment, etc 
Status of Nesina treatment 
○ 
○ 
Status 
of 
concomitant 
medication 
treatment
(hypoglycemic agents* / other than hypoglycemic
agents) 
 
○ 
○ 
Status of compliance with Nesina 
○ 
○ 
○ 
○ 
○ 
Status of compliance with diet/exercise therapy 
○ 
○ 
○ 
○ 
○ 
○ 
Laboratory/Observation Parameters, etc 
Pulse rate, blood pressure 
○ 
○ 
○ 
○ 
○ 
○ 
Weight 
○ 
○ 
○ 
○ 
○ 
○ 
Laboratory values 
• HbA1c (NGSP value) 
• Fasting glucose 
• Fasting insulin 
• Fasting glucagon 
• Fasting triglyceride 
• Total cholesterol 
• HDL-cholesterol 
• LDL-cholesterol 
• Serum creatinine 
• BUN 
• Urinary albumin (corrected by creatinine) 
• AST 
• ALT 
• γ-GTP 
• ALP 
• Total bilirubin 
• Amylase 
• Lipase 
 
○ 
○ 
○ 
○ 
○ 
○ 
Electrocardiogram 
○ 
 
 
 
○ 
○ 
Waist circumference 
○ 
○ 
○ 
Tests 
for 
coronary 
arteriosclerosis 
and 
arteriosclerosis 
 
○ 
 
 
 
○ 
○ 
Pregnancy (yes or no) (females only) 
 
○ 
○ 
Adverse event 
○ 
○ 
○ 
To be performed 

 
13 
 
 ○ 
To be performed throughout the period 
*Including hypoglycemic agents discontinued within 3 months before the start of Nesina treatment 

 
 
 
 
Protocol for 
Nesina Tablets Specified Drug-use Survey "Type 2 
Diabetes Mellitus: Combination Therapy With 
Hypoglycemic Drug (Insulin Preparation or 
Rapid-acting Insulin Secretagogues, Etc)" 
 
 
 
 
 
 
 
 
 
Version 
Fifth version 
Creation date 
November 9, 2016 
Sponsor 
Takeda Pharmaceutical Company Limited. 
 
 
 
 

 
 
 
Table of Contents 
1.0 
Background .................................................................................................................................................... 1 
2.0 
Objectives ....................................................................................................................................................... 1 
3.0 
Number of Planned Participants and the Rationales ...................................................................................... 1 
3.1 
Number of Planned Participants ............................................................................................................. 1 
3.2 
Rationales ............................................................................................................................................... 1 
4.0 
Patients for Survey ......................................................................................................................................... 2 
4.1 
Inclusion Criteria .................................................................................................................................... 2 
4.2 
Exclusion Criteria ................................................................................................................................... 2 
5.0 
Dosage and Administration ............................................................................................................................ 2 
6.0 
Number of Scheduled Sites by Department ................................................................................................... 3 
7.0 
Methods .......................................................................................................................................................... 3 
7.1 
Observation period ................................................................................................................................. 3 
7.2 
Request for Sites and Agreement ........................................................................................................... 3 
7.3 
Patient Enrollment Methods patients...................................................................................................... 3 
7.4 
Creation and Submission of Survey Sheet ............................................................................................. 3 
7.5 
Measures for Development of Serious Adverse Events ......................................................................... 4 
8.0 
Scheduled Period ............................................................................................................................................ 4 
9.0 
Matters to be Surveyed ................................................................................................................................... 4 
9.1 
Description Details in Patient Enrollment Sheet .................................................................................... 4 
9.2 
Description Items in Survey Sheet ......................................................................................................... 4 
9.2.1 
Front Cover of Survey Sheet .............................................................................................................. 4 
9.2.2 
Patient Demographics ......................................................................................................................... 4 
9.2.3 
Details of Treatment ........................................................................................................................... 5 
9.2.4 
Compliance with Nesina and Compliance with Diet/Exercise Therapy ............................................. 5 
9.2.5 
Laboratory/Observation Parameters ................................................................................................... 6 
9.2.5.1 
Vital Signs .......................................................................................................................................... 6 
9.2.5.2 
Laboratory Values ............................................................................................................................... 6 
9.2.5.3 
Electrocardiography ........................................................................................................................... 6 
9.2.5.4 
Tests for Waist Circumference, Coronary Arteriosclerosis, and Arteriosclerosis ............................... 6 
9.2.5.5 
Other Parameters ................................................................................................................................ 7 
9.2.6 
Adverse Event .................................................................................................................................... 7 
10.0 
Analysis Parameters and Methods ................................................................................................................. 9 
10.1 
Patient Component Parameters .............................................................................................................. 9 
10.2 
Patient Demographics............................................................................................................................. 9 
10.3 
Details of Treatment ............................................................................................................................... 9 
10.4 
Safety Parameters ................................................................................................................................... 9 
10.4.1 
Occurrence of Adverse Events ........................................................................................................... 9 
10.4. 2 
Factors Probably Affecting Safety .................................................................................................... 10 
10.5 
Efficacy Parameters .............................................................................................................................. 10 

 
 
 
10.5.1 
Change in HbA1c ............................................................................................................................. 10 
10.5.2 
Changes in Laboratory Test Values .................................................................................................. 10 
10.5.3 
Factors Probably Affecting Efficacy ................................................................................................ 10 
10.6 
Parameters in Patients with Special Demographics ............................................................................. 10 
11.0 
Registration of Survey Data ......................................................................................................................... 10 
12.0 
Organizations ............................................................................................................................................... 10 
12.1 
Manager ................................................................................................................................................ 10 
12.2 
Central Enrollment Center .................................................................................................................... 11 
13.0 
CRO.............................................................................................................................................................. 11 
14.0 
Other Necessary Matters .............................................................................................................................. 11 
14.1 
Protocol Revision ................................................................................................................................. 11 
14.2 
Measures for Issues or Questions ......................................................................................................... 11 
 
Appendix Observation Schedule  ............................................................................................................................ 12 

 
1 
 
1.0 
Background 
Nesina tablets (hereinafter, Nesina) are dipeptidyl peptidase-4inhibitors (hereinafter, 
DPP-4inhibitors) and oral hypoglycemic drugs mainly characterized by glucose level-dependent 
insulin secretion promotion via a GLP-1 increase and pancreas protection. Since oral 
hypoglycemic drugs have been generally used for a long period in patients and since multiple 
hypoglycemic drugs may be used simultaneously, it is important that long-term results of oral 
hypoglycemic drugs should be obtained from a daily clinical practice. The Specified Drug-use 
Survey of Nesina has been conducted in type 2 diabetes mellitus patients who have had an 
inadequate response to diet/exercise therapies only or diet/exercise therapies plus α-glucosidase 
inhibitors, thiazolidines, sulfonylureas, or biguanides. In the future, the specified drug-use 
survey of complication with Nesina and insulin preparations and insulin secretagogues is also 
expected to be conducted. 
Therefore, the Nesina Tablets Specified Drug-use Survey "Type 2 Diabetic Patients Receiving 
Combination Therapy With a Hypoglycemic Agent (e.g., Insulin Preparations or Rapid-acting 
Insulin Secretagogues)” (hereinafter, this survey) is planned aiming to evaluate the safety and 
efficacy of Nesina when administered for 1 year in type 2 diabetic patients who have had an 
inadequate response to hypoglycemic agents (e.g., insulin preparations, rapid-acting insulin 
secretagogues) in addition to dietary/exercise therapy in daily medical practice. 
This survey is conducted according to the relevant regulatory requirements including the GPSP 
ordinance. 
 
2.0 
Objectives 
This survey is designed to evaluate the safety and efficacy of long-term use of alogliptin tablets 
(Nesina Tablets) in type 2 diabetic patients who have had an inadequate response to 
hypoglycemic agents (e.g., insulin preparations or rapid-acting insulin secretagogues)* in 
addition to dietary/exercise therapy in daily medical practice. 
*Hypoglycemic agents which have not been used in the past Nesina Specified Drug-use Survey (i.e., other 
than α-glucosidase inhibitors, thiazolidines, sulfonylureas, and biguanides) 
 
3.0 
Number of Planned Participants and the Rationales 
3.1 
Number of Planned Participants 
1,000 participants 
 
3.2 
Rationales 
The Specified Drug-use Survey of Nesina has been conducted in type 2 diabetes mellitus 
patients who have had an inadequate response to diet/exercise therapies only or diet/exercise 
therapies plus α-glucosidase inhibitors, thiazolidines, sulfonylureas, or biguanides. In the future, 
the specified drug-use survey of complication with Nesina and insulin preparations and insulin 

 
2 
 
secretagogues is also expected to be conducted. 
Therefore, the planned participants was established as 1,000 to collect as many as participants 
who receive a long-term complication therapy with Nesina and these hypoglycemic agents (e.g., 
insulin preparations, rapid-acting insulin secretagogues). 
In the pooled tabulation of participants in the past Nesina Specified Drug-use Survey (as of 
November 30, 2013; Safety Analysis Set, 10,025 participants), the proportion of participants was 
as follows: elderly, 58.0%; renal impairment participants, 15.1%; and hepatic impairment 
participants, 13.3%. By establishment of the planned participants of 1,000 in this survey, data 
will be collected from approximately 600 elderly participants, approximately 150 renal 
impairment participants, and approximately 100 hepatic impairment participants. This 
establishment is not based on the statistical evidence. 
 
4.0 
Patients for Survey 
Patients with type 2 diabetes mellitus. However, participants must meet the inclusion criteria and 
none of the exclusion criteria, described below. Refer to the Precaution in the package insert. 
4.1 
Inclusion Criteria 
Patients who meet the following criterion are included in this survey: 
Patients who have had an inadequate response to the following medications/therapies: 
 
Use of one hypoglycemic agent such as insulin preparations and rapid-acting insulin 
secretagogues, excluding other types of hypoglycemic agents (e.g., α-glucosidase inhibitors, 
thiazolidines, sulfonylureas, biguanides)*, in addition to dietary/exercise therapy 
*For use of Nesina Tablets in combination with these agents, a specified drug-use survey is currently 
ongoing. 
 
4.2 
Exclusion Criteria 
Patients who meet any of the following criteria are excluded from this survey:  
Patients with contraindications for Nesina Tablets 
（1） Those with severe ketosis, in a state of diabetic coma or precoma, or with type 1 
diabetes mellitus [Quickly rectifying hyperglycemia with administration of intravenous 
fluid or insulin is essential in these patients; therefore, administration of Nesina Tablets 
is not appropriate.] 
（2） Those with severe infections, before or after surgery, or with serious trauma [Controlling 
blood glucose with an injection of insulin is desirable for these patients; therefore, 
administration of Nesina Tablets is not appropriate.] 
（3） Those with a history of hypersensitivity to any of the ingredients of Nesina Tablets 
 
5.0 
Dosage and Administration 
For adults, 25 mg of alogliptin is usually administered orally once daily. Refer to the Precaution 

 
3 
 
in the package insert. For renal impairment patients, refer to the Precaution with Respect to 
Dosage and Administration in the package insert. 
 
6.0 
Number of Scheduled Sites by Department 
Internal medicine or other department: Approximately 200 sites 
 
7.0 
Methods 
7.1 
Observation period 
12 months 
 
7.2 
Request for Sites and Agreement 
The survey is conducted using the paper survey sheet. Before asking survey, the parson in charge 
of medical information in Takeda Pharmaceutical Company Limited. (Hereinafter, Takeda MRs) 
will fully explain to the Investigator about the objectives, details, and methods of this survey, 
based on “Request for Cooperation of Specified Drug-use Survey,” “Summary for Survey,” 
“Patient Enrollment Sheet (sample),” and “Survey Sheet (sample)” and will finalize written 
agreement with survey sites to ask requests for surveillance within the specified period. 
 
7.3 
Patient Enrollment Methods patients 
This survey is conducted by Fax using Central Enrollment System. The Investigator will enroll 
patients for whom Nesina was prescribed after the start date of agreement with a survey site, by 
faxing to the Central Enrollment Center (refer to Section 12.2) the “Patient Enrollment Sheet” 
including the information regarding patient enrollment (refer to Section 9.1) before 14 days after 
the Nesina prescription date (define the prescription date as “0 day” and one day after the 
prescription date as “1 day”). Patients for whom Nesina prescription is scheduled cannot be 
enrolled earlier. The participant who assessed as ineligible for the survey for any reason cannot 
be enrolled in the survey. The Investigator will enroll a new participant using the “Patient 
Enrollment Sheet” supplied by the Takeda MR. The Takeda MR will supply for the Investigator 
the survey sheet issued after the Central Enrollment Center enrolled the participant. 
 
7.4 
Creation and Submission of Survey Sheet 
The Investigator will create the survey sheet for all enrolled participants and submit it to the 
Takeda around within 1 month after the end of the observation period. If Nesina administration 
cannot be confirmed, specify it (do not specify other columns). 
For participants who early discontinue treatment with Nesina during the observation period for 
any reason, the Investigator will create the survey sheet for him/her and submit it to the Takeda 
around within 1 month after the end of necessary observation. However, for participants who 
early discontinue treatment with Nesina due to an adverse event, the Investigator will continue 

 
4 
 
observation even after treatment discontinuation, wherever possible, until the adverse event 
resolve or is resolving and will create the survey sheet and submit it to the Takeda. 
 
7.5 
Measures for Development of Serious Adverse Events 
In case of development of a serious adverse event in the observation period, the Investigator will 
immediately contact the parson in charge in Takeda Pharmaceutical Company Limited. (person 
in charge in Takeda). If the person in charge in Takeda requests additional detailed information, 
the Investigator will provide it. 
 
8.0 
Scheduled Period 
Survey period: June 2014 to June 30, 2017 
Patient enrollment period: June 2014 to June 30, 2016* 
*Even if Nesina is prescribed before June 30 2016, the patients cannot be enrolled (fax of the Patient 
Enrollment Sheet) after July 1 2016. 
In case that the enrolled participants reach the scheduled number of participants in the survey before June 30 
2016, the enrollment will close earlier than the scheduled patient enrollment period. If patient enrollment 
period is shorten, the survey period will be also changed according to the shorten period. 
9.0 
Matters to be Surveyed 
The Investigator will describe the data described below in the Patient Enrollment Sheet and the 
survey sheet. The schedule of this survey is shown in the Appendix. 
9.1 
Description Details in Patient Enrollment Sheet 
1) Matters to be surveyed 
Name of survey site, name of the investigator who describe in the Patient Enrollment Sheet, 
Nesina prescription date, Patient ID Number, patient initial, sex, birth date, inclusion criteria 
assessment, and exclusion criteria assessment 
2) Survey period 
At patient enrollment 
 
9.2 
Description Items in Survey Sheet 
9.2.1 Front Cover of Survey Sheet 
Last description date in the survey sheet and name of the Investigator who described the survey 
sheet 
 
9.2.2 Patient Demographics 
1) Matters to be surveyed 
Diagnosis period of type 2 diabetes mellitus, category of clinical practice, disposition of 
hypersensitivity (yes/no and detail), concurrent disease (yes/no and detail), past medical 
history (yes/no and detail), height, smoking history, drinking history, presence or absence of 

 
5 
 
serum creatinine within 1 month after the start of Nesina treatment, serum creatinine level (if 
serum creatinine present), and severity of renal impairment and rationale for the assessment 
(if serum creatinine absent). 
2) Survey period 
At the start of Nesina treatment 
 
9.2.3 
Details of Treatment 
1) Matters to be surveyed 
Details of Nesina treatment (daily dose, administration period, and reason for 
discontinuation), and status of concomitant medications (hypoglycemic agents*) (yes/no, 
drug name, daily dose, route of administration, administration period, and objective of 
administration) 
*Hypoglycemic agents which are discontinued within 3 months prior to Nesina treatment are included. 
2) Survey period 
Period from the start of Nesina treatment to 12 months after treatment (or treatment 
discontinuation) 
 
9.2.4 
Compliance with Nesina and Compliance with Diet/Exercise Therapy 
1) Matters to be surveyed 
Compliance with Nesina* and compliance with diet/exercise therapy** 
 
 
*Criteria for assessment of compliance with Nesina 
1. ≥ 90% (A participant won’t miss administration, or even if he/she missed 
administration, the frequency is twice or three times a month.) 
2. ≥ 70% (A participant missed administration once or twice weekly.) 
3. ≥ 50% (A participant missed administration three times a week.) 
4. < 50% (A participant missed administration four times or more a week.) 
 
**Criteria for assessment of compliance with diet/exercise therapy 
1. ≥ 90% (A participant complied as instructed.) 
2. ≥ 70% (A participant mostly complied as instructed.) 
3. ≥ 50% (A participant did not complied well as instructed.) 
4. < 50% (A participant did not mostly complied as instructed.) 
5. Not performed 
6. Unknown 
 
2) Survey period 

 
6 
 
At the start of Nesina treatment (compliance with diet/exercise therapy only), 1 month, 3 
months, 6 months, and 12 months after the start of treatment (or treatment discontinuation) 
 
9.2.5 
Laboratory/Observation Parameters 
9.2.5.1 Vital Signs 
1) Laboratory/observation parameters 
Pulse rate, blood pressure (systolic/diastolic), and weight 
2) Survey period 
Each time point at the start of Nesina treatment, 1 month, 3 months, 6 months, and 12 months 
after the start of treatment (or treatment discontinuation) 
 
9.2.5.2 Laboratory Values 
1) Laboratory parameters 
HbA1c (NGSP value, same hereafter), fasting glucose, fasting insulin, fasting glucagon, 
fasting triglyceride, total cholesterol, HDL-cholesterol, LDL-cholesterol, serum creatinine, 
BUN, urinary albumin (corrected by creatinine), AST, ALT, γ-GTP, ALP, total bilirubin, 
amylase, and lipase 
2) Survey period 
Each time point at the start of Nesina treatment, 1 month, 3 months, 6 months, and 12 months 
after the start of treatment (or treatment discontinuation) 
 
9.2.5.3 Electrocardiography 
1) Observation Parameters 
Electrocardiograms (assessment and findings) 
2) Survey period 
Each time point from the start of Nesina treatment to 12 months after treatment (or treatment 
discontinuation) 
 
9.2.5.4 Tests for Waist Circumference, Coronary Arteriosclerosis, and Arteriosclerosis 
1) Observation Parameters 
Tests for waist circumference,* coronary arteriosclerosis and arteriosclerosis** (e.g., pulse 
wave velocity, cardio-ankle vascular index, intima-media thickness, intra-vascular 
ultrasound) 
*Measure the waist diameter during light expiration at standing position and at the level of the navel. If the 
lower deviation of the navel occurs because of significant abdominal fat accumulation, measure the waist 
diameter at the level of the midpoint between the inferior rib border and anterior superior iliac spine. 
**Any methods can be used. In principle, however, use the same methods for each test. If there are no 
devices for measurement, the tests can be omitted. 

 
7 
 
2) Survey period 
Each time point from the start of Nesina treatment to 12 months after treatment (or treatment 
discontinuation) 
 
9.2.5.5 Other Parameters 
1) Observation parameters 
Pregnancy during the observation period (yes or no) (females only) 
In case of pregnancy in the observation period, the Investigator will immediately contact the 
person in charge in Takeda. The Investigator will provide detailed information (including the 
information until the delivery, as possible, such as preterm delivery) using the separate 
pregnancy sheet after the request from the person in charge in Takeda. 
2) Survey period 
Period from the start of Nesina treatment to 12 months after treatment (or treatment 
discontinuation) 
 
9.2.6 
Adverse Event 
1) Matters to be surveyed 
Presence or absence of adverse events (refer to Table 1), term of adverse events, onset date, 
seriousness and the reason (refer to Table 2), presence or absence of Nesina discontinuation, 
outcome assessment date, outcome, and causal relationship to Nesina* (refer to Table 3). 
If the outcome is assessed as Not resolved or Unknown and if the causal relationship cannot 
be assessed, the participant will be followed up, wherever possible. 
The detailed information (e.g., clinical course, laboratory tests for diagnosis) will be collected 
as possible for development of hypoglycemia, acute pancreatitis, renal impairment / jaundice, 
skin disorder including oculomucocutaneous syndrome (Stevens-Johnson syndrome) and 
erythema multiforme, rhabdomyolysis, intestinal obstruction, interstitial pneumonia, 
angioedema, infection, malignant tumor, pemphigoid, and cardiovascular system-related 
event (e.g., symptomatic coronary artery disease, cerebrovascular disorder, arteriosclerosis 
obliterans, cardiovascular death, sudden death) 
*If the causal relationship to Nesina is assessed as Not related, collect the rationales for assessment. If the 
relationship is assessed as Not assessable, collected the reason for Not assessable. 
 
Note) Matters that should be considered for adverse events 
Abnormal exacerbation of the target disease, i.e., worsening beyond expected natural 
clinical course, is defined as an adverse event; however, the expected worsening is not 
defined as an adverse vent. 
2) Survey period 
Period from the start of Nesina treatment to 12 months after treatment (or treatment 

 
8 
 
discontinuation) 
 
Table 1 Definition of adverse event 
An adverse event (AE) is defined as any unfavorable event that develops after a pharmaceutical 
product is administered and which does not necessarily have a causal relationship with treatment.  
An adverse event can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding, for example), symptom, or disease temporally associated with the use of a 
medicinal product, whether or not considered related to the medicinal product. 
The following events will be handled as adverse events: 
• Symptoms present in infants breastfed by a Nesina taking mother 
• Symptoms present in children who received the relevant drug 
• Symptoms due to occupational exposure to the relevant drug 
• Symptoms due to counterfeit medications of the legitimate medicinal products manufactured by 
Takeda 
• Unfavorable symptoms present in the patient who received the relevant drug, known by a lawsuit or 
other legal actions 
 
Table 2 Criteria for severity assessment 
An event which meet any of the following criteria will be assessed as “Serious:” 
1. Results in death (death). 
2. Is life-threatening (potential death threat). 
3. Requires inpatient hospitalization or prolongation of existing hospitalization (admission / prolonged 
hospitalization). 
4. Results in persistent or significant disability/incapacity (disability). 
5. Is a congenital anomaly/birth defect (congenital anomaly). 
6. Other significant medical conditions which do not meet the above criteria 1 to 5. Events listed in the 
“Takeda Medically Significant AE List are included in this section criteria. 
 
Takeda Medically Significant AE List 
• Acute respiratory failure / acute respiratory 
distress syndrome (ARDS) 
• Anaphylactic shock 
• Torsade de pointes / ventricular fibrillation / 
ventricular tachycardia 
• Acute renal failure 
• Malignant hypertension 
• Pulmonary hypertension 
• Convulsive seizure (including convulsion and 
epilepsy) 
• Pulmonary fibrosis (including interstitial 
pneumonia) 
• Agranulocytosis 
• Malignant syndrome / malignant hyperthermia 
• Aplastic anemia 
• Spontaneous abortion / stillbirth and fetal death 
• Toxic epidermal necrolysis / 
oculomucocutaneous syndrome (Stevens-Johnson 
• Spread of infection via drug or suspected spread 

 
9 
 
syndrome) 
• Hepatic necrosis 
• Acute hepatic failure 
• Endotoxic shock or suspected endotoxic shock 
Table 3 Criteria for causality assessment between adverse events and Nesina 
Assessment 
Assessment criterion 
Related 
Temporally correlation (including the post-treatment clinical course) present. Or an 
adverse event that may have been caused by the primary disease, concurrent disease, 
concomitant medication, or other factor including concomitant procedures, but also 
suggested to be caused by the relevant drug. 
Not related 
No temporally correlation with the relevant drug. Or an adverse event presumably 
caused by the primary disease, concurrent disease, concomitant medication, or other 
factor. 
Not 
assessable 
Lack of information for assessment of temporal correlation (including the post-treatment 
clinical course), the primary disease, concurrent disease, concomitant medication, other 
factor, etc. 
 
10.0 
Analysis Parameters and Methods 
10.1 Patient Component Parameters 
The following will be tabulated: number of enrolled participants, number of survey sheet 
collected participants, number of the Safety Analysis Set, number of the Efficacy Analysis Set, 
and number of patients excluded from analysis and the reason for exclusion, etc. 
 
10.2 Patient Demographics 
Patient demographics including sex, age, disease period, hypersensitivity predisposition, and 
concurrent disease will be tabulated. 
 
10.3 Details of Treatment 
The following will be tabulated: status of Nesina treatment, status of concomitant medications, 
and compliance with Nesina treatment, etc. 
 
10.4 Safety Parameters 
The items described below will be tabulated in the Safety Analysis Set. Adverse events will be 
coded using the MedDRA/J and summarized by Preferred Term (PT) and System Organ Class 
(SOC). 
10.4.1 Occurrence of Adverse Events 
For adverse events reported in the observation period, the type and causal relationship to 
Nesina will be tabulated. 
 

 
10 
 
10.4. 2 Factors Probably Affecting Safety 
For adverse drug reactions reported in the observation period, the frequency of patient 
demographics (e.g., sex, age), details of treatment (e.g., status of Nesina, and status of 
concomitant medications) will be stratified. 
 
10.5 Efficacy Parameters 
The following will be tabulated in the Efficacy Analysis Set: 
10.5.1 Change in HbA1c 
HbA1c test values and the corresponding change from baseline at each testing time point (i.e., 
test value at each testing time point − test value at baseline) will be tabulated. In addition, the 
objective glycemic control achievement rate at each testing time point will be tabulated. 
 
10.5.2 Changes in Laboratory Test Values 
Test values (fasting blood glucose level, fasting insulin level, HOMA-R,* and HOMA-β*) 
and the corresponding changes from baseline at each testing time point (i.e., test value at each 
testing time point − test value at baseline) will be tabulated. 
*HOMA-R: Fasting insulin × Fasting glucose / 405 
**HOMA-β: (Fasting insulin × 360) / (Fasting glucose − 63) 
 
10.5.3 Factors Probably Affecting Efficacy 
For the changes in HbA1c and glycemic control achievement rate at 12 months after the start 
of treatment, the following will be stratified: patient demographics (e.g., sex, age, HbA1c at 
the start of Nesina treatment) and details of treatment (e.g., status of Nesina treatment, status 
of concomitant medications). 
 
10.6 Parameters in Patients with Special Demographics 
The safety and efficacy of Nesina will be stratified in elderly patients or patients with 
hepatic/renal impairment. 
 
11.0 
Registration of Survey Data 
Takeda Pharmaceutical Company Limited. will register the survey information in the following 
open websites before the start of this survey. 
• Japan Pharmaceutical Information Center-Clinical Trials Information 
• Clinical trial registration system of National Institute of Health (US): ClinicalTrials.gov 
 
12.0 
Organizations 
12.1 Manager 
Takeda Pharmaceutical Company Limited. 
 
PPD

 
11 
 
 
12.2 Central Enrollment Center 
 
13.0 
CRO 
 
14.0 
Other Necessary Matters 
14.1 Protocol Revision 
During the survey period, the protocol can be reviewed and revised, if the following are 
necessary to be changed after monitored: the survey progress, adverse drug reactions / serious 
adverse drug reactions unexpected from the Precautions, increased frequency of specified 
adverse drug reactions (yes or no), and parameter appropriateness. During the survey period, if 
partly changes of dosage and administration and indications are approved, the protocol revision 
will be also considered and performed as necessary. 
 
14.2 Measures for Issues or Questions 
If any question about the safety or efficacy is arisen, data will be investigated and the relevant 
persons will take measures for the question. 
 
 
PPD
PPD

 
12 
 
Appendix Observation Schedule 
 
Survey period 
 
 
Parameter 
Observation period 
At patient 
enrollment 
 
 
At start of 
treatment 
 
1 months after 
treatment 
 
3 months after 
treatment 
 
6 months after 
treatment 
 
12 months after 
treatment 
 
At treatment 
discontinuation 
 
Patient enrollment 
Nesina prescription date 
○ 
 
 
 
 
 
 
Patient ID Number 
○ 
Patients initial 
○ 
Sex 
○ 
Birth date 
○ 
Assessment of inclusion criteria / exclusion criteria 
○ 
 
 
 
 
 
 
At patient demographics 
Diagnosis period of type 2 diabetes mellitus 
○ 
 
 
 
Category of clinical practice 
○ 
 
 
 
 
Hypersensitivity predisposition 
○ 
 
 
 
 
Concurrent disease 
○ 
 
 
 
 
Past medical history 
○ 
 
 
 
 
Height 
○ 
 
 
 
Smoking history 
 
○ 
 
 
 
 
Drinking history 
 
○ 
 
 
 
 
Presence or absence of serum creatinine within 1 
month after the start of Nesina treatment, serum 
creatinine level (if serum creatinine present), and 
severity of renal impairment and rationale for the 
assessment (if serum creatinine absent). 
 
○ 
 
 
 
 
 
Details 
of 
treatment, etc. 
Status of Nesina treatment 
○ 
○ 
Status 
of 
concomitant 
medication 
treatment
(hypoglycemic agents* / other than hypoglycemic
agents) 
 
○ 
○ 
Status of compliance with Nesina 
○ 
○ 
○ 
○ 
○ 
Status of compliance with diet/exercise therapy 
○ 
○ 
○ 
○ 
○ 
○ 
Laboratory/Observation Parameters, etc 
Pulse rate, blood pressure 
○ 
○ 
○ 
○ 
○ 
○ 
Weight 
○ 
○ 
○ 
○ 
○ 
○ 
Laboratory values 
• HbA1c (NGSP value) 
• Fasting glucose 
• Fasting insulin 
• Fasting glucagon 
• Fasting triglyceride 
• Total cholesterol 
• HDL-cholesterol 
• LDL-cholesterol 
• Serum creatinine 
• BUN 
• Urinary albumin (corrected by creatinine) 
• AST 
• ALT 
• γ-GTP 
• ALP 
• Total bilirubin 
• Amylase 
• Lipase 
 
○ 
○ 
○ 
○ 
○ 
○ 
Electrocardiogram 
○ 
 
 
 
○ 
○ 
Waist circumference 
○ 
○ 
○ 
Tests 
for 
coronary 
arteriosclerosis 
and 
arteriosclerosis 
 
○ 
 
 
 
○ 
○ 
Pregnancy (yes or no) (females only) 
 
○ 
○ 
Adverse event 
○ 
○ 
○ 
: To be performed 

 
13 
 
 ○ 
: To be performed throughout the period 
*Including hypoglycemic agents discontinued within 3 months before the start of Nesina treatment 

 
 
 
 
Protocol for 
Nesina Tablets Specified Drug-use Survey "Type 2 
Diabetes Mellitus: Combination Therapy With 
Hypoglycemic Drug (Insulin Preparation or 
Rapid-acting Insulin Secretagogues, Etc)" 
 
 
 
 
 
 
 
 
 
 
Version 
Fourth version 
Creation date 
February 1, 2016 
Sponsor 
Takeda Pharmaceutical Company Limited. 
 
 
 
 

 
 
 
Table of Contents1.0 ...................................................................................................................... Background 
1 
2.0 
Objectives ....................................................................................................................................................... 1 
3.0 
Number of Planned Participants and the Rationales ...................................................................................... 1 
3.1 
Number of Planned Participants ............................................................................................................. 1 
3.2 
Rationales ............................................................................................................................................... 1 
4.0 
Patients for Survey ......................................................................................................................................... 2 
4.1 
Inclusion Criteria .................................................................................................................................... 2 
4.2 
Exclusion Criteria ................................................................................................................................... 2 
5.0 
Dosage and Administration ............................................................................................................................ 2 
6.0 
Number of Scheduled Sites by Department ................................................................................................... 3 
7.0 
Methods .......................................................................................................................................................... 3 
7.1 
Observation period ................................................................................................................................. 3 
7.2 
Request for Sites and Agreement ........................................................................................................... 3 
7.3 
Patient Enrollment Methods patients...................................................................................................... 3 
7.4 
Creation and Submission of Survey Sheet ............................................................................................. 3 
7.5 
Measures for Development of Serious Adverse Events ......................................................................... 4 
8.0 
Scheduled Period ............................................................................................................................................ 4 
9.0 
Matters to be Surveyed ................................................................................................................................... 4 
9.1 
Description Details in Patient Enrollment Sheet .................................................................................... 4 
9.2 
Description Items in Survey Sheet ......................................................................................................... 4 
9.2.1 
Front Cover of Survey Sheet .............................................................................................................. 4 
9.2.2 
Patient Demographics ......................................................................................................................... 4 
9.2.3 
Details of Treatment ........................................................................................................................... 5 
9.2.4 
Compliance with Nesina and Compliance with Diet/Exercise Therapy ............................................. 5 
9.2.5 
Laboratory/Observation Parameters ................................................................................................... 6 
9.2.5.1 
Vital Signs .......................................................................................................................................... 6 
9.2.5.2 
Laboratory Values ............................................................................................................................... 6 
9.2.5.3 
Electrocardiography ........................................................................................................................... 6 
9.2.5.4 
Tests for Waist Circumference, Coronary Arteriosclerosis, and Arteriosclerosis ............................... 6 
9.2.5.5 
Other Parameters ................................................................................................................................ 7 
9.2.6 
Adverse Event .................................................................................................................................... 7 
10.0 
Analysis Parameters and Methods ................................................................................................................. 9 
10.1 
Patient Component Parameters .............................................................................................................. 9 
10.2 
Patient Demographics............................................................................................................................. 9 
10.3 
Details of Treatment ............................................................................................................................... 9 
10.4 
Safety Parameters ................................................................................................................................... 9 
10.4.1 
Occurrence of Adverse Events ........................................................................................................... 9 
10.4. 2 
Factors Probably Affecting Safety .................................................................................................... 10 
10.5 
Efficacy Parameters .............................................................................................................................. 10 
10.5.1 
Change in HbA1c ............................................................................................................................. 10 

 
 
 
10.5.2 
Changes in Laboratory Test Values .................................................................................................. 10 
10.5.3 
Factors Probably Affecting Efficacy ................................................................................................ 10 
10.6 
Parameters in Patients with Special Demographics ............................................................................. 10 
11.0 
Registration of Survey Data ......................................................................................................................... 10 
12.0 
Organizations ............................................................................................................................................... 10 
12.1 
Manager ................................................................................................................................................ 10 
12.2 
Central Enrollment Center .................................................................................................................... 11 
13.0 
CRO.............................................................................................................................................................. 11 
14.0 
Other Necessary Matters .............................................................................................................................. 11 
14.1 
Protocol Revision ................................................................................................................................. 11 
14.2 
Measures for Issues or Questions ......................................................................................................... 11 
 
Appendix Observation Schedule  ............................................................................................................................ 12 

 
1 
 
1.0 
Background 
Nesina tablets (hereinafter, Nesina) are dipeptidyl peptidase-4inhibitors (hereinafter, 
DPP-4inhibitors) and oral hypoglycemic drugs mainly characterized by glucose level-dependent 
insulin secretion promotion via a GLP-1 increase and pancreas protection. Since oral 
hypoglycemic drugs have been generally used for a long period in patients and since multiple 
hypoglycemic drugs may be used simultaneously, it is important that long-term results of oral 
hypoglycemic drugs should be obtained from a daily clinical practice. The Specified Drug-use 
Survey of Nesina has been conducted in type 2 diabetes mellitus patients who have had an 
inadequate response to diet/exercise therapies only or diet/exercise therapies plus α-glucosidase 
inhibitors, thiazolidines, sulfonylureas, or biguanides. In the future, the specified drug-use 
survey of complication with Nesina and insulin preparations and insulin secretagogues is also 
expected to be conducted. 
Therefore, the Nesina Tablets Specified Drug-use Survey "Type 2 Diabetic Patients Receiving 
Combination Therapy With a Hypoglycemic Agent (e.g., Insulin Preparations or Rapid-acting 
Insulin Secretagogues)” (hereinafter, this survey) is planned aiming to evaluate the safety and 
efficacy of Nesina when administered for 1 year in type 2 diabetic patients who have had an 
inadequate response to hypoglycemic agents (e.g., insulin preparations, rapid-acting insulin 
secretagogues) in addition to dietary/exercise therapy in daily medical practice. 
This survey is conducted according to the relevant regulatory requirements including the GPSP 
ordinance. 
 
2.0 
Objectives 
This survey is designed to evaluate the safety and efficacy of long-term use of alogliptin tablets 
(Nesina Tablets) in type 2 diabetic patients who have had an inadequate response to 
hypoglycemic agents (e.g., insulin preparations or rapid-acting insulin secretagogues)* in 
addition to dietary/exercise therapy in daily medical practice. 
*Hypoglycemic agents which have not been used in the past Nesina Specified Drug-use Survey (i.e., other 
than α-glucosidase inhibitors, thiazolidines, sulfonylureas, and biguanides) 
 
3.0 
Number of Planned Participants and the Rationales 
3.1 
Number of Planned Participants 
1,000 participants 
 
3.2 
Rationales 
The Specified Drug-use Survey of Nesina has been conducted in type 2 diabetes mellitus 
patients who have had an inadequate response to diet/exercise therapies only or diet/exercise 
therapies plus α-glucosidase inhibitors, thiazolidines, sulfonylureas, or biguanides. In the future, 
the specified drug-use survey of complication with Nesina and insulin preparations and insulin 

 
2 
 
secretagogues is also expected to be conducted. 
Therefore, the planned participants was established as 1,000 to collect as many as participants 
who receive a long-term complication therapy with Nesina and these hypoglycemic agents (e.g., 
insulin preparations, rapid-acting insulin secretagogues). 
In the pooled tabulation of participants in the past Nesina Specified Drug-use Survey (as of 
November 30, 2013; Safety Analysis Set, 10,025 participants), the proportion of participants was 
as follows: elderly, 58.0%; renal impairment participants, 15.1%; and hepatic impairment 
participants, 13.3%. By establishment of the planned participants of 1,000 in this survey, data 
will be collected from approximately 600 elderly participants, approximately 150 renal 
impairment participants, and approximately 100 hepatic impairment participants. This 
establishment is not based on the statistical evidence. 
 
4.0 
Patients for Survey 
Patients with type 2 diabetes mellitus. However, participants must meet the inclusion criteria and 
none of the exclusion criteria, described below. Refer to the Precaution in the package insert. 
4.1 
Inclusion Criteria 
Patients who meet the following criterion are included in this survey: 
Patients who have had an inadequate response to the following medications/therapies: 
 
Use of one hypoglycemic agent such as insulin preparations and rapid-acting insulin 
secretagogues, excluding other types of hypoglycemic agents (e.g., α-glucosidase inhibitors, 
thiazolidines, sulfonylureas, biguanides)*, in addition to dietary/exercise therapy 
*For use of Nesina Tablets in combination with these agents, a specified drug-use survey is currently 
ongoing. 
 
4.2 
Exclusion Criteria 
Patients who meet any of the following criteria are excluded from this survey:  
Patients with contraindications for Nesina Tablets 
(1) 
Those with severe ketosis, in a state of diabetic coma or precoma, or with type 1 
diabetes mellitus [Quickly rectifying hyperglycemia with administration of intravenous 
fluid or insulin is essential in these patients; therefore, administration of Nesina Tablets 
is not appropriate.] 
(2) 
Those with severe infections, before or after surgery, or with serious trauma [Controlling 
blood glucose with an injection of insulin is desirable for these patients; therefore, 
administration of Nesina Tablets is not appropriate.] 
(3) 
Those with a history of hypersensitivity to any of the ingredients of Nesina Tablets 
 
5.0 
Dosage and Administration 
For adults, 25 mg of alogliptin is usually administered orally once daily. Refer to the Precaution 

 
3 
 
in the package insert. For renal impairment patients, refer to the Precaution with Respect to 
Dosage and Administration in the package insert. 
 
6.0 
Number of Scheduled Sites by Department 
Internal medicine or other department: Approximately 200 sites 
 
7.0 
Methods 
7.1 
Observation period 
12 months 
 
7.2 
Request for Sites and Agreement 
The survey is conducted using the paper survey sheet. Before asking survey, the parson in charge 
of medical information in Takeda Pharmaceutical Company Limited. (Hereinafter, Takeda MRs) 
will fully explain to the Investigator about the objectives, details, and methods of this survey, 
based on “Request for Cooperation of Specified Drug-use Survey,” “Summary for Survey,” 
“Patient Enrollment Sheet (sample),” and “Survey Sheet (sample)” and will finalize written 
agreement with survey sites to ask requests for surveillance within the specified period. 
 
7.3 
Patient Enrollment Methods patients 
This survey is conducted by Fax using Central Enrollment System. The Investigator will enroll 
patients for whom Nesina was prescribed after the start date of agreement with a survey site, by 
faxing to the Central Enrollment Center (refer to Section 12.2) the “Patient Enrollment Sheet” 
including the information regarding patient enrollment (refer to Section 9.1) before 14 days after 
the Nesina prescription date (define the prescription date as “0 day” and one day after the 
prescription date as “1 day”). Patients for whom Nesina prescription is scheduled cannot be 
enrolled earlier. The participant who assessed as ineligible for the survey for any reason cannot 
be enrolled in the survey. The Investigator will enroll a new participant using the “Patient 
Enrollment Sheet” supplied by the Takeda MR. The Takeda MR will supply for the Investigator 
the survey sheet issued after the Central Enrollment Center enrolled the participant. 
 
7.4 
Creation and Submission of Survey Sheet 
The Investigator will create the survey sheet for all enrolled participants and submit it to the 
Takeda around within 1 month after the end of the observation period. If Nesina administration 
cannot be confirmed, specify it (do not specify other columns). 
For participants who early discontinue treatment with Nesina during the observation period for 
any reason, the Investigator will create the survey sheet for him/her and submit it to the Takeda 
around within 1 month after the end of necessary observation. However, for participants who 
early discontinue treatment with Nesina due to an adverse event, the Investigator will continue 

 
4 
 
observation even after treatment discontinuation, wherever possible, until the adverse event 
resolve or is resolving and will create the survey sheet and submit it to the Takeda. 
 
7.5 
Measures for Development of Serious Adverse Events 
In case of development of a serious adverse event in the observation period, the Investigator will 
immediately contact the parson in charge in Takeda Pharmaceutical Company Limited. (person 
in charge in Takeda). If the person in charge in Takeda requests additional detailed information, 
the Investigator will provide it. 
 
8.0 
Scheduled Period 
Survey period: June 2014 to June 30, 2017 
Patient enrollment period: June 2014 to June 30, 2016* 
*Even if Nesina is prescribed before June 30 2016, the patients cannot be enrolled (fax of the Patient 
Enrollment Sheet) after July 1 2016. 
In case that the enrolled participants reach the scheduled number of participants in the survey before June 30 
2016, the enrollment will close earlier than the scheduled patient enrollment period. If patient enrollment 
period is shorten, the survey period will be also changed according to the shorten period. 
9.0 
Matters to be Surveyed 
The Investigator will describe the data described below in the Patient Enrollment Sheet and the 
survey sheet. The schedule of this survey is shown in the Appendix. 
9.1 
Description Details in Patient Enrollment Sheet 
1) Matters to be surveyed 
Name of survey site, name of the investigator who describe in the Patient Enrollment Sheet, 
Nesina prescription date, Patient ID Number, patient initial, sex, birth date, inclusion criteria 
assessment, and exclusion criteria assessment 
2) Survey period 
 
At patient enrollment 
 
9.2 
Description Items in Survey Sheet 
9.2.1 Front Cover of Survey Sheet 
Last description date in the survey sheet and name of the Investigator who described the survey 
sheet 
 
9.2.2 Patient Demographics 
1) Matters to be surveyed 
Diagnosis period of type 2 diabetes mellitus, category of clinical practice, disposition of 
hypersensitivity (yes/no and detail), concurrent disease (yes/no and detail), past medical 
history (yes/no and detail), height, smoking history, drinking history, presence or absence of 

 
5 
 
serum creatinine within 1 month after the start of Nesina treatment, serum creatinine level (if 
serum creatinine present), and severity of renal impairment and rationale for the assessment 
(if serum creatinine absent). 
2) Survey period 
At the start of Nesina treatment 
 
9.2.3 
Details of Treatment 
1) Matters to be surveyed 
Details of Nesina treatment (daily dose, administration period, and reason for 
discontinuation), and status of concomitant medications (hypoglycemic agents*) (yes/no, 
drug name, daily dose, route of administration, administration period, and objective of 
administration) 
*Hypoglycemic agents which are discontinued within 3 months prior to Nesina treatment are included. 
2) Survey period 
Period from the start of Nesina treatment to 12 months after treatment (or treatment 
discontinuation) 
 
9.2.4 
Compliance with Nesina and Compliance with Diet/Exercise Therapy 
1) Matters to be surveyed 
Compliance with Nesina* and compliance with diet/exercise therapy** 
 
 
*Criteria for assessment of compliance with Nesina 
1. ≥ 90% (A participant won’t miss administration, or even if he/she missed 
administration, the frequency is twice or three times a month.) 
2. ≥ 70% (A participant missed administration once or twice weekly.) 
3. ≥ 50% (A participant missed administration three times a week.) 
4. < 50% (A participant missed administration four times or more a week.) 
 
**Criteria for assessment of compliance with diet/exercise therapy 
1. ≥ 90% (A participant complied as instructed.) 
2. ≥ 70% (A participant mostly complied as instructed.) 
3. ≥ 50% (A participant did not complied well as instructed.) 
4. < 50% (A participant did not mostly complied as instructed.) 
5. Not performed 
6. Unknown 
 
2) Survey period 

 
6 
 
At the start of Nesina treatment (compliance with diet/exercise therapy only), 1 month, 3 
months, 6 months, and 12 months after the start of treatment (or treatment discontinuation) 
 
9.2.5 
Laboratory/Observation Parameters 
9.2.5.1 Vital Signs 
1) Laboratory/observation parameters 
Pulse rate, blood pressure (systolic/diastolic), and weight 
2) Survey period 
Each time point at the start of Nesina treatment, 1 month, 3 months, 6 months, and 12 months 
after the start of treatment (or treatment discontinuation) 
 
9.2.5.2 Laboratory Values 
1) Laboratory parameters 
HbA1c (NGSP value, same hereafter), fasting glucose, fasting insulin, fasting glucagon, 
fasting triglyceride, total cholesterol, HDL-cholesterol, LDL-cholesterol, serum creatinine, 
BUN, urinary albumin (corrected by creatinine), AST, ALT, γ-GTP, ALP, total bilirubin, 
amylase, and lipase 
2) Survey period 
Each time point at the start of Nesina treatment, 1 month, 3 months, 6 months, and 12 months 
after the start of treatment (or treatment discontinuation) 
 
9.2.5.3 Electrocardiography 
1) Observation Parameters 
Electrocardiograms (assessment and findings) 
2) Survey period 
Each time point from the start of Nesina treatment to 12 months after treatment (or treatment 
discontinuation) 
 
9.2.5.4 Tests for Waist Circumference, Coronary Arteriosclerosis, and Arteriosclerosis 
1) Observation Parameters 
Tests for waist circumference,* coronary arteriosclerosis and arteriosclerosis** (e.g., pulse 
wave velocity, cardio-ankle vascular index, intima-media thickness, intra-vascular 
ultrasound) 
*Measure the waist diameter during light expiration at standing position and at the level of the navel. If the 
lower deviation of the navel occurs because of significant abdominal fat accumulation, measure the waist 
diameter at the level of the midpoint between the inferior rib border and anterior superior iliac spine. 
**Any methods can be used. In principle, however, use the same methods for each test. If there are no 
devices for measurement, the tests can be omitted. 

 
7 
 
2) Survey period 
Each time point from the start of Nesina treatment to 12 months after treatment (or treatment 
discontinuation) 
 
9.2.5.5 Other Parameters 
1) Observation parameters 
Pregnancy during the observation period (yes or no) (females only) 
In case of pregnancy in the observation period, the Investigator will immediately contact the 
person in charge in Takeda. The Investigator will provide detailed information (including the 
information until the delivery, as possible, such as preterm delivery) using the separate 
pregnancy sheet after the request from the person in charge in Takeda. 
2) Survey period 
Period from the start of Nesina treatment to 12 months after treatment (or treatment 
discontinuation) 
 
9.2.6 
Adverse Event 
1) Matters to be surveyed 
Presence or absence of adverse events (refer to Table 1), term of adverse events, onset date, 
seriousness and the reason (refer to Table 2), presence or absence of Nesina discontinuation, 
outcome assessment date, outcome, and causal relationship to Nesina* (refer to Table 3). 
If the outcome is assessed as Not resolved or Unknown and if the causal relationship cannot 
be assessed, the participant will be followed up, wherever possible. 
The detailed information (e.g., clinical course, laboratory tests for diagnosis) will be collected 
as possible for development of hypoglycemia, acute pancreatitis, renal impairment / jaundice, 
skin disorder including oculomucocutaneous syndrome (Stevens-Johnson syndrome) and 
erythema multiforme, rhabdomyolysis, intestinal obstruction, interstitial pneumonia, 
angioedema, infection, malignant tumor, and cardiovascular system-related event (e.g., 
symptomatic coronary artery disease, cerebrovascular disorder, arteriosclerosis obliterans, 
cardiovascular death, sudden death) 
*If the causal relationship to Nesina is assessed as Not related, collect the rationales for assessment. If the 
relationship is assessed as Not assessable, collected the reason for Not assessable. 
 
Note) Matters that should be considered for adverse events 
Abnormal exacerbation of the target disease, i.e., worsening beyond expected natural 
clinical course, is defined as an adverse event; however, the expected worsening is not 
defined as an adverse vent. 
2) Survey period 
Period from the start of Nesina treatment to 12 months after treatment (or treatment 

 
8 
 
discontinuation) 
 
Table 1 Definition of adverse event 
An adverse event (AE) is defined as any unfavorable event that develops after a pharmaceutical 
product is administered and which does not necessarily have a causal relationship with treatment.  
An adverse event can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding, for example), symptom, or disease temporally associated with the use of a 
medicinal product, whether or not considered related to the medicinal product. 
The following events will be handled as adverse events: 
• Symptoms present in infants breastfed by a Nesina taking mother 
• Symptoms present in children who received the relevant drug 
• Symptoms due to occupational exposure to the relevant drug 
• Symptoms due to counterfeit medications of the legitimate medicinal products manufactured by 
Takeda 
• Unfavorable symptoms present in the patient who received the relevant drug, known by a lawsuit or 
other legal actions 
 
Table 2 Criteria for severity assessment 
An event which meet any of the following criteria will be assessed as “Serious:” 
1. Results in death (death). 
2. Is life-threatening (potential death threat). 
3. Requires inpatient hospitalization or prolongation of existing hospitalization (admission / prolonged 
hospitalization). 
4. Results in persistent or significant disability/incapacity (disability). 
5. Is a congenital anomaly/birth defect (congenital anomaly). 
6. Other significant medical conditions which do not meet the above criteria 1 to 5. Events listed in the 
“Takeda Medically Significant AE List are included in this section criteria. 
 
Takeda Medically Significant AE List 
• Acute respiratory failure / acute respiratory distress 
syndrome (ARDS) 
• Anaphylactic shock 
• Torsade de pointes / ventricular fibrillation / ventricular 
tachycardia 
• Acute renal failure 
• Malignant hypertension 
• Pulmonary hypertension 
• Convulsive seizure (including convulsion and epilepsy) 
• Pulmonary fibrosis (including interstitial 
pneumonia) 
• Agranulocytosis 
• Malignant syndrome / malignant 
hyperthermia 
• Aplastic anemia 
• Spontaneous abortion / stillbirth and fetal 
death 

 
9 
 
• Toxic epidermal necrolysis / oculomucocutaneous 
syndrome (Stevens-Johnson syndrome) 
• Spread of infection via drug or suspected 
spread 
• Hepatic necrosis 
• Acute hepatic failure 
• Endotoxic shock or suspected endotoxic 
shock 
Table 3 Criteria for causality assessment between adverse events and Nesina 
Assessment 
Assessment criterion 
Related 
Temporally correlation (including the post-treatment clinical course) present. Or an 
adverse event that may have been caused by the primary disease, concurrent disease, 
concomitant medication, or other factor including concomitant procedures, but also 
suggested to be caused by the relevant drug. 
Not related 
No temporally correlation with the relevant drug. Or an adverse event presumably 
caused by the primary disease, concurrent disease, concomitant medication, or other 
factor. 
Not 
assessable 
Lack of information for assessment of temporal correlation (including the post-treatment 
clinical course), the primary disease, concurrent disease, concomitant medication, other 
factor, etc. 
 
10.0 
Analysis Parameters and Methods 
10.1 Patient Component Parameters 
The following will be tabulated: number of enrolled participants, number of survey sheet 
collected participants, number of the Safety Analysis Set, number of the Efficacy Analysis Set, 
and number of patients excluded from analysis and the reason for exclusion, etc. 
 
10.2 Patient Demographics 
Patient demographics including sex, age, disease period, hypersensitivity predisposition, and 
concurrent disease will be tabulated. 
 
10.3 Details of Treatment 
The following will be tabulated: status of Nesina treatment, status of concomitant medications, 
and compliance with Nesina treatment, etc. 
 
10.4 Safety Parameters 
The items described below will be tabulated in the Safety Analysis Set. Adverse events will be 
coded using the MedDRA/J and summarized by Preferred Term (PT) and System Organ Class 
(SOC). 
10.4.1 Occurrence of Adverse Events 
For adverse events reported in the observation period, the type and causal relationship to 
Nesina will be tabulated. 

 
10 
 
 
10.4. 2 Factors Probably Affecting Safety 
For adverse drug reactions reported in the observation period, the frequency of patient 
demographics (e.g., sex, age), details of treatment (e.g., status of Nesina, and status of 
concomitant medications) will be stratified. 
 
10.5 Efficacy Parameters 
The following will be tabulated in the Efficacy Analysis Set: 
10.5.1 Change in HbA1c 
HbA1c test values and the corresponding change from baseline at each testing time point (i.e., 
test value at each testing time point − test value at baseline) will be tabulated. In addition, the 
objective glycemic control achievement rate at each testing time point will be tabulated. 
 
10.5.2 Changes in Laboratory Test Values 
Test values (fasting blood glucose level, fasting insulin level, HOMA-R,* and HOMA-β*) 
and the corresponding changes from baseline at each testing time point (i.e., test value at each 
testing time point − test value at baseline) will be tabulated. 
*HOMA-R: Fasting insulin × Fasting glucose / 405 
**HOMA-β: (Fasting insulin × 360) / (Fasting glucose − 63) 
 
10.5.3 Factors Probably Affecting Efficacy 
For the changes in HbA1c and glycemic control achievement rate at 12 months after the start 
of treatment, the following will be stratified: patient demographics (e.g., sex, age, HbA1c at 
the start of Nesina treatment) and details of treatment (e.g., status of Nesina treatment, status 
of concomitant medications). 
 
10.6 Parameters in Patients with Special Demographics 
The safety and efficacy of Nesina will be stratified in elderly patients or patients with 
hepatic/renal impairment. 
 
11.0 
Registration of Survey Data 
Takeda Pharmaceutical Company Limited. will register the survey information in the following 
open websites before the start of this survey. 
• Japan Pharmaceutical Information Center-Clinical Trials Information 
• Clinical trial registration system of National Institute of Health (US): ClinicalTrials.gov 
 
12.0 
Organizations 
12.1 Manager 
Takeda Pharmaceutical Company Limited. 

 
11 
 
 
 
12.2 Central Enrollment Center 
 
13.0 
CRO 
 
14.0 
Other Necessary Matters 
14.1 Protocol Revision 
During the survey period, the protocol can be reviewed and revised, if the following are 
necessary to be changed after monitored: the survey progress, adverse drug reactions / serious 
adverse drug reactions unexpected from the Precautions, increased frequency of specified 
adverse drug reactions (yes or no), and parameter appropriateness. During the survey period, if 
partly changes of dosage and administration and indications are approved, the protocol revision 
will be also considered and performed as necessary. 
 
14.2 Measures for Issues or Questions 
If any question about the safety or efficacy is arisen, data will be investigated and the relevant 
persons will take measures for the question. 
 
 
PPD
PPD
PPD

 
12 
 
Appendix 
Observation Schedule 
 
Survey period 
 
 
Parameter 
Observation period 
At patient 
enrollment 
 
 
At start of 
treatment 
 
1 months after 
treatment 
 
3 months after 
treatment 
 
6 months after 
treatment 
 
12 months after 
treatment 
 
At treatment 
discontinuation 
 
Patient enrollment 
Nesina prescription date 
○ 
 
 
 
 
 
 
Patient ID Number 
○ 
Patients initial 
○ 
Sex 
○ 
Birth date 
○ 
Assessment of inclusion criteria / exclusion criteria 
○ 
 
 
 
 
 
 
At patient demographics 
Diagnosis period of type 2 diabetes mellitus 
○ 
 
 
 
Category of clinical practice 
○ 
 
 
 
 
Hypersensitivity predisposition 
○ 
 
 
 
 
Concurrent disease 
○ 
 
 
 
 
Past medical history 
○ 
 
 
 
 
Height 
○ 
 
 
 
Smoking history 
 
○ 
 
 
 
 
Drinking history 
 
○ 
 
 
 
 
Presence or absence of serum creatinine within 1 
month after the start of Nesina treatment, serum 
creatinine level (if serum creatinine present), and 
severity of renal impairment and rationale for the 
assessment (if serum creatinine absent). 
 
○ 
 
 
 
 
 
Details 
of 
treatment, etc 
Status of Nesina treatment 
○ 
○ 
Status 
of 
concomitant 
medication 
treatment
(hypoglycemic agents* / other than hypoglycemic
agents) 
 
○ 
○ 
Status of compliance with Nesina 
○ 
○ 
○ 
○ 
○ 
Status of compliance with diet/exercise therapy 
○ 
○ 
○ 
○ 
○ 
○ 
Laboratory/Observation Parameters, etc 
Pulse rate, blood pressure 
○ 
○ 
○ 
○ 
○ 
○ 
Weight 
○ 
○ 
○ 
○ 
○ 
○ 
Laboratory values 
• HbA1c (NGSP value) 
• Fasting glucose 
• Fasting insulin 
• Fasting glucagon 
• Fasting triglyceride 
• Total cholesterol 
• HDL-cholesterol 
• LDL-cholesterol 
• Serum creatinine 
• BUN 
• Urinary albumin (corrected by creatinine) 
• AST 
• ALT 
• γ-GTP 
• ALP 
• Total bilirubin 
• Amylase 
• Lipase 
 
○ 
○ 
○ 
○ 
○ 
○ 
Electrocardiogram 
○ 
 
 
 
○ 
○ 
Waist circumference 
○ 
○ 
○ 
Tests 
for 
coronary 
arteriosclerosis 
and 
arteriosclerosis 
 
○ 
 
 
 
○ 
○ 
Pregnancy (yes or no) (females only) 
 
○ 
○ 
Adverse event 
○ 
○ 
○ 
To be performed 

 
13 
 
 ○ 
To be performed throughout the period 
*Including hypoglycemic agents discontinued within 3 months before the start of Nesina treatment 

 
 
 
 
Protocol for 
Nesina Tablets Specified Drug-use Survey "Type 2 
Diabetes Mellitus: Combination Therapy With 
Hypoglycemic Drug (Insulin Preparation or 
Rapid-acting Insulin Secretagogues, Etc)" 
 
 
 
 
 
 
 
 
 
Version 
Third version 
Creation date 
November 27, 2015 
Sponsor 
Takeda Pharmaceutical Company Limited. 
 
 
 
 

 
 
 
Table of Contents 
1.0 
Background .................................................................................................................................................... 1 
2.0 
Objectives ....................................................................................................................................................... 1 
3.0 
Number of Planned Participants and the Rationales ...................................................................................... 1 
3.1 
Number of Planned Participants ............................................................................................................. 1 
3.2 
Rationales ............................................................................................................................................... 1 
4.0 
Patients for Survey ......................................................................................................................................... 2 
4.1 
Inclusion Criteria .................................................................................................................................... 2 
4.2 
Exclusion Criteria ................................................................................................................................... 2 
5.0 
Dosage and Administration ............................................................................................................................ 2 
6.0 
Number of Scheduled Sites by Department ................................................................................................... 3 
7.0 
Methods .......................................................................................................................................................... 3 
7.1 
Observation period ................................................................................................................................. 3 
7.2 
Request for Sites and Agreement ........................................................................................................... 3 
7.3 
Patient Enrollment Methods patients...................................................................................................... 3 
7.4 
Creation and Submission of Survey Sheet ............................................................................................. 3 
7.5 
Measures for Development of Serious Adverse Events ......................................................................... 4 
8.0 
Scheduled Period ............................................................................................................................................ 4 
9.0 
Matters to be Surveyed ................................................................................................................................... 4 
9.1 
Description Details in Patient Enrollment Sheet .................................................................................... 4 
9.2 
Description Items in Survey Sheet ......................................................................................................... 4 
9.2.1 
Front Cover of Survey Sheet .............................................................................................................. 4 
9.2.2 
Patient Demographics ......................................................................................................................... 4 
9.2.3 
Details of Treatment ........................................................................................................................... 5 
9.2.4 
Compliance with Nesina and Compliance with Diet/Exercise Therapy ............................................. 5 
9.2.5 
Laboratory/Observation Parameters ................................................................................................... 6 
9.2.5.1 
Vital Signs .......................................................................................................................................... 6 
9.2.5.2 
Laboratory Values ............................................................................................................................... 6 
9.2.5.3 
Electrocardiography ........................................................................................................................... 6 
9.2.5.4 
Tests for Waist Circumference, Coronary Arteriosclerosis, and Arteriosclerosis ............................... 6 
9.2.5.5 
Other Parameters ................................................................................................................................ 7 
9.2.6 
Adverse Event .................................................................................................................................... 7 
10.0 
Analysis Parameters and Methods ................................................................................................................. 9 
10.1 
Patient Component Parameters .............................................................................................................. 9 
10.2 
Patient Demographics............................................................................................................................. 9 
10.3 
Details of Treatment ............................................................................................................................... 9 
10.4 
Safety Parameters ................................................................................................................................... 9 
10.4.1 
Occurrence of Adverse Events ........................................................................................................... 9 
10.4. 2 
Factors Probably Affecting Safety .................................................................................................... 10 
10.5 
Efficacy Parameters .............................................................................................................................. 10 

 
 
 
10.5.1 
Change in HbA1c ............................................................................................................................. 10 
10.5.2 
Changes in Laboratory Test Values .................................................................................................. 10 
10.5.3 
Factors Probably Affecting Efficacy ................................................................................................ 10 
10.6 
Parameters in Patients with Special Demographics ............................................................................. 10 
11.0 
Registration of Survey Data ......................................................................................................................... 10 
12.0 
Organizations ............................................................................................................................................... 10 
12.1 
Manager ................................................................................................................................................ 10 
12.2 
Central Enrollment Center .................................................................................................................... 11 
13.0 
CRO.............................................................................................................................................................. 11 
14.0 
Other Necessary Matters .............................................................................................................................. 11 
14.1 
Protocol Revision ................................................................................................................................. 11 
14.2 
Measures for Issues or Questions ......................................................................................................... 11 
 
Appendix Observation Schedule  ............................................................................................................................ 12 

 
1 
 
1.0 
Background 
Nesina tablets (hereinafter, Nesina) are dipeptidyl peptidase-4inhibitors (hereinafter, 
DPP-4inhibitors) and oral hypoglycemic drugs mainly characterized by glucose level-dependent 
insulin secretion promotion via a GLP-1 increase and pancreas protection. Since oral 
hypoglycemic drugs have been generally used for a long period in patients and since multiple 
hypoglycemic drugs may be used simultaneously, it is important that long-term results of oral 
hypoglycemic drugs should be obtained from a daily clinical practice. The Specified Drug-use 
Survey of Nesina has been conducted in type 2 diabetes mellitus patients who have had an 
inadequate response to diet/exercise therapies only or diet/exercise therapies plus α-glucosidase 
inhibitors, thiazolidines, sulfonylureas, or biguanides. In the future, the specified drug-use 
survey of complication with Nesina and insulin preparations and insulin secretagogues is also 
expected to be conducted. 
Therefore, the Nesina Tablets Specified Drug-use Survey "Type 2 Diabetic Patients Receiving 
Combination Therapy With a Hypoglycemic Agent (e.g., Insulin Preparations or Rapid-acting 
Insulin Secretagogues)” (hereinafter, this survey) is planned aiming to evaluate the safety and 
efficacy of Nesina when administered for 1 year in type 2 diabetic patients who have had an 
inadequate response to hypoglycemic agents (e.g., insulin preparations, rapid-acting insulin 
secretagogues) in addition to dietary/exercise therapy in daily medical practice. 
This survey is conducted according to the relevant regulatory requirements including the GPSP 
ordinance. 
 
2.0 
Objectives 
This survey is designed to evaluate the safety and efficacy of long-term use of alogliptin tablets 
(Nesina Tablets) in type 2 diabetic patients who have had an inadequate response to 
hypoglycemic agents (e.g., insulin preparations or rapid-acting insulin secretagogues)* in 
addition to dietary/exercise therapy in daily medical practice. 
*Hypoglycemic agents which have not been used in the past Nesina Specified Drug-use Survey (i.e., other 
than α-glucosidase inhibitors, thiazolidines, sulfonylureas, and biguanides) 
 
3.0 
Number of Planned Participants and the Rationales 
3.1 
Number of Planned Participants 
1,000 participants 
 
3.2 
Rationales 
The Specified Drug-use Survey of Nesina has been conducted in type 2 diabetes mellitus 
patients who have had an inadequate response to diet/exercise therapies only or diet/exercise 
therapies plus α-glucosidase inhibitors, thiazolidines, sulfonylureas, or biguanides. In the future, 
the specified drug-use survey of complication with Nesina and insulin preparations and insulin 

 
2 
 
secretagogues is also expected to be conducted. 
Therefore, the planned participants was established as 1,000 to collect as many as participants 
who receive a long-term complication therapy with Nesina and these hypoglycemic agents (e.g., 
insulin preparations, rapid-acting insulin secretagogues). 
In the pooled tabulation of participants in the past Nesina Specified Drug-use Survey (as of 
November 30, 2013; Safety Analysis Set, 10,025 participants), the proportion of participants was 
as follows: elderly, 58.0%; renal impairment participants, 15.1%; and hepatic impairment 
participants, 13.3%. By establishment of the planned participants of 1,000 in this survey, data 
will be collected from approximately 600 elderly participants, approximately 150 renal 
impairment participants, and approximately 100 hepatic impairment participants. This 
establishment is not based on the statistical evidence. 
 
4.0 
Patients for Survey 
Patients with type 2 diabetes mellitus. However, participants must meet the inclusion criteria and 
none of the exclusion criteria, described below. Refer to the Precaution in the package insert. 
4.1 
Inclusion Criteria 
Patients who meet the following criterion are included in this survey: 
Patients who have had an inadequate response to the following medications/therapies: 
 
Use of one hypoglycemic agent such as insulin preparations and rapid-acting insulin 
secretagogues, excluding other types of hypoglycemic agents (e.g., α-glucosidase inhibitors, 
thiazolidines, sulfonylureas, biguanides)*, in addition to dietary/exercise therapy 
*For use of Nesina Tablets in combination with these agents, a specified drug-use survey is currently 
ongoing. 
 
4.2 
Exclusion Criteria 
Patients who meet any of the following criteria are excluded from this survey:  
Patients with contraindications for Nesina Tablets 
(1) 
Those with severe ketosis, in a state of diabetic coma or precoma, or with type 1 
diabetes mellitus [Quickly rectifying hyperglycemia with administration of intravenous 
fluid or insulin is essential in these patients; therefore, administration of Nesina Tablets 
is not appropriate.] 
(2) 
Those with severe infections, before or after surgery, or with serious trauma [Controlling 
blood glucose with an injection of insulin is desirable for these patients; therefore, 
administration of Nesina Tablets is not appropriate.] 
(3) 
Those with a history of hypersensitivity to any of the ingredients of Nesina Tablets 
 
5.0 
Dosage and Administration 
For adults, 25 mg of alogliptin is usually administered orally once daily. Refer to the Precaution 

 
3 
 
in the package insert. For renal impairment patients, refer to the Precaution with Respect to 
Dosage and Administration in the package insert. 
 
6.0 
Number of Scheduled Sites by Department 
Internal medicine or other department: Approximately 200 sites 
 
7.0 
Methods 
7.1 
Observation period 
12 months 
 
7.2 
Request for Sites and Agreement 
The survey is conducted using the paper survey sheet. Before asking survey, the parson in charge 
of medical information in Takeda Pharmaceutical Company Limited. (Hereinafter, Takeda MRs) 
will fully explain to the Investigator about the objectives, details, and methods of this survey, 
based on “Request for Cooperation of Specified Drug-use Survey,” “Summary for Survey,” 
“Patient Enrollment Sheet (sample),” and “Survey Sheet (sample)” and will finalize written 
agreement with survey sites to ask requests for surveillance within the specified period. 
 
7.3 
Patient Enrollment Methods patients 
This survey is conducted by Fax using Central Enrollment System. The Investigator will enroll 
patients for whom Nesina was prescribed after the start date of agreement with a survey site, by 
faxing to the Central Enrollment Center (refer to Section 12.2) the “Patient Enrollment Sheet” 
including the information regarding patient enrollment (refer to Section 9.1) before 14 days after 
the Nesina prescription date (define the prescription date as “0 day” and one day after the 
prescription date as “1 day”). Patients for whom Nesina prescription is scheduled cannot be 
enrolled earlier. The participant who assessed as ineligible for the survey for any reason cannot 
be enrolled in the survey. The Investigator will enroll a new participant using the “Patient 
Enrollment Sheet” supplied by the Takeda MR. The Takeda MR will supply for the Investigator 
the survey sheet issued after the Central Enrollment Center enrolled the participant. 
 
7.4 
Creation and Submission of Survey Sheet 
The Investigator will create the survey sheet for all enrolled participants and submit it to the 
Takeda around within 1 month after the end of the observation period. If Nesina administration 
cannot be confirmed, specify it (do not specify other columns). 
For participants who early discontinue treatment with Nesina during the observation period for 
any reason, the Investigator will create the survey sheet for him/her and submit it to the Takeda 
around within 1 month after the end of necessary observation. However, for participants who 
early discontinue treatment with Nesina due to an adverse event, the Investigator will continue 

 
4 
 
observation even after treatment discontinuation, wherever possible, until the adverse event 
resolve or is resolving and will create the survey sheet and submit it to the Takeda. 
 
7.5 
Measures for Development of Serious Adverse Events 
In case of development of a serious adverse event in the observation period, the Investigator will 
immediately contact the Takeda MR. If the Takeda MR requests additional detailed information, 
the Investigator will provide it. 
 
8.0 
Scheduled Period 
Survey period: June 2014 to February 28, 2017 
Patient enrollment period: June 2014 to February 29, 2016* 
*Even if Nesina is prescribed before February 29 2016, the patients cannot be enrolled (fax of the Patient 
Enrollment Sheet) after March 1 2016. 
In case that the enrolled participants reach the scheduled number of participants in the survey before February 
29 2016, the enrollment will close earlier than the scheduled patient enrollment period. If patient enrollment 
period is shorten, the survey period will be also changed according to the shorten period. 
9.0 
Matters to be Surveyed 
The Investigator will describe the data described below in the Patient Enrollment Sheet and the 
survey sheet. The schedule of this survey is shown in the Appendix. 
9.1 
Description Details in Patient Enrollment Sheet 
1) Matters to be surveyed 
Name of survey site, name of the investigator who describe in the Patient Enrollment Sheet, 
Nesina prescription date, Patient ID Number, patient initial, sex, birth date, inclusion criteria 
assessment, and exclusion criteria assessment 
2) Survey period 
At patient enrollment 
 
9.2 
Description Items in Survey Sheet 
9.2.1 Front Cover of Survey Sheet 
Last description date in the survey sheet and name of the Investigator who described the survey 
sheet 
 
9.2.2 Patient Demographics 
1) Matters to be surveyed 
Diagnosis period of type 2 diabetes mellitus, category of clinical practice, disposition of 
hypersensitivity (yes/no and detail), concurrent disease (yes/no and detail), past medical 
history (yes/no and detail), height, smoking history, drinking history, presence or absence of 
serum creatinine within 1 month after the start of Nesina treatment, serum creatinine level (if 

 
5 
 
serum creatinine present), and severity of renal impairment and rationale for the assessment 
(if serum creatinine absent). 
2) Survey period 
At the start of Nesina treatment 
 
9.2.3 
Details of Treatment 
1) Matters to be surveyed 
Details of Nesina treatment (daily dose, administration period, and reason for 
discontinuation), and status of concomitant medications (hypoglycemic agents*) (yes/no, 
drug name, daily dose, route of administration, administration period, and objective of 
administration) 
*Hypoglycemic agents which are discontinued within 3 months prior to Nesina treatment are included. 
2) Survey period 
Period from the start of Nesina treatment to 12 months after treatment (or treatment 
discontinuation) 
 
9.2.4 
Compliance with Nesina and Compliance with Diet/Exercise Therapy 
1) Matters to be surveyed 
Compliance with Nesina* and compliance with diet/exercise therapy** 
 
 
*Criteria for assessment of compliance with Nesina 
1. ≥ 90% (A participant won’t miss administration, or even if he/she missed 
administration, the frequency is twice or three times a month.) 
2. ≥ 70% (A participant missed administration once or twice weekly.) 
3. ≥ 50% (A participant missed administration three times a week.) 
4. < 50% (A participant missed administration four times or more a week.) 
 
**Criteria for assessment of compliance with diet/exercise therapy 
1. ≥ 90% (A participant complied as instructed.) 
2. ≥ 70% (A participant mostly complied as instructed.) 
3. ≥ 50% (A participant did not complied well as instructed.) 
4. < 50% (A participant did not mostly complied as instructed.) 
5. Not performed 
6. Unknown 
 
2) Survey period 
At the start of Nesina treatment (compliance with diet/exercise therapy only), 1 month, 3 

 
6 
 
months, 6 months, and 12 months after the start of treatment (or treatment discontinuation) 
 
9.2.5 
Laboratory/Observation Parameters 
9.2.5.1 Vital Signs 
1) Laboratory/observation parameters 
Pulse rate, blood pressure (systolic/diastolic), and weight 
2) Survey period 
Each time point at the start of Nesina treatment, 1 month, 3 months, 6 months, and 12 months 
after the start of treatment (or treatment discontinuation) 
 
9.2.5.2 Laboratory Values 
1) Laboratory parameters 
HbA1c (NGSP value, same hereafter), fasting glucose, fasting insulin, fasting glucagon, 
fasting triglyceride, total cholesterol, HDL-cholesterol, LDL-cholesterol, serum creatinine, 
BUN, urinary albumin (corrected by creatinine), AST, ALT, γ-GTP, ALP, total bilirubin, 
amylase, and lipase 
2) Survey period 
Each time point at the start of Nesina treatment, 1 month, 3 months, 6 months, and 12 months 
after the start of treatment (or treatment discontinuation) 
 
9.2.5.3 Electrocardiography 
1) Observation Parameters 
Electrocardiograms (assessment and findings) 
2) Survey period 
Each time point from the start of Nesina treatment to 12 months after treatment (or treatment 
discontinuation) 
 
9.2.5.4 Tests for Waist Circumference, Coronary Arteriosclerosis, and Arteriosclerosis 
1) Observation Parameters 
Tests for waist circumference,* coronary arteriosclerosis and arteriosclerosis** (e.g., pulse 
wave velocity, cardio-ankle vascular index, intima-media thickness, intra-vascular 
ultrasound) 
*Measure the waist diameter during light expiration at standing position and at the level of the navel. If the 
lower deviation of the navel occurs because of significant abdominal fat accumulation, measure the waist 
diameter at the level of the midpoint between the inferior rib border and anterior superior iliac spine. 
**Any methods can be used. In principle, however, use the same methods for each test. If there are no 
devices for measurement, the tests can be omitted. 
2) Survey period 

 
7 
 
Each time point from the start of Nesina treatment to 12 months after treatment (or treatment 
discontinuation) 
 
9.2.5.5 Other Parameters 
1) Observation parameters 
Pregnancy during the observation period (yes or no) (females only) 
In case of pregnancy in the observation period, the Investigator will immediately contact the 
Takeda MR. The Investigator will provide detailed information (including the information 
until the delivery, as possible, such as preterm delivery) using the separate pregnancy sheet 
after the request from the Takeda MR. 
2) Survey period 
Period from the start of Nesina treatment to 12 months after treatment (or treatment 
discontinuation) 
 
9.2.6 
Adverse Event 
1) Matters to be surveyed 
Presence or absence of adverse events (refer to Table 1), term of adverse events, onset date, 
seriousness and the reason (refer to Table 2), presence or absence of Nesina discontinuation, 
outcome assessment date, outcome, and causal relationship to Nesina* (refer to Table 3). 
If the outcome is assessed as Not resolved or Unknown and if the causal relationship cannot 
be assessed, the participant will be followed up, wherever possible. 
The detailed information (e.g., clinical course, laboratory tests for diagnosis) will be collected 
as possible for development of hypoglycemia, acute pancreatitis, renal impairment / jaundice, 
skin disorder including oculomucocutaneous syndrome (Stevens-Johnson syndrome) and 
erythema multiforme, rhabdomyolysis, intestinal obstruction, interstitial pneumonia, 
angioedema, infection, malignant tumor, and cardiovascular system-related event (e.g., 
symptomatic coronary artery disease, cerebrovascular disorder, arteriosclerosis obliterans, 
cardiovascular death, sudden death) 
*If the causal relationship to Nesina is assessed as Not related, collect the rationales for assessment. If the 
relationship is assessed as Not assessable, collected the reason for Not assessable. 
 
Note) Matters that should be considered for adverse events 
Abnormal exacerbation of the target disease, i.e., worsening beyond expected natural 
clinical course, is defined as an adverse event; however, the expected worsening is not 
defined as an adverse vent. 
2) Survey period 
Period from the start of Nesina treatment to 12 months after treatment (or treatment 
discontinuation) 
 

 
8 
 
Table 1 Definition of adverse event 
An adverse event (AE) is defined as any unfavorable event that develops after a pharmaceutical 
product is administered and which does not necessarily have a causal relationship with treatment.  
An adverse event can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding, for example), symptom, or disease temporally associated with the use of a 
medicinal product, whether or not considered related to the medicinal product. 
The following events will be handled as adverse events: 
• Symptoms present in infants breastfed by a Nesina taking mother 
• Symptoms present in children who received the relevant drug 
• Symptoms due to occupational exposure to the relevant drug 
• Symptoms due to counterfeit medications of the legitimate medicinal products manufactured by 
Takeda 
• Unfavorable symptoms present in the patient who received the relevant drug, known by a lawsuit or 
other legal actions 
 
Table 2 Criteria for severity assessment 
An event which meet any of the following criteria will be assessed as “Serious:” 
1. Results in death (death). 
2. Is life-threatening (potential death threat). 
3. Requires inpatient hospitalization or prolongation of existing hospitalization (admission / prolonged 
hospitalization). 
4. Results in persistent or significant disability/incapacity (disability). 
5. Is a congenital anomaly/birth defect (congenital anomaly). 
6. Other significant medical conditions which do not meet the above criteria 1 to 5. Events listed in the 
“Takeda Medically Significant AE List are included in this section criteria. 
 
Takeda Medically Significant AE List 
• Acute respiratory failure / acute respiratory distress 
syndrome (ARDS) 
• Anaphylactic shock 
• Torsade de pointes / ventricular fibrillation / 
ventricular tachycardia 
• Acute renal failure 
• Malignant hypertension 
• Pulmonary hypertension 
• Convulsive seizure (including convulsion and 
epilepsy) 
• Pulmonary fibrosis (including interstitial 
pneumonia) 
• Agranulocytosis 
• Malignant syndrome / malignant 
hyperthermia 
• Aplastic anemia 
• Spontaneous abortion / stillbirth and fetal 
death 
• Toxic epidermal necrolysis / oculomucocutaneous 
syndrome (Stevens-Johnson syndrome) 
• Spread of infection via drug or suspected 
spread 

 
9 
 
• Hepatic necrosis 
• Acute hepatic failure 
• Endotoxic shock or suspected endotoxic 
shock 
Table 3 Criteria for causality assessment between adverse events and Nesina 
Assessment 
Assessment criterion 
Related 
Temporally correlation (including the post-treatment clinical course) present. Or an 
adverse event that may have been caused by the primary disease, concurrent disease, 
concomitant medication, or other factor including concomitant procedures, but also 
suggested to be caused by the relevant drug. 
Not related 
No temporally correlation with the relevant drug. Or an adverse event presumably 
caused by the primary disease, concurrent disease, concomitant medication, or other 
factor. 
Not 
assessable 
Lack of information for assessment of temporal correlation (including the post-treatment 
clinical course), the primary disease, concurrent disease, concomitant medication, other 
factor, etc. 
 
10.0 
Analysis Parameters and Methods 
10.1 Patient Component Parameters 
The following will be tabulated: number of enrolled participants, number of survey sheet 
collected participants, number of the Safety Analysis Set, number of the Efficacy Analysis Set, 
and number of patients excluded from analysis and the reason for exclusion, etc. 
 
10.2 Patient Demographics 
Patient demographics including sex, age, disease period, hypersensitivity predisposition, and 
concurrent disease will be tabulated. 
 
10.3 Details of Treatment 
The following will be tabulated: status of Nesina treatment, status of concomitant medications, 
and compliance with Nesina treatment, etc. 
 
10.4 Safety Parameters 
The items described below will be tabulated in the Safety Analysis Set. Adverse events will be 
coded using the MedDRA/J and summarized by Preferred Term (PT) and System Organ Class 
(SOC). 
10.4.1 Occurrence of Adverse Events 
For adverse events reported in the observation period, the type and causal relationship to 
Nesina will be tabulated. 
 

 
10 
 
10.4. 2 Factors Probably Affecting Safety 
For adverse drug reactions reported in the observation period, the frequency of patient 
demographics (e.g., sex, age), details of treatment (e.g., status of Nesina, and status of 
concomitant medications) will be stratified. 
 
10.5 Efficacy Parameters 
The following will be tabulated in the Efficacy Analysis Set: 
10.5.1 Change in HbA1c 
HbA1c test values and the corresponding change from baseline at each testing time point (i.e., 
test value at each testing time point − test value at baseline) will be tabulated. In addition, the 
objective glycemic control achievement rate at each testing time point will be tabulated. 
 
10.5.2 Changes in Laboratory Test Values 
Test values (fasting blood glucose level, fasting insulin level, HOMA-R,* and HOMA-β*) 
and the corresponding changes from baseline at each testing time point (i.e., test value at each 
testing time point − test value at baseline) will be tabulated. 
*HOMA-R: Fasting insulin × Fasting glucose / 405 
**HOMA-β: (Fasting insulin × 360) / (Fasting glucose − 63) 
 
10.5.3 Factors Probably Affecting Efficacy 
For the changes in HbA1c and glycemic control achievement rate at 12 months after the start 
of treatment, the following will be stratified: patient demographics (e.g., sex, age, HbA1c at 
the start of Nesina treatment) and details of treatment (e.g., status of Nesina treatment, status 
of concomitant medications). 
 
10.6 Parameters in Patients with Special Demographics 
The safety and efficacy of Nesina will be stratified in elderly patients or patients with 
hepatic/renal impairment. 
 
11.0 
Registration of Survey Data 
Takeda Pharmaceutical Company Limited. will register the survey information in the following 
open websites before the start of this survey. 
• Japan Pharmaceutical Information Center-Clinical Trials Information 
• Clinical trial registration system of National Institute of Health (US): Clinical Trials.gov 
 
12.0 
Organizations 
12.1 Manager 
Takeda Pharmaceutical Company Limited. 
 
PPD

 
11 
 
 
12.2 Central Enrollment Center 
 
13.0 
CRO 
 
14.0 
Other Necessary Matters 
14.1 Protocol Revision 
During the survey period, the protocol can be reviewed and revised, if the following are 
necessary to be changed after monitored: the survey progress, adverse drug reactions / serious 
adverse drug reactions unexpected from the Precautions, increased frequency of specified 
adverse drug reactions (yes or no), and parameter appropriateness. During the survey period, if 
partly changes of dosage and administration and indications are approved, the protocol revision 
will be also considered and performed as necessary. 
 
14.2 Measures for Issues or Questions 
If any question about the safety or efficacy is arisen, data will be investigated and the relevant 
persons will take measures for the question. 
 
 
PPD
PPD

 
12 
 
Appendix 
Observation Schedule 
 
Survey period 
 
 
Parameter 
Observation period 
At patient 
enrollment 
 
 
At start of 
treatment 
 
1 months after 
treatment 
 
3 months after 
treatment 
 
6 months after 
treatment 
 
12 months after 
treatment 
 
At treatment 
discontinuation 
 
Patient enrollment 
Nesina prescription date 
○ 
 
 
 
 
 
 
Patient ID Number 
○ 
Patients initial 
○ 
Sex 
○ 
Birth date 
○ 
Inclusion criteria / exclusion criteria 
○ 
 
 
 
 
 
 
At patient demographics 
Diagnosis period of type 2 diabetes mellitus 
○ 
 
 
 
Category of clinical practice 
○ 
 
 
 
 
Hypersensitivity predisposition 
○ 
 
 
 
 
Concurrent disease 
○ 
 
 
 
 
Past medical history 
○ 
 
 
 
 
Height 
○ 
 
 
 
Smoking history 
 
○ 
 
 
 
 
Drinking history 
 
○ 
 
 
 
 
Presence or absence of serum creatinine within 1 
month after the start of Nesina treatment, serum 
creatinine level (if serum creatinine present), and 
severity of renal impairment and rationale for the 
assessment (if serum creatinine absent). 
 
○ 
 
 
 
 
 
Details 
of 
treatment, etc 
Status of Nesina treatment 
○ 
○ 
Status 
of 
concomitant 
medication 
treatment
(hypoglycemic agents* / other than hypoglycemic
agents) 
 
○ 
○ 
Status of compliance with Nesina 
○ 
○ 
○ 
○ 
○ 
Status of compliance with diet/exercise therapy 
○ 
○ 
○ 
○ 
○ 
○ 
Laboratory/Observation Parameters, etc 
Pulse rate, blood pressure 
○ 
○ 
○ 
○ 
○ 
○ 
Weight 
○ 
○ 
○ 
○ 
○ 
○ 
Laboratory values 
• HbA1c (NGSP value) 
• Fasting glucose 
• Fasting insulin 
• Fasting glucagon 
• Fasting triglyceride 
• Total cholesterol 
• HDL-cholesterol 
• LDL-cholesterol 
• Serum creatinine 
• BUN 
• Urinary albumin (corrected by creatinine) 
• AST 
• ALT 
• γ-GTP 
• ALP 
• Total bilirubin 
• Amylase 
• Lipase 
 
○ 
○ 
○ 
○ 
○ 
○ 
Electrocardiogram 
○ 
 
 
 
○ 
○ 
Waist circumference 
○ 
○ 
○ 
Tests 
for 
coronary 
arteriosclerosis 
and 
arteriosclerosis 
 
○ 
 
 
 
○ 
○ 
Pregnancy (yes or no) (females only) 
 
○ 
○ 
Adverse event 
○ 
○ 

 
13 
 
○ 
: To be performed 
 ○ 
: To be performed throughout the period 
*Including hypoglycemic agents discontinued within 3 months before the start of Nesina treatment 

 
 
 
 
Protocol for 
Nesina Tablets Specified Drug-use Survey "Type 2 
Diabetes Mellitus: Combination Therapy With 
Hypoglycemic Drug (Insulin Preparation or 
Rapid-acting Insulin Secretagogues, Etc)" 
 
 
 
 
 
 
 
 
 
 
Version 
Second version 
Creation date 
April 1, 2015 
Sponsor 
Takeda Pharmaceutical Company Limited. 
 
 
 
 

 
 
 
Table of Contents 
1.0 
Background .................................................................................................................................................... 1 
2.0 
Objectives ....................................................................................................................................................... 1 
3.0 
Number of Planned Participants and the Rationales ...................................................................................... 1 
3.1 
Number of Planned Participants ............................................................................................................. 1 
3.2 
Rationales ............................................................................................................................................... 1 
4.0 
Patients for Survey ......................................................................................................................................... 2 
4.1 
Inclusion Criteria .................................................................................................................................... 2 
4.2 
Exclusion Criteria ................................................................................................................................... 2 
5.0 
Dosage and Administration ............................................................................................................................ 2 
6.0 
Number of Scheduled Sites by Department ................................................................................................... 3 
7.0 
Methods .......................................................................................................................................................... 3 
7.1 
Observation period ................................................................................................................................. 3 
7.2 
Request for Sites and Agreement ........................................................................................................... 3 
7.3 
Patient Enrollment Methods patients...................................................................................................... 3 
7.4 
Creation and Submission of Survey Sheet ............................................................................................. 3 
7.5 
Measures for Development of Serious Adverse Events ......................................................................... 4 
8.0 
Scheduled Period ............................................................................................................................................ 4 
9.0 
Matters to be Surveyed ................................................................................................................................... 4 
9.1 
Description Details in Patient Enrollment Sheet .................................................................................... 4 
9.2 
Description Items in Survey Sheet ......................................................................................................... 4 
9.2.1 
Front Cover of Survey Sheet .............................................................................................................. 4 
9.2.2 
Patient Demographics ......................................................................................................................... 4 
9.2.3 
Details of Treatment ........................................................................................................................... 5 
9.2.4 
Compliance with Nesina and Compliance with Diet/Exercise Therapy ............................................. 5 
9.2.5 
Laboratory/Observation Parameters ................................................................................................... 6 
9.2.5.1 
Vital Signs .......................................................................................................................................... 6 
9.2.5.2 
Laboratory Values ............................................................................................................................... 6 
9.2.5.3 
Electrocardiography ........................................................................................................................... 6 
9.2.5.4 
Tests for Waist Circumference, Coronary Arteriosclerosis, and Arteriosclerosis ............................... 6 
9.2.5.5 
Other Parameters ................................................................................................................................ 7 
9.2.6 
Adverse Event .................................................................................................................................... 7 
10.0 
Analysis Parameters and Methods ................................................................................................................. 9 
10.1 
Patient Component Parameters .............................................................................................................. 9 
10.2 
Patient Demographics............................................................................................................................. 9 
10.3 
Details of Treatment ............................................................................................................................... 9 
10.4 
Safety Parameters ................................................................................................................................... 9 
10.4.1 
Occurrence of Adverse Events ........................................................................................................... 9 
10.4. 2 
Factors Probably Affecting Safety ...................................................................................................... 9 
10.5 
Efficacy Parameters .............................................................................................................................. 10 

 
 
 
10.5.1 
Change in HbA1c ............................................................................................................................. 10 
10.5.2 
Changes in Laboratory Test Values .................................................................................................. 10 
10.5.3 
Factors Probably Affecting Efficacy ................................................................................................ 10 
10.6 
Parameters in Patients with Special Demographics ............................................................................. 10 
11.0 
Registration of Survey Data ......................................................................................................................... 10 
12.0 
Organizations ............................................................................................................................................... 10 
12.1 
Manager ................................................................................................................................................ 10 
12.2 
Central Enrollment Center .................................................................................................................... 10 
13.0 
CRO.............................................................................................................................................................. 11 
14.0 
Other Necessary Matters .............................................................................................................................. 11 
14.1 
Protocol Revision ................................................................................................................................. 11 
14.2 
Measures for Issues or Questions ......................................................................................................... 11 
 
Appendix Observation Schedule  ............................................................................................................................ 12 

 
1 
 
1.0 
Background 
Nesina tablets (hereinafter, Nesina) are dipeptidyl peptidase-4inhibitors (hereinafter, 
DPP-4inhibitors) and oral hypoglycemic drugs mainly characterized by glucose level-dependent 
insulin secretion promotion via a GLP-1 increase and pancreas protection. Since oral 
hypoglycemic drugs have been generally used for a long period in patients and since multiple 
hypoglycemic drugs may be used simultaneously, it is important that long-term results of oral 
hypoglycemic drugs should be obtained from a daily clinical practice. The Specified Drug-use 
Survey of Nesina has been conducted in type 2 diabetes mellitus patients who have had an 
inadequate response to diet/exercise therapies only or diet/exercise therapies plus α-glucosidase 
inhibitors, thiazolidines, sulfonylureas, or biguanides. In the future, the specified drug-use 
survey of complication with Nesina and insulin preparations and insulin secretagogues is also 
expected to be conducted. 
Therefore, the Nesina Tablets Specified Drug-use Survey "Type 2 Diabetic Patients Receiving 
Combination Therapy With a Hypoglycemic Agent (e.g., Insulin Preparations or Rapid-acting 
Insulin Secretagogues)” (hereinafter, this survey) is planned aiming to evaluate the safety and 
efficacy of Nesina when administered for 1 year in type 2 diabetic patients who have had an 
inadequate response to hypoglycemic agents (e.g., insulin preparations, rapid-acting insulin 
secretagogues) in addition to dietary/exercise therapy in daily medical practice. 
This survey is conducted according to the relevant regulatory requirements including the GPSP 
ordinance. 
 
2.0 
Objectives 
This survey is designed to evaluate the safety and efficacy of long-term use of alogliptin tablets 
(Nesina Tablets) in type 2 diabetic patients who have had an inadequate response to 
hypoglycemic agents (e.g., insulin preparations or rapid-acting insulin secretagogues)* in 
addition to dietary/exercise therapy in daily medical practice. 
*Hypoglycemic agents which have not been used in the past Nesina Specified Drug-use Survey (i.e., other 
than α-glucosidase inhibitors, thiazolidines, sulfonylureas, and biguanides) 
 
3.0 
Number of Planned Participants and the Rationales 
3.1 
Number of Planned Participants 
1,000 participants 
 
3.2 
Rationales 
The Specified Drug-use Survey of Nesina has been conducted in type 2 diabetes mellitus 
patients who have had an inadequate response to diet/exercise therapies only or diet/exercise 
therapies plus α-glucosidase inhibitors, thiazolidines, sulfonylureas, or biguanides. In the future, 
the specified drug-use survey of complication with Nesina and insulin preparations and insulin 

 
2 
 
secretagogues is also expected to be conducted. 
Therefore, the planned participants was established as 1,000 to collect as many as participants 
who receive a long-term complication therapy with Nesina and these hypoglycemic agents (e.g., 
insulin preparations, rapid-acting insulin secretagogues). 
In the pooled tabulation of participants in the past Nesina Specified Drug-use Survey (as of 
November 30, 2013; Safety Analysis Set, 10,025 participants), the proportion of participants was 
as follows: elderly, 58.0%; renal impairment participants, 15.1%; and hepatic impairment 
participants, 13.3%. By establishment of the planned participants of 1,000 in this survey, data 
will be collected from approximately 600 elderly participants, approximately 150 renal 
impairment participants, and approximately 100 hepatic impairment participants. This 
establishment is not based on the statistical evidence. 
 
4.0 
Patients for Survey 
Patients with type 2 diabetes mellitus. However, participants must meet the inclusion criteria and 
none of the exclusion criteria, described below. Refer to the Precaution in the package insert. 
4.1 
Inclusion Criteria 
Patients who meet the following criterion are included in this survey: 
Patients who have had an inadequate response to the following medications/therapies: 
 
Use of one hypoglycemic agent such as insulin preparations and rapid-acting insulin 
secretagogues, excluding other types of hypoglycemic agents (e.g., α-glucosidase inhibitors, 
thiazolidines, sulfonylureas, biguanides)*, in addition to dietary/exercise therapy 
*For use of Nesina Tablets in combination with these agents, a specified drug-use survey is currently 
ongoing. 
 
4.2 
Exclusion Criteria 
Patients who meet any of the following criteria are excluded from this survey:  
Patients with contraindications for Nesina Tablets 
(1) 
Those with severe ketosis, in a state of diabetic coma or precoma, or with type 1 
diabetes mellitus [Quickly rectifying hyperglycemia with administration of intravenous 
fluid or insulin is essential in these patients; therefore, administration of Nesina Tablets 
is not appropriate.] 
(2) 
Those with severe infections, before or after surgery, or with serious trauma [Controlling 
blood glucose with an injection of insulin is desirable for these patients; therefore, 
administration of Nesina Tablets is not appropriate.] 
(3) 
Those with a history of hypersensitivity to any of the ingredients of Nesina Tablets 
 
5.0 
Dosage and Administration 
For adults, 25 mg of alogliptin is usually administered orally once daily. Refer to the Precaution 

 
3 
 
in the package insert. For renal impairment patients, refer to the Precaution with Respect to 
Dosage and Administration in the package insert. 
 
6.0 
Number of Scheduled Sites by Department 
Internal medicine or other department: Approximately 200 sites 
 
7.0 
Methods 
7.1 
Observation period 
12 months 
 
7.2 
Request for Sites and Agreement 
The survey is conducted using the paper survey sheet. Before asking survey, the parson in charge 
of medical information in Takeda Pharmaceutical Company Limited. (Hereinafter, Takeda MRs) 
will fully explain to the Investigator about the objectives, details, and methods of this survey, 
based on “Request for Cooperation of Specified Drug-use Survey,” “Summary for Survey,” 
“Patient Enrollment Sheet (sample),” and “Survey Sheet (sample)” and will finalize written 
agreement with survey sites to ask requests for surveillance within the specified period. 
 
7.3 
Patient Enrollment Methods patients 
This survey is conducted by Fax using Central Enrollment System. The Investigator will enroll 
patients for whom Nesina was prescribed after the start date of agreement with a survey site, by 
faxing to the Central Enrollment Center (refer to Section 12.2) the “Patient Enrollment Sheet” 
including the information regarding patient enrollment (refer to Section 9.1) before 14 days after 
the Nesina prescription date (define the prescription date as “0 day” and one day after the 
prescription date as “1 day”). Patients for whom Nesina prescription is scheduled cannot be 
enrolled earlier. The participant who assessed as ineligible for the survey for any reason cannot 
be enrolled in the survey. The Investigator will enroll a new participant using the “Patient 
Enrollment Sheet” supplied by the Takeda MR. The Takeda MR will supply for the Investigator 
the survey sheet issued after the Central Enrollment Center enrolled the participant. 
 
7.4 
Creation and Submission of Survey Sheet 
The Investigator will create the survey sheet for all enrolled participants and submit it to the 
Takeda around within 1 month after the end of the observation period. If Nesina administration 
cannot be confirmed, specify it (do not specify other columns). 
For participants who early discontinue treatment with Nesina during the observation period for 
any reason, the Investigator will create the survey sheet for him/her and submit it to the Takeda 
around within 1 month after the end of necessary observation. However, for participants who 
early discontinue treatment with Nesina due to an adverse event, the Investigator will continue 

 
4 
 
observation even after treatment discontinuation, wherever possible, until the adverse event 
resolve or is resolving and will create the survey sheet and submit it to the Takeda. 
 
7.5 
Measures for Development of Serious Adverse Events 
In case of development of a serious adverse event in the observation period, the Investigator will 
immediately contact the parson in charge in Takeda Pharmaceutical Company Limited. (person 
in charge in Takeda). If the person in charge in Takeda requests additional detailed information, 
the Investigator will provide it. 
 
8.0 
Scheduled Period 
Survey period: June 2014 to November 30, 2016 
Patient enrollment period: June 2014 to November 30, 2015* 
*Even if Nesina is prescribed before November 30 2015, the patients cannot be enrolled (fax of the Patient 
Enrollment Sheet) after December 1 2015. 
In case that the enrolled participants reach the scheduled number of participants in the survey before 
November 30 2015, the enrollment will close earlier than the scheduled patient enrollment period. If patient 
enrollment period is shorten, the survey period will be also changed according to the shorten period. 
9.0 
Matters to be Surveyed 
The Investigator will describe the data described below in the Patient Enrollment Sheet and the 
survey sheet. The schedule of this survey is shown in the Appendix. 
9.1 
Description Details in Patient Enrollment Sheet 
1) Matters to be surveyed 
Name of survey site, name of the investigator who describe in the Patient Enrollment Sheet, 
Nesina prescription date, Patient ID Number, patient initial, sex, birth date, inclusion criteria 
assessment, and exclusion criteria assessment 
2) Survey period 
At patient enrollment 
 
9.2 
Description Items in Survey Sheet 
9.2.1 Front Cover of Survey Sheet 
Last description date in the survey sheet and name of the Investigator who described the survey 
sheet 
 
9.2.2 Patient Demographics 
1) Matters to be surveyed 
Diagnosis period of type 2 diabetes mellitus, category of clinical practice, disposition of 
hypersensitivity (yes/no and detail), concurrent disease (yes/no and detail), past medical 
history (yes/no and detail), height, smoking history, drinking history, presence or absence of 

 
5 
 
serum creatinine within 1 month after the start of Nesina treatment, serum creatinine level (if 
serum creatinine present), and severity of renal impairment and rationale for the assessment 
(if serum creatinine absent). 
2) Survey period 
At the start of Nesina treatment 
 
9.2.3 
Details of Treatment 
1) Matters to be surveyed 
Details of Nesina treatment (daily dose, administration period, and reason for 
discontinuation), and status of concomitant medications* (hypoglycemic agents) (yes/no, 
drug name, daily dose, route of administration, administration period, and objective of 
administration) 
*Hypoglycemic agents which are discontinued within 3 months prior to Nesina treatment are included. 
2) Survey period 
Period from the start of Nesina treatment to 12 months after treatment (or treatment 
discontinuation) 
 
9.2.4 
Compliance with Nesina and Compliance with Diet/Exercise Therapy 
1) Matters to be surveyed 
Compliance with Nesina* and compliance with diet/exercise therapy** 
 
 
*Criteria for assessment of compliance with Nesina 
1. ≥ 90% (A participant won’t miss administration, or even if he/she missed 
administration, the frequency is twice or three times a month.) 
2. ≥ 70% (A participant missed administration once or twice weekly.) 
3. ≥ 50% (A participant missed administration three times a week.) 
4. < 50% (A participant missed administration four times or more a week.) 
 
**Criteria for assessment of compliance with diet/exercise therapy 
1. ≥ 90% (A participant complied as instructed.) 
2. ≥ 70% (A participant mostly complied as instructed.) 
3. ≥ 50% (A participant did not complied well as instructed.) 
4. < 50% (A participant did not mostly complied as instructed.) 
5. Not performed 
6. Unknown 
 
2) Survey period 

 
6 
 
At the start of Nesina treatment (compliance with diet/exercise therapy only), 1 month, 3 
months, 6 months, and 12 months after the start of treatment (or treatment discontinuation) 
 
9.2.5 
Laboratory/Observation Parameters 
9.2.5.1 Vital Signs 
1) Laboratory/observation parameters 
Pulse rate, blood pressure (systolic/diastolic), and weight 
2) Survey period 
Each time point at the start of Nesina treatment, 1 month, 3 months, 6 months, and 12 months 
after the start of treatment (or treatment discontinuation) 
 
9.2.5.2 Laboratory Values 
1) Laboratory parameters 
HbA1c (NGSP value, same hereafter), fasting glucose, fasting insulin, fasting glucagon, 
fasting triglyceride, total cholesterol, HDL-cholesterol, LDL-cholesterol, serum creatinine, 
BUN, urinary albumin (corrected by creatinine), AST, ALT, γ-GTP, ALP, total bilirubin, 
amylase, and lipase 
2) Survey period 
Each time point at the start of Nesina treatment, 1 month, 3 months, 6 months, and 12 months 
after the start of treatment (or treatment discontinuation) 
 
9.2.5.3 Electrocardiography 
1) Observation Parameters 
Electrocardiograms (assessment and findings) 
2) Survey period 
Each time point from the start of Nesina treatment to 12 months after treatment (or treatment 
discontinuation) 
 
9.2.5.4 Tests for Waist Circumference, Coronary Arteriosclerosis, and Arteriosclerosis 
1) Observation Parameters 
Tests for waist circumference,* coronary arteriosclerosis and arteriosclerosis** (e.g., pulse 
wave velocity, cardio-ankle vascular index, intima-media thickness, intra-vascular 
ultrasound) 
*Measure the waist diameter during light expiration at standing position and at the level of the navel. If the 
lower deviation of the navel occurs because of significant abdominal fat accumulation, measure the waist 
diameter at the level of the midpoint between the inferior rib border and anterior superior iliac spine. 
**Any methods can be used. In principle, however, use the same methods for each test. If there are no 
devices for measurement, the tests can be omitted. 

 
7 
 
2) Survey period 
Each time point from the start of Nesina treatment to 12 months after treatment (or treatment 
discontinuation) 
 
9.2.5.5 Other Parameters 
1) Observation parameters 
Pregnancy during the observation period (yes or no) (females only) 
In case of pregnancy in the observation period, the Investigator will immediately contact the 
person in charge in Takeda. The Investigator will provide detailed information (including the 
information until the delivery, as possible, such as preterm delivery) using the separate 
pregnancy sheet after the request from the person in charge in Takeda. 
2) Survey period 
Period from the start of Nesina treatment to 12 months after treatment (or treatment 
discontinuation) 
 
9.2.6 
Adverse Event 
1) Matters to be surveyed 
Presence or absence of adverse events (refer to Table 1), term of adverse events, onset date, 
seriousness and the reason (refer to Table 2), presence or absence of Nesina discontinuation, 
outcome assessment date, outcome, and causal relationship to Nesina* (refer to Table 3). 
If the outcome is assessed as Not resolved or Unknown and if the causal relationship cannot 
be assessed, the participant will be followed up, wherever possible. 
The detailed information (e.g., clinical course, laboratory tests for diagnosis) will be collected 
as possible for development of hypoglycemia, acute pancreatitis, renal impairment / jaundice, 
skin disorder including oculomucocutaneous syndrome (Stevens-Johnson syndrome) and 
erythema multiforme, rhabdomyolysis, intestinal obstruction, interstitial pneumonia, 
angioedema, infection, malignant tumor, and cardiovascular system-related event (e.g., 
symptomatic coronary artery disease, cerebrovascular disorder, arteriosclerosis obliterans, 
cardiovascular death, sudden death) 
*If the causal relationship to Nesina is assessed as Not related, collect the rationales for assessment. If the 
relationship is assessed as Not assessable, collected the reason for Not assessable. 
 
Note) Matters that should be considered for adverse events 
Abnormal exacerbation of the target disease, i.e., worsening beyond expected natural 
clinical course, is defined as an adverse event; however, the expected worsening is not 
defined as an adverse vent. 
2) Survey period 
Period from the start of Nesina treatment to 12 months after treatment (or treatment 

 
8 
 
discontinuation) 
 
Table 1 Definition of adverse event 
An adverse event (AE) is defined as any unfavorable event that develops after a pharmaceutical 
product is administered and which does not necessarily have a causal relationship with treatment.  
An adverse event can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding, for example), symptom, or disease temporally associated with the use of a 
medicinal product, whether or not considered related to the medicinal product. 
The following events will be handled as adverse events: 
• Symptoms present in infants breastfed by a Nesina taking mother 
• Symptoms present in children who received the relevant drug 
• Symptoms due to occupational exposure to the relevant drug 
• Symptoms due to counterfeit medications of the legitimate medicinal products manufactured by 
Takeda 
 
Table 2 Criteria for severity assessment 
An event which meet any of the following criteria will be assessed as “Serious:” 
1. Results in death (death). 
2. Is life-threatening (potential death threat). 
3. Requires inpatient hospitalization or prolongation of existing hospitalization (admission / prolonged 
hospitalization). 
4. Results in persistent or significant disability/incapacity (disability). 
5. Is a congenital anomaly/birth defect (congenital anomaly). 
6. Other significant medical conditions which do not meet the above criteria 1 to 5. Events listed in the 
“Takeda Medically Significant AE List are included in this section criteria. 
 
Takeda Medically Significant AE List 
• Acute respiratory failure / acute respiratory 
distress syndrome (ARDS) 
• Anaphylactic shock 
• Torsade de pointes / ventricular fibrillation / 
ventricular tachycardia 
• Acute renal failure 
• Malignant hypertension 
• Pulmonary hypertension 
• Convulsive seizure (including convulsion and 
epilepsy) 
• Pulmonary fibrosis (including interstitial 
pneumonia) 
• Agranulocytosis 
• Malignant syndrome / malignant hyperthermia 
• Aplastic anemia 
• Spontaneous abortion / stillbirth and fetal death 
• Toxic epidermal necrolysis / oculomucocutaneous 
syndrome (Stevens-Johnson syndrome) 
• Spread of infection via drug or suspected spread 
• Hepatic necrosis 
• Acute hepatic failure 
• Endotoxic shock or suspected endotoxic 
shock 

 
9 
 
Table 3 Criteria for causality assessment between adverse events and Nesina 
Assessment 
Assessment criterion 
Related 
Temporally correlation (including the post-treatment clinical course) present. Or an 
adverse event that may have been caused by the primary disease, concurrent disease, 
concomitant medication, or other factor including concomitant procedures, but also 
suggested to be caused by the relevant drug. 
Not related 
No temporally correlation with the relevant drug. Or an adverse event presumably 
caused by the primary disease, concurrent disease, concomitant medication, or other 
factor. 
Not 
assessable 
Lack of information for assessment of temporal correlation (including the post-treatment 
clinical course), the primary disease, concurrent disease, concomitant medication, other 
factor, etc. 
 
10.0 
Analysis Parameters and Methods 
10.1 Patient Component Parameters 
The following will be tabulated: number of enrolled participants, number of survey sheet 
collected participants, number of the Safety Analysis Set, number of the Efficacy Analysis Set, 
and number of patients excluded from analysis and the reason for exclusion, etc. 
 
10.2 Patient Demographics 
Patient demographics including sex, age, disease period, hypersensitivity predisposition, and 
concurrent disease will be tabulated. 
 
10.3 Details of Treatment 
The following will be tabulated: status of Nesina treatment, status of concomitant medications, 
and compliance with Nesina treatment, etc. 
 
10.4 Safety Parameters 
The items described below will be tabulated in the Safety Analysis Set. Adverse events will be 
coded using the MedDRA/J and summarized by Preferred Term (PT) and System Organ Class 
(SOC). 
10.4.1 Occurrence of Adverse Events 
For adverse events reported in the observation period, the type and causal relationship to 
Nesina will be tabulated. 
 
10.4. 2 Factors Probably Affecting Safety 
For adverse drug reactions reported in the observation period, the frequency of patient 
demographics (e.g., sex, age), details of treatment (e.g., status of Nesina, and status of 

 
10 
 
concomitant medications) will be stratified. 
 
10.5 Efficacy Parameters 
The following will be tabulated in the Efficacy Analysis Set: 
10.5.1 Change in HbA1c 
HbA1c test values and the corresponding change from baseline at each testing time point (i.e., 
test value at each testing time point − test value at baseline) will be tabulated. In addition, the 
objective glycemic control achievement rate at each testing time point will be tabulated. 
 
10.5.2 Changes in Laboratory Test Values 
Test values (fasting blood glucose level, fasting insulin level, HOMA-R,* and HOMA-β*) 
and the corresponding changes from baseline at each testing time point (i.e., test value at each 
testing time point − test value at baseline) will be tabulated. 
*HOMA-R: Fasting insulin × Fasting glucose / 405 
**HOMA-β: (Fasting insulin × 360) / (Fasting glucose − 63) 
 
10.5.3 Factors Probably Affecting Efficacy 
For the changes in HbA1c and glycemic control achievement rate at 12 months after the start 
of treatment, the following will be stratified: patient demographics (e.g., sex, age, HbA1c at 
the start of Nesina treatment) and details of treatment (e.g., status of Nesina treatment, status 
of concomitant medications). 
 
10.6 Parameters in Patients with Special Demographics 
The safety and efficacy of Nesina will be stratified in elderly patients or patients with 
hepatic/renal impairment. 
 
11.0 
Registration of Survey Data 
Takeda Pharmaceutical Company Limited. will register the survey information in the 
ClinicalTrials.gov and an open website (JAPIC-CTI*) before the start of this survey. 
*Japan Pharmaceutical Information Center-Clinical Trials Information 
 
12.0 
Organizations 
12.1 Manager 
Takeda Pharmaceutical Company Limited. 
 
 
12.2 Central Enrollment Center 
 
PPD
PPD

 
11 
 
 
 
13.0 
CRO 
 
14.0 
Other Necessary Matters 
14.1 Protocol Revision 
During the survey period, the protocol can be reviewed and revised, if the following are 
necessary to be changed after monitored: the survey progress, adverse drug reactions / serious 
adverse drug reactions unexpected from the Precautions, increased frequency of specified 
adverse drug reactions (yes or no), and parameter appropriateness. During the survey period, if 
partly changes of dosage and administration and indications are approved, the protocol revision 
will be also considered and performed as necessary. 
 
14.2 Measures for Issues or Questions 
If any question about the safety or efficacy is arisen, data will be investigated and the relevant 
persons will take measures for the question. 
 
 
PPD
PPD

 
12 
 
Appendix 
Observation Schedule 
 
Survey period 
 
 
Parameter 
Observation period 
At patient 
enrollment 
 
 
At start of 
treatment 
 
1 months after 
treatment 
 
3 months after 
treatment 
 
6 months after 
treatment 
 
12 months after 
treatment 
 
At treatment 
discontinuation 
 
Patient enrollment 
Nesina prescription date 
○ 
 
 
 
 
 
 
Patient ID Number 
○ 
Patients initial 
○ 
Sex 
○ 
Birth date 
○ 
Inclusion criteria / exclusion criteria 
○ 
 
 
 
 
 
 
At patient demographics 
Diagnosis period of type 2 diabetes mellitus 
○ 
 
 
 
Category of clinical practice 
○ 
 
 
 
 
Hypersensitivity predisposition 
○ 
 
 
 
 
Concurrent disease 
○ 
 
 
 
 
Past medical history 
○ 
 
 
 
 
Height 
○ 
 
 
 
Smoking history 
 
○ 
 
 
 
 
Drinking history 
 
○ 
 
 
 
 
Presence or absence of serum creatinine within 1 
month after the start of Nesina treatment, serum 
creatinine level (if serum creatinine present), and 
severity of renal impairment and rationale for the 
assessment (if serum creatinine absent). 
 
○ 
 
 
 
 
 
Details 
of 
treatment, etc 
Status of Nesina treatment 
○ 
○ 
Status 
of 
concomitant 
medication 
treatment
(hypoglycemic agents / other than hypoglycemic agents)
 
○ 
○ 
Status of compliance with Nesina 
○ 
○ 
○ 
○ 
○ 
Status of compliance with diet/exercise therapy 
○ 
○ 
○ 
○ 
○ 
○ 
Laboratory/Observation Parameters, etc 
Pulse rate, blood pressure 
○ 
○ 
○ 
○ 
○ 
○ 
Weight 
○ 
○ 
○ 
○ 
○ 
○ 
Laboratory values 
• HbA1c (NGSP value) 
• Fasting glucose 
• Fasting insulin 
• Fasting glucagon 
• Fasting triglyceride 
• Total cholesterol 
• HDL-cholesterol 
• LDL-cholesterol 
• Serum creatinine 
• BUN 
• Urinary albumin (corrected by creatinine) 
• AST 
• ALT 
• γ-GTP 
• ALP 
• Total bilirubin 
• Amylase 
• Lipase 
 
○ 
○ 
○ 
○ 
○ 
○ 
Electrocardiogram 
○ 
 
 
 
○ 
○ 
Waist circumference 
○ 
○ 
○ 
Tests for coronary arteriosclerosis and arteriosclerosis 
○ 
○ 
○ 
Pregnancy (yes or no) (females only) 
 
○ 
○ 
Adverse event 
○ 
○ 
○ 
: To be performed 
 ○ 
: To be performed throughout the period 

 
 
 
 
Protocol for 
Nesina Tablets Specified Drug-use Survey "Type 2 
Diabetes Mellitus: Combination Therapy With 
Hypoglycemic Drug (Insulin Preparation or 
Rapid-acting Insulin Secretagogues, Etc)" 
 
 
 
 
 
 
 
 
 
 
Version 
First version 
Creation date 
May 7, 2014 
Sponsor 
Takeda Pharmaceutical Company Limited. 
 
 
 
 

 
 
 
Table of Contents 
1.0 
Background .................................................................................................................................................... 1 
2.0 
Objectives ....................................................................................................................................................... 1 
3.0 
Number of Planned Participants and the Rationales ...................................................................................... 1 
3.1 
Number of Planned Participants ............................................................................................................. 1 
3.2 
Rationales ............................................................................................................................................... 1 
4.0 
Patients for Survey ......................................................................................................................................... 2 
4.1 
Inclusion Criteria .................................................................................................................................... 2 
4.2 
Exclusion Criteria ................................................................................................................................... 2 
5.0 
Dosage and Administration ............................................................................................................................ 2 
6.0 
Number of Scheduled Sites by Department ................................................................................................... 3 
7.0 
Methods .......................................................................................................................................................... 3 
7.1 
Observation period ................................................................................................................................. 3 
7.2 
Request for Sites and Agreement ........................................................................................................... 3 
7.3 
Patient Enrollment Methods patients...................................................................................................... 3 
7.4 
Creation and Submission of Survey Sheet ............................................................................................. 3 
7.5 
Measures for Development of Serious Adverse Events ......................................................................... 4 
8.0 
Scheduled Period ............................................................................................................................................ 4 
9.0 
Matters to be Surveyed ................................................................................................................................... 4 
9.1 
Description Details in Patient Enrollment Sheet .................................................................................... 4 
9.2 
Description Items in Survey Sheet ......................................................................................................... 4 
9.2.1 
Front Cover of Survey Sheet .............................................................................................................. 4 
9.2.2 
Patient Demographics ......................................................................................................................... 4 
9.2.3 
Details of Treatment ........................................................................................................................... 5 
9.2.4 
Compliance with Nesina and Compliance with Diet/Exercise Therapy ............................................. 5 
9.2.5 
Laboratory/Observation Parameters ................................................................................................... 6 
9.2.5.1 
Vital Signs ...................................................................................................................................... 6 
9.2.5.2 
Laboratory Values ........................................................................................................................... 6 
9.2.5.3 
Electrocardiography ....................................................................................................................... 6 
9.2.5.4 
Tests for Waist Circumference, Coronary Arteriosclerosis, and Arteriosclerosis ........................... 6 
9.2.5.5 
Other Parameters ............................................................................................................................ 7 
9.2.6 
Adverse Event .................................................................................................................................... 7 
10.0 
Analysis Parameters and Methods ................................................................................................................. 9 
10.1 
Patient Component Parameters .............................................................................................................. 9 
10.2 
Patient Demographics............................................................................................................................. 9 
10.3 
Details of Treatment ............................................................................................................................... 9 
10.4 
Safety Parameters ................................................................................................................................... 9 
10.4.1 
Occurrence of Adverse Events ........................................................................................................... 9 
10.4. 2 
Factors Probably Affecting Safety .................................................................................................. 9 
10.5 
Efficacy Parameters .............................................................................................................................. 10 

 
 
 
10.5.1 
Change in HbA1c ............................................................................................................................. 10 
10.5.2 
Changes in Laboratory Test Values .................................................................................................. 10 
10.5.3 
Factors Probably Affecting Efficacy ................................................................................................ 10 
10.6 
Parameters in Patients with Special Demographics ............................................................................. 10 
11.0 
Registration of Survey Data ......................................................................................................................... 10 
12.0 
Organizations ............................................................................................................................................... 10 
12.1 
Manager ................................................................................................................................................ 10 
12.2 
Central Enrollment Center .................................................................................................................... 11 
13.0 
CRO.............................................................................................................................................................. 11 
14.0 
Other Necessary Matters .............................................................................................................................. 11 
14.1 
Protocol Revision ................................................................................................................................. 11 
14.2 
Measures for Issues or Questions ......................................................................................................... 11 
 
Appendix Observation Schedule  ............................................................................................................................ 12 

 
1 
 
1.0 
Background 
Nesina tablets (hereinafter, Nesina) are dipeptidyl peptidase-4inhibitors (hereinafter, 
DPP-4inhibitors) and oral hypoglycemic drugs mainly characterized by glucose level-dependent 
insulin secretion promotion via a GLP-1 increase and pancreas protection. Since oral 
hypoglycemic drugs have been generally used for a long period in patients and since multiple 
hypoglycemic drugs may be used simultaneously, it is important that long-term results of oral 
hypoglycemic drugs should be obtained from a daily clinical practice. The Specified Drug-use 
Survey of Nesina has been conducted in type 2 diabetes mellitus patients who have had an 
inadequate response to diet/exercise therapies only or diet/exercise therapies plus α-glucosidase 
inhibitors, thiazolidines, sulfonylureas, or biguanides. In the future, the specified drug-use 
survey of complication with Nesina and insulin preparations and insulin secretagogues is also 
expected to be conducted. 
Therefore, the Nesina Tablets Specified Drug-use Survey "Type 2 Diabetic Patients Receiving 
Combination Therapy With a Hypoglycemic Agent (e.g., Insulin Preparations or Rapid-acting 
Insulin Secretagogues)” (hereinafter, this survey) is planned aiming to evaluate the safety and 
efficacy of Nesina when administered for 1 year in type 2 diabetic patients who have had an 
inadequate response to hypoglycemic agents (e.g., insulin preparations, rapid-acting insulin 
secretagogues) in addition to dietary/exercise therapy in daily medical practice. 
This survey is conducted according to the relevant regulatory requirements including the GPSP 
ordinance. 
 
2.0 
Objectives 
This survey is designed to evaluate the safety and efficacy of long-term use of alogliptin tablets 
(Nesina Tablets) in type 2 diabetic patients who have had an inadequate response to 
hypoglycemic agents (e.g., insulin preparations or rapid-acting insulin secretagogues)* in 
addition to dietary/exercise therapy in daily medical practice. 
*Hypoglycemic agents which have not been used in the past Nesina Specified Drug-use Survey (i.e., other 
than α-glucosidase inhibitors, thiazolidines, sulfonylureas, and biguanides) 
 
3.0 
Number of Planned Participants and the Rationales 
3.1 
Number of Planned Participants 
1,000 participants 
 
3.2 
Rationales 
The Specified Drug-use Survey of Nesina has been conducted in type 2 diabetes mellitus 
patients who have had an inadequate response to diet/exercise therapies only or diet/exercise 
therapies plus α-glucosidase inhibitors, thiazolidines, sulfonylureas, or biguanides. In the future, 
the specified drug-use survey of complication with Nesina and insulin preparations and insulin 

 
2 
 
secretagogues is also expected to be conducted. 
Therefore, the planned participants was established as 1,000 to collect as many as participants 
who receive a long-term complication therapy with Nesina and these hypoglycemic agents (e.g., 
insulin preparations, rapid-acting insulin secretagogues). 
In the pooled tabulation of participants in the past Nesina Specified Drug-use Survey (as of 
November 30, 2013; Safety Analysis Set, 10,025 participants), the proportion of participants was 
as follows: elderly, 58.0%; renal impairment participants, 15.1%; and hepatic impairment 
participants, 13.3%. By establishment of the planned participants of 1,000 in this survey, data 
will be collected from approximately 600 elderly participants, approximately 150 renal 
impairment participants, and approximately 100 hepatic impairment participants. This 
establishment is not based on the statistical evidence. 
 
4.0 
Patients for Survey 
Patients with type 2 diabetes mellitus. However, participants must meet the inclusion criteria and 
none of the exclusion criteria, described below. Refer to the Precaution in the package insert. 
4.1 
Inclusion Criteria 
Patients who meet the following criterion are included in this survey: 
Patients who have had an inadequate response to the following medications/therapies: 
 
Use of one hypoglycemic agent such as insulin preparations and rapid-acting insulin 
secretagogues, excluding other types of hypoglycemic agents (e.g., α-glucosidase inhibitors, 
thiazolidines, sulfonylureas, biguanides)*, in addition to dietary/exercise therapy 
*For use of Nesina Tablets in combination with these agents, a specified drug-use survey is currently 
ongoing. 
 
4.2 
Exclusion Criteria 
Patients who meet any of the following criteria are excluded from this survey:  
Patients with contraindications for Nesina Tablets 
(1) 
Those with severe ketosis, in a state of diabetic coma or precoma, or with type 1 
diabetes mellitus [Quickly rectifying hyperglycemia with administration of intravenous 
fluid or insulin is essential in these patients; therefore, administration of Nesina Tablets 
is not appropriate.] 
(2) 
Those with severe infections, before or after surgery, or with serious trauma [Controlling 
blood glucose with an injection of insulin is desirable for these patients; therefore, 
administration of Nesina Tablets is not appropriate.] 
(3) 
Those with a history of hypersensitivity to any of the ingredients of Nesina Tablets 
 
5.0 
Dosage and Administration 
For adults, 25 mg of alogliptin is usually administered orally once daily. Refer to the Precaution 

 
3 
 
in the package insert. For renal impairment patients, refer to the Precaution with Respect to 
Dosage and Administration in the package insert. 
 
6.0 
Number of Scheduled Sites by Department 
Internal medicine or other department: Approximately 200 sites 
 
7.0 
Methods 
7.1 
Observation period 
12 months 
 
7.2 
Request for Sites and Agreement 
The survey is conducted using the paper survey sheet. Before asking survey, the parson in charge 
of medical information in Takeda Pharmaceutical Company Limited. (Hereinafter, Takeda MRs) 
will fully explain to the Investigator about the objectives, details, and methods of this survey, 
based on “Request for Cooperation of Specified Drug-use Survey,” “Summary for Survey,” 
“Patient Enrollment Sheet (sample),” and “Survey Sheet (sample)” and will finalize written 
agreement with survey sites to ask requests for surveillance within the specified period. 
 
7.3 
Patient Enrollment Methods patients 
This survey is conducted by Fax using Central Enrollment System. The Investigator will enroll 
patients for whom Nesina was prescribed after the start date of agreement with a survey site, by 
faxing to the Central Enrollment Center (refer to Section 12.2) the “Patient Enrollment Sheet” 
including the information regarding patient enrollment (refer to Section 9.1) before 14 days after 
the Nesina prescription date (define the prescription date as “0 day” and one day after the 
prescription date as “1 day”). Patients for whom Nesina prescription is scheduled cannot be 
enrolled earlier. The participant who assessed as ineligible for the survey for any reason cannot 
be enrolled in the survey. The Investigator will enroll a new participant using the “Patient 
Enrollment Sheet” supplied by the Takeda MR. The Takeda MR will supply for the Investigator 
the survey sheet issued after the Central Enrollment Center enrolled the participant. 
 
7.4 
Creation and Submission of Survey Sheet 
The Investigator will create the survey sheet for all enrolled participants and submit it to the 
Takeda MR around within 1 month after the end of the observation period. If Nesina 
administration cannot be confirmed, specify it (do not specify other columns). 
For participants who early discontinue treatment with Nesina during the observation period for 
any reason, the Investigator will create the survey sheet for him/her and submit it to the Takeda 
MR around within 1 month after the end of necessary observation. However, for participants 
who early discontinue treatment with Nesina due to an adverse event, the Investigator will 

 
4 
 
continue observation even after treatment discontinuation, wherever possible, until the adverse 
event resolve or is resolving and will create the survey sheet and submit it to the Takeda MR. 
 
7.5 
Measures for Development of Serious Adverse Events 
In case of development of a serious adverse event in the observation period, the Investigator will 
immediately contact the Takeda MR. If the Takeda MR requests additional detailed information, 
the Investigator will provide it. 
 
8.0 
Scheduled Period 
Survey period: June 2014 to November 30, 2016 
Patient enrollment period: June 2014 to November 30, 2015* 
*Even if Nesina is prescribed before November 30 2015, the patients cannot be enrolled (fax of the Patient 
Enrollment Sheet) after December 1 2015. 
In case that the enrolled participants reach the scheduled number of participants in the survey before 
November 30 2015, the enrollment will close earlier than the scheduled patient enrollment period. If patient 
enrollment period is shorten, the survey period will be also changed according to the shorten period. 
9.0 
Matters to be Surveyed 
The Investigator will describe the data described below in the Patient Enrollment Sheet and the 
survey sheet. The schedule of this survey is shown in the Appendix. 
9.1 
Description Details in Patient Enrollment Sheet 
1) Matters to be surveyed 
Name of survey site, name of the investigator who describe in the Patient Enrollment Sheet, 
Nesina prescription date, Patient ID Number, patient initial, sex, birth date, inclusion criteria 
assessment, and exclusion criteria assessment 
2) Survey period 
At patient enrollment 
 
9.2 
Description Items in Survey Sheet 
9.2.1 Front Cover of Survey Sheet 
Last description date in the survey sheet and name of the Investigator who described the survey 
sheet 
 
9.2.2 Patient Demographics 
1) Matters to be surveyed 
Diagnosis period of type 2 diabetes mellitus, category of clinical practice, disposition of 
hypersensitivity (yes/no and detail), concurrent disease (yes/no and detail), past medical 
history (yes/no and detail), height, smoking history, drinking history, presence or absence of 
serum creatinine within 1 month after the start of Nesina treatment, serum creatinine level (if 

 
5 
 
serum creatinine present), and severity of renal impairment and rationale for the assessment 
(if serum creatinine absent). 
2) Survey period 
At the start of Nesina treatment 
 
9.2.3 
Details of Treatment 
1) Matters to be surveyed 
Details of Nesina treatment (daily dose, administration period, and reason for 
discontinuation), and status of concomitant medications* (hypoglycemic agents) (yes/no, 
drug name, daily dose, route of administration, administration period, and objective of 
administration) 
*Hypoglycemic agents which are discontinued within 3 months prior to Nesina treatment are included. 
2) Survey period 
Period from the start of Nesina treatment to 12 months after treatment (or treatment 
discontinuation) 
 
9.2.4 
Compliance with Nesina and Compliance with Diet/Exercise Therapy 
1) Matters to be surveyed 
Compliance with Nesina* and compliance with diet/exercise therapy** 
 
 
*Criteria for assessment of compliance with Nesina 
1. ≥ 90% (A participant won’t miss administration, or even if he/she missed 
administration, the frequency is twice or three times a month.) 
2. ≥ 70% (A participant missed administration once or twice weekly.) 
3. ≥ 50% (A participant missed administration three times a week.) 
4. < 50% (A participant missed administration four times or more a week.) 
 
**Criteria for assessment of compliance with diet/exercise therapy 
1. ≥ 90% (A participant complied as instructed.) 
2. ≥ 70% (A participant mostly complied as instructed.) 
3. ≥ 50% (A participant did not complied well as instructed.) 
4. < 50% (A participant did not mostly complied as instructed.) 
5. Not performed 
6. Unknown 
 
2) Survey period 
At the start of Nesina treatment (compliance with diet/exercise therapy only), 1 month, 3 

 
6 
 
months, 6 months, and 12 months after the start of treatment (or treatment discontinuation) 
 
9.2.5 
Laboratory/Observation Parameters 
9.2.5.1 Vital Signs 
1) Laboratory/observation parameters 
Pulse rate, blood pressure (systolic/diastolic), and weight 
2) Survey period 
Each time point at the start of Nesina treatment, 1 month, 3 months, 6 months, and 12 months 
after the start of treatment (or treatment discontinuation) 
 
9.2.5.2 Laboratory Values 
1) Laboratory parameters 
HbA1c (NGSP value, same hereafter), fasting glucose, fasting insulin, fasting glucagon, 
fasting triglyceride, total cholesterol, HDL-cholesterol, LDL-cholesterol, serum creatinine, 
BUN, urinary albumin (corrected by creatinine), AST, ALT, γ-GTP, ALP, total bilirubin, 
amylase, and lipase 
2) Survey period 
Each time point at the start of Nesina treatment, 1 month, 3 months, 6 months, and 12 months 
after the start of treatment (or treatment discontinuation) 
 
9.2.5.3 Electrocardiography 
1) Observation Parameters 
Electrocardiograms (assessment and findings) 
2) Survey period 
Each time point from the start of Nesina treatment to 12 months after treatment (or treatment 
discontinuation) 
 
9.2.5.4 Tests for Waist Circumference, Coronary Arteriosclerosis, and Arteriosclerosis 
1) Observation Parameters 
Tests for waist circumference,* coronary arteriosclerosis and arteriosclerosis** (e.g., pulse 
wave velocity, cardio-ankle vascular index, intima-media thickness, intra-vascular 
ultrasound) 
*Measure the waist diameter during light expiration at standing position and at the level of the navel. If the 
lower deviation of the navel occurs because of significant abdominal fat accumulation, measure the waist 
diameter at the level of the midpoint between the inferior rib border and anterior superior iliac spine. 
**Any methods can be used. In principle, however, use the same methods for each test. If there are no 
devices for measurement, the tests can be omitted. 
2) Survey period 

 
7 
 
Each time point from the start of Nesina treatment to 12 months after treatment (or treatment 
discontinuation) 
 
9.2.5.5 Other Parameters 
1) Observation parameters 
Pregnancy during the observation period (yes or no) (females only) 
In case of pregnancy in the observation period, the Investigator will immediately contact the 
Takeda MR. The Investigator will provide detailed information (including the information 
until the delivery, as possible, such as preterm delivery) using the separate pregnancy sheet 
after the request from the Takeda MR. 
2) Survey period 
Period from the start of Nesina treatment to 12 months after treatment (or treatment 
discontinuation) 
 
9.2.6 
Adverse Event 
1) Matters to be surveyed 
Presence or absence of adverse events (refer to Table 1), term of adverse events, onset date, 
seriousness and the reason (refer to Table 2), presence or absence of Nesina discontinuation, 
outcome assessment date, outcome, and causal relationship to Nesina* (refer to Table 3). 
If the outcome is assessed as Not resolved or Unknown and if the causal relationship cannot 
be assessed, the participant will be followed up, wherever possible. 
The detailed information (e.g., clinical course, laboratory tests for diagnosis) will be collected 
as possible for development of hypoglycemia, acute pancreatitis, renal impairment / jaundice, 
skin disorder including oculomucocutaneous syndrome (Stevens-Johnson syndrome) and 
erythema multiforme, rhabdomyolysis, intestinal obstruction, interstitial pneumonia, 
angioedema, infection, malignant tumor, and cardiovascular system-related event (e.g., 
symptomatic coronary artery disease, cerebrovascular disorder, arteriosclerosis obliterans, 
cardiovascular death, sudden death) 
*If the causal relationship to Nesina is assessed as Not related, collect the rationales for assessment. If the 
relationship is assessed as Not assessable, collected the reason for Not assessable. 
 
Note) Matters that should be considered for adverse events 
Abnormal exacerbation of the target disease, i.e., worsening beyond expected natural 
clinical course, is defined as an adverse event; however, the expected worsening is not 
defined as an adverse vent. 
2) Survey period 
Period from the start of Nesina treatment to 12 months after treatment (or treatment 
discontinuation) 
 

 
8 
 
Table 1 Definition of adverse event 
An adverse event (AE) is defined as any unfavorable event that develops after a pharmaceutical 
product is administered and which does not necessarily have a causal relationship with treatment.  
An adverse event can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding, for example), symptom, or disease temporally associated with the use of a 
medicinal product, whether or not considered related to the medicinal product. 
The following events will be handled as adverse events: 
• Symptoms present in infants breastfed by a Nesina taking mother 
• Symptoms present in children who received the relevant drug 
• Symptoms due to occupational exposure to the relevant drug 
• Symptoms due to counterfeit medications of the legitimate medicinal products manufactured by 
Takeda 
 
Table 2 Criteria for severity assessment 
An event which meet any of the following criteria will be assessed as “Serious:” 
1. Results in death (death). 
2. Is life-threatening (potential death threat). 
3. Requires inpatient hospitalization or prolongation of existing hospitalization (admission / prolonged 
hospitalization). 
4. Results in persistent or significant disability/incapacity (disability). 
5. Is a congenital anomaly/birth defect (congenital anomaly). 
6. Other significant medical conditions which do not meet the above criteria 1 to 5. Events listed in the 
“Takeda Medically Significant AE List are included in this section criteria. 
 
Takeda Medically Significant AE List 
• Acute respiratory failure / acute respiratory distress 
syndrome (ARDS) 
• Anaphylactic shock 
• Torsade de pointes / ventricular fibrillation / 
ventricular tachycardia 
• Acute renal failure 
• Malignant hypertension 
• Pulmonary hypertension 
• Convulsive seizure (including convulsion and 
epilepsy) 
• Pulmonary fibrosis (including interstitial 
pneumonia) 
• Agranulocytosis 
• Malignant syndrome / malignant hyperthermia 
• Aplastic anemia 
• Spontaneous abortion / stillbirth and fetal 
death 
• Toxic epidermal necrolysis / oculomucocutaneous 
syndrome (Stevens-Johnson syndrome) 
• Spread of infection via drug or suspected 
spread 
• Hepatic necrosis 
• Endotoxic shock or suspected endotoxic 
shock 
• Acute hepatic failure 
suspected endotoxic shock 

 
9 
 
Table 3 Criteria for causality assessment between adverse events and Nesina 
Assessment 
Assessment criterion 
Related 
Temporally correlation (including the post-treatment clinical course) present. Or an 
adverse event that may have been caused by the primary disease, concurrent disease, 
concomitant medication, or other factor including concomitant procedures, but also 
suggested to be caused by the relevant drug. 
Not related 
No temporally correlation with the relevant drug. Or an adverse event presumably 
caused by the primary disease, concurrent disease, concomitant medication, or other 
factor. 
Not 
assessable 
Lack of information for assessment of temporal correlation (including the post-treatment 
clinical course), the primary disease, concurrent disease, concomitant medication, other 
factor, etc. 
 
10.0 
Analysis Parameters and Methods 
10.1 Patient Component Parameters 
The following will be tabulated: number of enrolled participants, number of survey sheet 
collected participants, number of the Safety Analysis Set, number of the Efficacy Analysis Set, 
and number of patients excluded from analysis and the reason for exclusion, etc. 
 
10.2 Patient Demographics 
Patient demographics including sex, age, disease period, hypersensitivity predisposition, and 
concurrent disease will be tabulated. 
 
10.3 Details of Treatment 
The following will be tabulated: status of Nesina treatment, status of concomitant medications, 
and compliance with Nesina treatment, etc. 
 
10.4 Safety Parameters 
The items described below will be tabulated in the Safety Analysis Set. Adverse events will be 
coded using the MedDRA/J and summarized by Preferred Term (PT) and System Organ Class 
(SOC). 
10.4.1 Occurrence of Adverse Events 
For adverse events reported in the observation period, the type and causal relationship to 
Nesina will be tabulated. 
 
10.4. 2 Factors Probably Affecting Safety 
For adverse drug reactions reported in the observation period, the frequency of patient 
demographics (e.g., sex, age), details of treatment (e.g., status of Nesina, and status of 

 
10 
 
concomitant medications) will be stratified. 
 
10.5 Efficacy Parameters 
The following will be tabulated in the Efficacy Analysis Set: 
10.5.1 Change in HbA1c 
HbA1c test values and the corresponding change from baseline at each testing time point (i.e., 
test value at each testing time point − test value at baseline) will be tabulated. In addition, the 
objective glycemic control achievement rate at each testing time point will be tabulated. 
 
10.5.2 Changes in Laboratory Test Values 
Test values (fasting blood glucose level, fasting insulin level, HOMA-R,* and HOMA-β*) 
and the corresponding changes from baseline at each testing time point (i.e., test value at each 
testing time point − test value at baseline) will be tabulated. 
*HOMA-R: Fasting insulin × Fasting glucose / 405 
**HOMA-β: (Fasting insulin × 360) / (Fasting glucose − 63) 
 
10.5.3 Factors Probably Affecting Efficacy 
For the changes in HbA1c and glycemic control achievement rate at 12 months after the start 
of treatment, the following will be stratified: patient demographics (e.g., sex, age, HbA1c at 
the start of Nesina treatment) and details of treatment (e.g., status of Nesina treatment, status 
of concomitant medications). 
 
10.6 Parameters in Patients with Special Demographics 
The safety and efficacy of Nesina will be stratified in elderly patients or patients with 
hepatic/renal impairment. 
 
11.0 
Registration of Survey Data 
Takeda Pharmaceutical Company Limited. will register the survey information in the 
ClinicalTrials.gov and an open website (JAPIC-CTI*) before the start of this survey. 
*Japan Pharmaceutical Information Center-Clinical Trials Information 
 
12.0 
Organizations 
12.1 Manager 
 Takeda Pharmaceutical 
Company Limited. 
 
 
PPD
PPD

 
11 
 
12.2 Central Enrollment Center 
 
13.0 
CRO 
 
14.0 
Other Necessary Matters 
14.1 Protocol Revision 
During the survey period, the protocol can be reviewed and revised, if the following are 
necessary to be changed after monitored: the survey progress, adverse drug reactions / serious 
adverse drug reactions unexpected from the Precautions, increased frequency of specified 
adverse drug reactions (yes or no), and parameter appropriateness. During the survey period, if 
partly changes of dosage and administration and indications are approved, the protocol revision 
will be also considered and performed as necessary. 
 
14.2 Measures for Issues or Questions 
If any question about the safety or efficacy is arisen, data will be investigated and the relevant 
persons will take measures for the question. 
 
 
PPD
PPD

 
12 
 
Appendix Observation Schedule 
 
Survey period 
 
 
Parameter 
Observation period 
At patient 
enrollment 
 
 
At start of 
treatment 
 
1 months after 
treatment 
 
3 months after 
treatment 
 
6 months after 
treatment 
 
12 months after 
treatment 
 
At treatment 
discontinuation 
 
Patient enrollment 
Nesina prescription date 
○ 
 
 
 
 
 
 
Patient ID Number 
○ 
Patients initial 
○ 
Sex 
○ 
Birth date 
○ 
Inclusion criteria / exclusion criteria 
○ 
 
 
 
 
 
 
At patient demographics 
 
Diagnosis period of type 2 diabetes mellitus 
○ 
 
 
 
Category of clinical practice 
○ 
 
 
 
 
Hypersensitivity predisposition 
○ 
 
 
 
 
Concurrent disease 
○ 
 
 
 
 
Past medical history 
○ 
 
 
 
 
Height 
○ 
 
 
 
Smoking history 
 
○ 
 
 
 
 
Drinking history 
 
○ 
 
 
 
 
Presence or absence of serum creatinine within 1 
month after the start of Nesina treatment, serum 
creatinine level (if serum creatinine present), and 
severity of renal impairment and rationale for the 
assessment (if serum creatinine absent). 
 
○ 
 
 
 
 
 
Details 
of 
treatment, etc. 
Status of Nesina treatment 
○ 
○ 
Status 
of 
concomitant 
medication 
treatment
(hypoglycemic agents / other than hypoglycemic
agents) 
 
○ 
○ 
Status of compliance with Nesina 
○ 
○ 
○ 
○ 
○ 
Status of compliance with diet/exercise therapy 
○ 
○ 
○ 
○ 
○ 
○ 
Laboratory/Observation Parameters, etc 
Pulse rate, blood pressure 
○ 
○ 
○ 
○ 
○ 
○ 
Weight 
○ 
○ 
○ 
○ 
○ 
○ 
Laboratory values 
• HbA1c (NGSP value) 
• Fasting glucose 
• Fasting insulin 
• Fasting glucagon 
• Fasting triglyceride 
• Total cholesterol 
• HDL-cholesterol 
• LDL-cholesterol 
• Serum creatinine 
• BUN 
• Urinary albumin (corrected by creatinine) 
• AST 
• ALT 
• γ-GTP 
• ALP 
• Total bilirubin 
• Amylase 
• Lipase 
 
○ 
○ 
○ 
○ 
○ 
○ 
Electrocardiogram 
○ 
 
 
 
○ 
○ 
Waist circumference 
○ 
○ 
○ 
Tests 
for 
coronary 
arteriosclerosis 
and 
arteriosclerosis 
 
○ 
 
 
 
○ 
○ 
Pregnancy (yes or no) (females only) 
 
○ 
○ 
Adverse event 
○ 
○ 
○ 
:To be performed 

 
13 
 
 ○ 
:To be performed throughout the period