Alogliptin (Nesina) Tablets Special Drug Use Surveillance: Mild Type 2 Diabetes Mellitus
Conditions: Type 2 Diabetes Mellitus
Sponsor: Takeda

 
 
Title: Nesina Tablets Special Drug Use Surveillance: Mild Type 2 Diabetes Mellitus 
 
NCT Number: NCT01964963 
Protocol Approve Date: 02-Mar-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 Special Drug Use Surveillance: Mild 
Type 2 Diabetes Mellitus 
 
 
 
 
 
 
 
 
 
 
Version 
Fifth version 
Creation date 
March 2, 2017 
Sponsor 
Takeda Pharmaceutical Company Limited. 
 

 
Table of Contents 
1.0 
Surveillance Background ............................................................................................................................... 1 
2.0 
Objectives of Surveillance.............................................................................................................................. 1 
3.0 
Number of Planned Patients for Surveillance and the Rationales .................................................................. 2 
3.1 
Number of Planned Patients for Surveillance......................................................................................... 2 
3.2 
Rationales ............................................................................................................................................... 2 
4.0 
Patients for Surveillance ................................................................................................................................. 2 
4.1 
Inclusion Criteria .................................................................................................................................... 2 
4.2 
Exclusion Criteria ................................................................................................................................... 2 
5.0 
Dosage and Administration for Patients to be Surveyed ................................................................................ 3 
6.0 
Number of To-be Survey Sites by Department .............................................................................................. 3 
7.0 
Survey Methods.............................................................................................................................................. 3 
7.1 
Observation Period ................................................................................................................................. 3 
7.2 
Request for Sites and Agreement ........................................................................................................... 3 
7.3 
Methods for Registration of Patients to be Surveyed ............................................................................. 3 
7.4 
Entry on Survey Sheet (Electronic) and Electronic Signature................................................................ 3 
7.5 
Measures for Development of Adverse Events ...................................................................................... 4 
8.0 
Scheduled Survey Period ............................................................................................................................... 4 
9.0 
Matters to be Surveyed ................................................................................................................................... 4 
9.1 
Patient Registration Data ........................................................................................................................ 4 
9.2 
Survey sheet: patient demographic data ................................................................................................. 5 
9.3 
Survey sheet: details of treatment........................................................................................................... 5 
9.4 
Laboratory/Observation Parameters ....................................................................................................... 5 
9.5 
Adverse Event ........................................................................................................................................ 5 
10.0 
Analysis Parameters and Methods ................................................................................................................. 8 
10.1 
Patient Component Parameters .............................................................................................................. 8 
10.2 
Patient Demographics............................................................................................................................. 8 
10.3 
Details of Treatment ............................................................................................................................... 8 
10.4 
Safety Parameters ................................................................................................................................... 8 
 
Occurrence of Adverse Drug Reactions ............................................................................................. 8 
10.4.1
 
Factors Probably Affecting Safety ...................................................................................................... 8 
10.4.2
10.5 
Efficacy Parameters ................................................................................................................................ 8 
 
Changes in HbA1c over Time ............................................................................................................ 8 
10.5.1
 
Factors Probably Affecting Efficacy .................................................................................................. 8 
10.5.2
10.6 
Parameters in Patients with Special Demographics ............................................................................... 9 
10.7 
Interim Analysis ..................................................................................................................................... 9 
11.0 
Surveillance Organizations ............................................................................................................................. 9 
11.1 
Investigator ............................................................................................................................................. 9 
12.0 
Name and address of CRO and Scope of the CRO Task ................................................................................ 9 
13.0 
Other Necessary Matters ................................................................................................................................ 9 

 
13.1 
Revision of the Protocol ......................................................................................................................... 9 
13.2 
Measures for Issues or Questions ........................................................................................................... 9 
 
Appendix Surveillance Schedule.............................................................................................................................. 10 
 

 
1 
1.0 
Surveillance Background 
The goal of diabetes mellitus treatment is to maintain patients’ QOLs as those in healthy 
people and to secure their lifetimes through management for a favorable blood glucose level 
for a long time. In particular, early drug treatment is considered important for patients with 
mild type 2 diabetes mellitus, which maintains a favorable blood glucose level and inhibits the 
diabetes progress, along with prevention of microangiopathy. 
As an oral drug started to be administered early to patients with mild type 2 diabetes mellitus, 
the desirable drug should have a low risk of hypoglycemia, be well tolerable, and not exhaust 
pancreatic function. 
DPP-4 inhibitors selectively inhibit DPP-4, increase blood GLP-1 levels, and prompt the 
pancreas to secrete insulin in a glucose level-dependent manner. Taken together, DPP-4 
inhibitors are expected to be highly effective for patients with mild type 2 diabetes mellitus. 
As a DPP-4 inhibitor, Nesina tablets (generic name: alogliptin benzoate) are confirmed to be 
highly effective and safe when administered alone and combined with various oral diabetic 
drugs in clinical studies conducted in Japan. The following are approved indications for 
Nesina: 
 
Indications for Nesina tablets 
Type 2 diabetes mellitus 
However, this indication is limited only for patients who had an insufficient response to the 
following therapies: 
(1) Only diet and exercise therapies. 
(2) α-glucosidase inhibitors used in addition to diet and exercise therapies. 
(3) Thiazolidines used in addition to diet and exercise therapies. 
(4) Sulfonylureas used in addition to diet and exercise therapies. 
(5) Biguanides used in addition to diet and exercise therapies. 
 
However, the efficacy and safety of Nesina has not been well evaluated for patients with mild 
type 2 diabetes mellitus because Nesina tablets have been administered to type 2 diabetes 
mellitus patients with HbA1c of ≥ 6.5% (for patients treated with sulfonylureas, HbA1c of ≥ 
7.0%) in clinical studies conducted before drug approval. 
Therefore, this Special Drug Use Surveillance (hereinafter, the Surveillance) was planned to 
evaluate the long-term safety and efficacy of Nesina tablets (hereinafter, Nesina) for patients 
with mild type 2 diabetes mellitus patients in a daily clinical practice. 
 
2.0 
Objectives of Surveillance 
To examine the safety and efficacy of long-term treatment with alogliptin (Nesina) in patients 
with mild type 2 diabetes mellitus in the routine clinical setting. 
 

 
2 
3.0 
Number of Planned Patients for Surveillance and the Rationales 
3.1 Number of Planned Patients for Surveillance 
20000 patients 
 
3.2 Rationales 
According to database of 16 hospitals in Japan, supplied by 
., of 
142358 patients documented as visited from October to December 2010, 15141 were patients 
with type 2 diabetes mellitus. Of these, 4165 patients had HbA1c (JDS) of ≤ 7.0%, which 
were the target population in this Surveillance. For patients with indications for Nesina, in 
addition, 1864 patients (70.4%) received only diet and exercise therapies (no diabetic drugs); 
226 patients (8.5%) received α-glucosidase inhibitors; 175 patients (6.6%) received 
thiazolidines; 273 patients (10.3%) received sulfonylureas; 109 patients (4.1%) received 
biguanides (each drug was administered alone). 
 
In order to identify adverse drug reactions with a frequency of ≥ 0.5% using ≥ a 95% 
confidence level, 600 patients will be required. Assuming that the proportion of drugs in 
patients with mild type 2 diabetes mellitus is same as the above, if data in 20000 patients with 
mild type 2 diabetes mellitus are collected in this Surveillance, 14084 patients will be required 
for Nesina treatment alone; 1708 patients will be required for combination with α-glucosidase 
inhibitors; 1322 patients will be required for combination with thiazolidines; 2063 patients 
will be required for combination with sulfonylureas; 824 patients will be required for 
combination with biguanides. Since any combination can identify the adverse drug reactions 
with a frequency of ≥ 0.5% using ≥ a 95% confidence level, the number of planned patients 
for surveillance was established as 20000. 
 
4.0 
Patients for Surveillance 
Patients with mild type 2 diabetes mellitus will be evaluated for this Surveillance. However, 
patients must meet the inclusion criteria and none of the exclusion criteria, described below. 
Refer to the Precaution with Respect to Indication in the package insert. 
4.1 Inclusion Criteria 
Patients who meet the following criterion will be included in this Surveillance: 
(1) Patients with HbA1c (JDS value) ≤7.0% at the time of enrolment (within 3 months 
before initiation of Nesina therapy) 
* Regardless of the use of antidiabetic medication 
 
4.2 Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from this Surveillance: 
(1) Patients with severe ketosis, diabetic coma or precoma, or type 1 diabetes mellitus 
(2) Patients with severe infection, pre- or post-operative patients, or patients with serious 
traumatic injury 
PPD

 
3 
(3) Patients with a history of hypersensitivity to any ingredient of Nesina 
 
5.0 
Dosage and Administration for Patients to be Surveyed 
The usual adult dose of alogliptin is 25 mg administered orally once daily. Refer to the 
Precaution with Respect to Dosage and Administration in the package insert. 
 
6.0 
Number of To-be Survey Sites by Department 
Internal medicine or other department: Approximately 1000 sites 
 
7.0 
Survey Methods 
7.1 Observation Period 
The observation period will be 36 months after the start date of Nesina treatment. 
If Nesina treatment is discontinued for any reason, the survey will be ended at the 
discontinuation. 
 
7.2 Request for Sites and Agreement 
This surveillance will be conducted using the electronic data collection system via web 
(
 Before asking survey, MRs of Takeda Takeda Pharmaceutical Company Limited. 
(Hereinafter, Takeda MRs) will fully explain to the Investigator about the objectives, details, 
handling methods for 
 and handling of electronic signature, user ID, and 
passwords, based on “Request for Cooperation of Special Drug Use Surveillance,” “Summary 
for Surveillance,” “Entry Screen Images,” and “Brief Manual for Handling of 
 and 
will finalize written agreement with survey sites to ask requests for surveillance within the 
specified period. 
 
7.3 Methods for Registration of Patients to be Surveyed 
This Surveillance will be conducted using Central Registration System with 
 The 
Investigator will enter registration data on 
 (refer to Section 9.1) for patients who 
start Nesina treatment after the start date of agreement with a survey site, before 14 days after 
the start date of Nesina treatment (define the start date of treatment as “0 day” and one day 
after the start date of treatment as “1 day”). 
 
7.4 Entry on Survey Sheet (Electronic) and Electronic Signature 
The Investigator will enter patient demographic data and details of treatment on 
 at 
each data entry time point (at the start of Nesina treatment, 3 months, 6 months, 12 months, 18 
months, 24 months, 30 months, and 36 months after the start of Nesina treatment or treatment 
discontinuation). In addition, the Investigator will sign electronically on the survey sheet in 
 for “Patient Demographic Data and Details of Treatment by 12 Months of 
Treatment” after 12 months of treatment and for Patient Demographic Data and Details of 
Treatment by 36 Months of Treatment” after 36 months of treatment. 
CCI
CCI
CCI
CCI
CCI
CCI
CCI

 
4 
For patients who discontinue treatment with Nesina during the observation period for any 
reason, the Investigator will enter the patient demographic data and details of treatment on 
 and will sign electronically in the survey sheet around within 1 month after the end 
of necessary observation. However, for patients who discontinue treatment with Nesina due to 
an adverse event, the Investigator will continue observation after treatment discontinuation, 
wherever possible, until the adverse event resolve or is resolving and will enter the 
observation results on 
 as well as sign electronically in the survey sheet. 
In case that additional survey is required after Takeda checked the details, Takeda will ask 
request for re-survey on 
 The Investigator will check the details of request for 
re-survey and enter the re-survey results on 
 as well as sign electronically in the 
survey sheet. 
 
7.5 Measures for Development of Adverse Events 
In case of development of an adverse event, the Investigator will contact the person in charge 
of Takeda Pharmaceutical Company Limited (hereinafter, the person in charge of Takeda). If 
the person in charge of Takeda requests additional detailed information, the Investigator will 
provide it. 
 
8.0 
Scheduled Survey Period 
Survey period: July 2011 to July 31, 2017 
Patient registration period: July 2011 to July 31, 2013Note) 
Due date for entry of “Patient Data and Details of Treatment by 12 Months of Treatment:” 
August 31, 2014 
Due date for entry of “Patient Data and Details of Treatment by 36 Months of Treatment:” July 
31, 2017 
 
Note) Patients who will be treated with Nesina by July 31, 2013 can be registered. 
In case that the registered patients reach the scheduled number of patients to be surveyed 
before July 31 2013, the registration will close earlier than scheduled. 
 
9.0 
Matters to be Surveyed 
The Investigator will enter data of the parameters described below on 
 The 
schedule of this surveillance is shown in the Appendix. 
9.1 Patient Registration Data 
1) Matters to be surveyed 
Start date of Nesina treatment, Patient ID Number, patient initial, sex, birth date, HbA1c 
(JDS) within 3 months prior to Nesina treatment, inclusion criteria assessment, and 
exclusion criteria assessment 
2) Survey period 
At patient registration 
 
CCI
CCI
CCI
CCI
CCI

 
5 
9.2 Survey sheet: patient demographic data 
1) Matters to be surveyed 
Diagnosis period of type 2 diabetes mellitus, height, practice category (at the start of 
survey), presence or absence of pregnancy (females only), pregnancy week (if applicable), 
severity of renal impairment, rationale for assessment of the severity of renal impairment, 
concurrent disease, prior medical history, alcohol history, smoking history, and presence or 
absence of dietary intervention / exercise intervention 
2) Survey period 
At the start of Nesina treatment 
 
9.3 Survey sheet: details of treatment 
1) Matters to be surveyed 
Details of Nesina treatment (daily dose and administration period), status of end of Nesina 
treatment, reason for Nesina discontinuation (if applicable), details of other diabetic drug 
treatment* (drug name, daily dose, route of administration, and administration period), and 
status of concomitant medications (other than diabetic drugs) (drug name, route of 
administration, administration period, and objectives of administration) 
* Diabetic drugs which are discontinued within 3 months prior to Nesina treatment are 
included. 
2) Survey period 
Period from the start of Nesina treatment to 36 months after treatment (or treatment 
discontinuation) 
 
9.4 Laboratory/Observation Parameters 
1) Matters to be surveyed 
HbA1c (JDS, international standard value, or NGSP), fasting glucose, fasting insulin, 
fasting triglyceride, total cholesterol,” HDL-cholesterol, LDL-cholesterol, weight, and 
blood pressure 
2) Survey period 
At the start of Nesina treatment, 3 months , 6 months, 12 months, 18 months, 24 months, 
30 months, and 36 months of treatment (or treatment discontinuation) 
 
9.5 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), procedures related to Nesina, outcome, causal 
relationship to Nesina (refer to Table 3), presence or absence of diabetic complication 
(diabetic retinopathy, diabetic neuropathy, or diabetic nephropathy), change over time in 
clinically important laboratory values related to adverse events 
If the outcome is assessed as Not resolved or Unknown and if the causal relationship cannot 

 
6 
be assessed, the patient will be followed up, wherever possible. The detailed information 
(clinical course, laboratory tests for diagnosis, etc.) will be collected as possible for 
development of hypoglycemia, tumor, pancreatitis, edema, angioedema-related symptom, 
immune system disorder, skin disorder and subcutaneous tissue disorder, cardiovascular 
system event (symptomatic coronary artery disease, cerebrovascular disorder, 
arteriosclerosis obliterans, cardiovascular death, sudden death, etc.) 
2) Survey period 
Period from the start of Nesina treatment to 36 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 in infants breastfed by a Nesina taking mother 
• Symptoms in children who received the relevant drug 
• Symptoms in patients who received the relevant drug at a higher dose than approved or who took by 
themselves 
 

 
7 
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. (e.g., bronchospasm and 
the like, requiring a short-term intensive care in an emergency room and the like) 
 
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 
 
Table 3 Criteria for causality assessment between adverse events and Nesina 
Assessment 
Assessment criterion 
Related 
(Suspectedly related) 
Temporally evident 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 
(Unlikely related) 
No temporally evident 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. 

 
8 
 
10.0 
Analysis Parameters and Methods 
10.1 Patient Component Parameters 
The following will be tabulated: number of registered patients, number of survey sheet 
(electronic) collected patients, number of survey completer, number of survey discontinuations 
and the reason for discontinuation, 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 
The following patient demographics will be tabulated: age, sex, disease period, severity of 
renal impairment (including severity) (yes or no), concurrent disease, past medical history, 
alcohol history, smoking history, etc. 
 
10.3 Details of Treatment 
The following will be tabulated: status of Nesina treatment, status of concomitant medications 
(including the status of diabetic drugs at the start of 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 and summarized by Preferred Term (PT) and System Organ Class 
(SOC). 
 Occurrence of Adverse Drug Reactions 
10.4.1
The type, seriousness, onset period, and the like for adverse drug reactions reported in the 
observation period will be tabulated. 
 
 Factors Probably Affecting Safety 
10.4.2
For adverse drug reactions reported in the observation period, the frequency of patient 
demographics (e.g., age, sex), 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: 
 Changes in HbA1c over Time 
10.5.1
The HbA1c values at each time point and the changes (values at each time point − values at 
the start of Nesina treatment) will be tabulated. The achieving percent in glycemic control 
for HbA1c will be tabulated for each time point. 
 
 Factors Probably Affecting Efficacy 
10.5.2
For the changes in HbA1c and the achieving percent in glycemic control for HbA1c at 36 
months after the start of treatment, the following will be stratified: patients demographics 

 
9 
(e.g., age, sex, 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 
For the safety and efficacy in patients with moderate or higher renal impairment, the 
relationship between the severity of renal impairment and Nesina doses (each will be 
stratified) will be thoroughly evaluated. 
 
10.7 Interim Analysis 
After 1-year observation period is completed in all patients, the interim analysis for the 
parameters described in Sections 10.1 to 10.6 will be performed to confirm the early safety 
and efficacy of Nesina in patients with mild type 2 diabetes mellitus, based on the data entered 
in “Patient Data and Details of Treatment by 12 Months of Treatment.” 
 
11.0 
Surveillance Organizations 
11.1 Investigator 
 Takeda Pharmaceutical Company Limited. 
 
12.0 
Name and address of CRO and Scope of the CRO Task 
 
13.0 
Other Necessary Matters 
13.1 Revision of the Protocol 
During the surveillance period, the protocol can be reviewed and revised, if the following are 
necessary to be changed after monitored: the survey progress, number of dropouts, 
development of 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 surveillance period, if partly changes of dosage and 
administration and indications are approved, the protocol revision will be also considered and 
performed as necessary. 
 
13.2 Measures for Issues or Questions 
If any question about the safety or efficacy is arisen, data will be thoroughly investigated and 
the relevant persons will take measures for the question. 
PPD
PPD

 
10 
Appendix Surveillance Schedule 
 
Survey/data entry time point 
 
 
 
Parameters 
Observation period 
At patient 
registration 
At start of 
treatment 
3 months after 
treatment 
6 months after 
treatment 
12 months 
after treatment 
18 months 
after treatment 
24 months 
after treatment 
30 months 
after treatment 
36 months 
after treatment 
 
At treatment 
discontinuation 
 
Patient registration data 
Start date of Nesina treatment  
○ 
 
 
 
 
 
 
 
 
 
Patient ID Number 
○ 
Patients initial 
○ 
Sex 
○ 
Birth date 
○ 
HbA1c within 3 months prior to Nesina 
treatment 
○ 
 
 
 
 
 
 
 
 
 
Inclusion criteria / exclusion criteria 
○ 
 
 
 
 
 
 
 
Patient demographic data 
Diagnosis period of type 2 diabetes 
mellitus 
 
○ 
 
 
 
 
 
 
 
 
Height 
○ 
 
 
 
 
 
 
 
Category of clinical practice (at start of 
survey) 
 
○ 
 
 
 
 
 
 
 
 
Pregnancy (yes or no) (females only) 
○ 
 
 
 
 
 
 
 
Week of pregnancy (if applicable) 
○ 
 
 
 
 
 
 
 
Severity of renal impairment 
○ 
 
 
 
 
 
 
 
Rationale for severity assessment of renal 
impairment 
 
○ 
 
 
 
 
 
 
 
 
Concurrent disease 
○ 
 
 
 
 
 
 
 
Past medical history 
○ 
 
 
 
 
 
 
Alcohol history 
○ 
 
 
 
 
 
 
Smoking history 
○ 
 
 
 
 
 
 
Dietary/exercise intervention (yes or no) 
 
○ 
 
 
 
 
 
 
 
Details of 
treatment 
Status of Nesina treatment 
○ 
○ 
Status of other diabetic drug 
○ 
○ 
Status of concomitant medication (other
than diabetic drugs) 
 
○ 
○ 
Laboratory/Observation Parameters, 
etc 
Laboratory values 
• HbA1c (JDS, international standard 
value, or NGSP) 
• Fasting glucose 
• Fasting insulin 
• Fasting triglyceride 
• Total cholesterol 
• HDL-cholesterol 
• LDL-cholesterol 
 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
Weight 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
Blood pressure 
○  
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
Adverse event 
○ 
○ 
○ 
Performed 
○ 
Performed throughout the period 
* Including the diabetic drugs discontinued within 3 months prior to the start of Nesina 
 

 
 
 
 
 
Protocol for 
Nesina Tablets Special Drug Use Surveillance: Mild 
Type 2 Diabetes Mellitus 
 
 
 
 
 
 
 
 
 
 
Version 
Fourth version 
Creation date 
June 30, 2016 
Sponsor 
Takeda Pharmaceutical Company Limited. 
 

 
Table of Contents 
1.0 
Surveillance Background ............................................................................................................................... 1 
2.0 
Objectives of Surveillance.............................................................................................................................. 1 
3.0 
Number of Planned Patients for Surveillance and the Rationales .................................................................. 2 
3.1 
Number of Planned Patients for Surveillance......................................................................................... 2 
3.2 
Rationales ............................................................................................................................................... 2 
4.0 
Patients for Surveillance ................................................................................................................................. 2 
4.1 
Inclusion Criteria .................................................................................................................................... 2 
4.2 
Exclusion Criteria ................................................................................................................................... 2 
5.0 
Dosage and Administration for Patients to be Surveyed ................................................................................ 3 
6.0 
Number of To-be Survey Sites by Department .............................................................................................. 3 
7.0 
Survey Methods.............................................................................................................................................. 3 
7.1 
Observation Period ................................................................................................................................. 3 
7.2 
Request for Sites and Agreement ........................................................................................................... 3 
7.3 
Methods for Registration of Patients to be Surveyed ............................................................................. 3 
7.4 
Entry on Survey Sheet (Electronic) and Electronic Signature................................................................ 3 
7.5 
Measures for Development of Adverse Events ...................................................................................... 4 
8.0 
Scheduled Survey Period ............................................................................................................................... 4 
9.0 
Matters to be Surveyed ................................................................................................................................... 4 
9.1 
Patient Registration Data ........................................................................................................................ 4 
9.2 
Survey sheet: patient demographic data ................................................................................................. 5 
9.3 
Survey sheet: details of treatment........................................................................................................... 5 
9.4 
Laboratory/Observation Parameters ....................................................................................................... 5 
9.5 
Adverse Event ........................................................................................................................................ 5 
10.0 
Analysis Parameters and Methods ................................................................................................................. 8 
10.1 
Patient Component Parameters .............................................................................................................. 8 
10.2 
Patient Demographics............................................................................................................................. 8 
10.3 
Details of Treatment ............................................................................................................................... 8 
10.4 
Safety Parameters ................................................................................................................................... 8 
 
Occurrence of Adverse Drug Reactions ............................................................................................. 8 
10.4.1
 
Factors Probably Affecting Safety ...................................................................................................... 8 
10.4.2
10.5 
Efficacy Parameters ................................................................................................................................ 8 
 
Changes in HbA1c over Time ............................................................................................................ 8 
10.5.1
 
Factors Probably Affecting Efficacy .................................................................................................. 8 
10.5.2
10.6 
Parameters in Patients with Special Demographics ............................................................................... 9 
10.7 
Interim Analysis ..................................................................................................................................... 9 
11.0 
Surveillance Organizations ............................................................................................................................. 9 
11.1 
Investigator ............................................................................................................................................. 9 
12.0 
Name and address of CRO and Scope of the CRO Task ................................................................................ 9 
13.0 
Other Necessary Matters ................................................................................................................................ 9 

 
13.1 
Revision of the Protocol ......................................................................................................................... 9 
13.2 
Measures for Issues or Questions ........................................................................................................... 9 
 
Appendix Surveillance Schedule.............................................................................................................................. 10 
 

 
1 
1.0 
Surveillance Background 
The goal of diabetes mellitus treatment is to maintain patients’ QOLs as those in healthy 
people and to secure their lifetimes through management for a favorable blood glucose level 
for a long time. In particular, early drug treatment is considered important for patients with 
mild type 2 diabetes mellitus, which maintains a favorable blood glucose level and inhibits the 
diabetes progress, along with prevention of microangiopathy. 
As an oral drug started to be administered early to patients with mild type 2 diabetes mellitus, 
the desirable drug should have a low risk of hypoglycemia, be well tolerable, and not exhaust 
pancreatic function. 
DPP-4 inhibitors selectively inhibit DPP-4, increase blood GLP-1 levels, and prompt the 
pancreas to secrete insulin in a glucose level-dependent manner. Taken together, DPP-4 
inhibitors are expected to be highly effective for patients with mild type 2 diabetes mellitus. 
As a DPP-4 inhibitor, Nesina tablets (generic name: alogliptin benzoate) are confirmed to be 
highly effective and safe when administered alone and combined with various oral diabetic 
drugs in clinical studies conducted in Japan. The following are approved indications for 
Nesina: 
 
Indications for Nesina tablets 
Type 2 diabetes mellitus 
However, this indication is limited only for patients who had an insufficient response to the 
following therapies: 
(1) Only diet and exercise therapies. 
(2) α-glucosidase inhibitors used in addition to diet and exercise therapies. 
(3) Thiazolidines used in addition to diet and exercise therapies. 
(4) Sulfonylureas used in addition to diet and exercise therapies. 
(5) Biguanides used in addition to diet and exercise therapies. 
 
However, the efficacy and safety of Nesina has not been well evaluated for patients with mild 
type 2 diabetes mellitus because Nesina tablets have been administered to type 2 diabetes 
mellitus patients with HbA1c of ≥ 6.5% (for patients treated with sulfonylureas, HbA1c of ≥ 
7.0%) in clinical studies conducted before drug approval. 
Therefore, this Special Drug Use Surveillance (hereinafter, the Surveillance) was planned to 
evaluate the long-term safety and efficacy of Nesina tablets (hereinafter, Nesina) for patients 
with mild type 2 diabetes mellitus patients in a daily clinical practice. 
 
2.0 
Objectives of Surveillance 
To examine the safety and efficacy of long-term treatment with alogliptin (Nesina) in patients 
with mild type 2 diabetes mellitus in the routine clinical setting. 
 

 
2 
3.0 
Number of Planned Patients for Surveillance and the Rationales 
3.1 Number of Planned Patients for Surveillance 
20000 patients 
 
3.2 Rationales 
According to database of 16 hospitals in Japan, supplied by 
 of 
142358 patients documented as visited from October to December 2010, 15141 were patients 
with type 2 diabetes mellitus. Of these, 4165 patients had HbA1c (JDS) of ≤ 7.0%, which 
were the target population in this Surveillance. For patients with indications for Nesina, in 
addition, 1864 patients (70.4%) received only diet and exercise therapies (no diabetic drugs); 
226 patients (8.5%) received α-glucosidase inhibitors; 175 patients (6.6%) received 
thiazolidines; 273 patients (10.3%) received sulfonylureas; 109 patients (4.1%) received 
biguanides (each drug was administered alone). 
 
In order to identify adverse drug reactions with a frequency of ≥ 0.5% using ≥ a 95% 
confidence level, 600 patients will be required. Assuming that the proportion of drugs in 
patients with mild type 2 diabetes mellitus is same as the above, if data in 20000 patients with 
mild type 2 diabetes mellitus are collected in this Surveillance, 14084 patients will be required 
for Nesina treatment alone; 1708 patients will be required for combination with α-glucosidase 
inhibitors; 1322 patients will be required for combination with thiazolidines; 2063 patients 
will be required for combination with sulfonylureas; 824 patients will be required for 
combination with biguanides. Since any combination can identify the adverse drug reactions 
with a frequency of ≥ 0.5% using ≥ a 95% confidence level, the number of planned patients 
for surveillance was established as 20000. 
 
4.0 
Patients for Surveillance 
Patients with mild type 2 diabetes mellitus will be evaluated for this Surveillance. However, 
patients must meet the inclusion criteria and none of the exclusion criteria, described below. 
Refer to the Precaution with Respect to Indication in the package insert. 
4.1 Inclusion Criteria 
Patients who meet the following criterion will be included in this Surveillance: 
(1) Patients with HbA1c (JDS value) ≤7.0% at the time of enrolment (within 3 months 
before initiation of Nesina therapy) 
* Regardless of the use of antidiabetic medication 
 
4.2 Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from this Surveillance: 
(1) Patients with severe ketosis, diabetic coma or precoma, or type 1 diabetes mellitus 
(2) Patients with severe infection, pre- or post-operative patients, or patients with serious 
traumatic injury 
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3 
(3) Patients with a history of hypersensitivity to any ingredient of Nesina 
 
5.0 
Dosage and Administration for Patients to be Surveyed 
The usual adult dose of alogliptin is 25 mg administered orally once daily. Refer to the 
Precaution with Respect to Dosage and Administration in the package insert. 
 
6.0 
Number of To-be Survey Sites by Department 
Internal medicine or other department: Approximately 1000 sites 
 
7.0 
Survey Methods 
7.1 Observation Period 
The observation period will be 36 months after the start date of Nesina treatment. 
If Nesina treatment is discontinued for any reason, the survey will be ended at the 
discontinuation. 
 
7.2 Request for Sites and Agreement 
This surveillance will be conducted using the electronic data collection system via web 
. Before asking survey, MRs of Takeda Takeda Pharmaceutical Company Limited. 
(Hereinafter, Takeda MRs) will fully explain to the Investigator about the objectives, details, 
handling methods for 
 and handling of electronic signature, user ID, and 
passwords, based on “Request for Cooperation of Special Drug Use Surveillance,” “Summary 
for Surveillance,” “Entry Screen Images,” and “Brief Manual for Handling of 
 and 
will finalize written agreement with survey sites to ask requests for surveillance within the 
specified period. 
 
7.3 Methods for Registration of Patients to be Surveyed 
This Surveillance will be conducted using Central Registration System with 
 The 
Investigator will enter registration data on 
 (refer to Section 9.1) for patients who 
start Nesina treatment after the start date of agreement with a survey site, before 14 days after 
the start date of Nesina treatment (define the start date of treatment as “0 day” and one day 
after the start date of treatment as “1 day”). 
 
7.4 Entry on Survey Sheet (Electronic) and Electronic Signature 
The Investigator will enter patient demographic data and details of treatment on 
 at 
each data entry time point (at the start of Nesina treatment, 3 months, 6 months, 12 months, 18 
months, 24 months, 30 months, and 36 months after the start of Nesina treatment or treatment 
discontinuation). In addition, the Investigator will sign electronically on the survey sheet in 
 for “Patient Demographic Data and Details of Treatment by 12 Months of 
Treatment” after 12 months of treatment and for Patient Demographic Data and Details of 
Treatment by 36 Months of Treatment” after 36 months of treatment. 
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For patients who discontinue treatment with Nesina during the observation period for any 
reason, the Investigator will enter the patient demographic data and details of treatment on 
 and will sign electronically in the survey sheet around within 1 month after the end 
of necessary observation. However, for patients who discontinue treatment with Nesina due to 
an adverse event, the Investigator will continue observation after treatment discontinuation, 
wherever possible, until the adverse event resolve or is resolving and will enter the 
observation results on 
 as well as sign electronically in the survey sheet. 
In case that additional survey is required after Takeda checked the details, Takeda will ask 
request for re-survey on 
 The Investigator will check the details of request for 
re-survey and enter the re-survey results on 
 as well as sign electronically in the 
survey sheet. 
 
7.5 Measures for Development of Adverse Events 
In case of development of an adverse event, the Investigator will contact the person in charge 
of Takeda Pharmaceutical Company Limited (hereinafter, the person in charge of Takeda). If 
the person in charge of Takeda requests additional detailed information, the Investigator will 
provide it. 
 
8.0 
Scheduled Survey Period 
Survey period: July 2011 to July 31, 2017 
Patient registration period: July 2011 to July 31, 2013Note) 
Due date for entry of “Patient Data and Details of Treatment by 12 Months of Treatment:” 
August 31, 2014 
Due date for entry of “Patient Data and Details of Treatment by 36 Months of Treatment:” 
February 28, 2017 
 
Note) Patients who will be treated with Nesina by July 31, 2013 can be registered. 
In case that the registered patients reach the scheduled number of patients to be surveyed 
before July 31 2013, the registration will close earlier than scheduled. 
 
9.0 
Matters to be Surveyed 
The Investigator will enter data of the parameters described below on 
 The 
schedule of this surveillance is shown in the Appendix. 
9.1 Patient Registration Data 
1) Matters to be surveyed 
Start date of Nesina treatment, Patient ID Number, patient initial, sex, birth date, HbA1c 
(JDS) within 3 months prior to Nesina treatment, inclusion criteria assessment, and 
exclusion criteria assessment 
2) Survey period 
At patient registration 
 
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9.2 Survey sheet: patient demographic data 
1) Matters to be surveyed 
Diagnosis period of type 2 diabetes mellitus, height, practice category (at the start of 
survey), presence or absence of pregnancy (females only), pregnancy week (if applicable), 
severity of renal impairment, rationale for assessment of the severity of renal impairment, 
concurrent disease, prior medical history, alcohol history, smoking history, and presence or 
absence of dietary intervention / exercise intervention 
2) Survey period 
At the start of Nesina treatment 
 
9.3 Survey sheet: details of treatment 
1) Matters to be surveyed 
Details of Nesina treatment (daily dose and administration period), status of end of Nesina 
treatment, reason for Nesina discontinuation (if applicable), details of other diabetic drug 
treatment* (drug name, daily dose, route of administration, and administration period), and 
status of concomitant medications (other than diabetic drugs) (drug name, route of 
administration, administration period, and objectives of administration) 
* Diabetic drugs which are discontinued within 3 months prior to Nesina treatment are 
included. 
2) Survey period 
Period from the start of Nesina treatment to 36 months after treatment (or treatment 
discontinuation) 
 
9.4 Laboratory/Observation Parameters 
1) Matters to be surveyed 
HbA1c (JDS, international standard value, or NGSP), fasting glucose, fasting insulin, 
fasting triglyceride, total cholesterol,” HDL-cholesterol, LDL-cholesterol, weight, and 
blood pressure 
2) Survey period 
At the start of Nesina treatment, 3 months , 6 months, 12 months, 18 months, 24 months, 
30 months, and 36 months of treatment (or treatment discontinuation) 
 
9.5 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), procedures related to Nesina, outcome, causal 
relationship to Nesina (refer to Table 3), presence or absence of diabetic complication 
(diabetic retinopathy, diabetic neuropathy, or diabetic nephropathy), change over time in 
clinically important laboratory values related to adverse events 
If the outcome is assessed as Not resolved or Unknown and if the causal relationship cannot 

 
6 
be assessed, the patient will be followed up, wherever possible. The detailed information 
(clinical course, laboratory tests for diagnosis, etc.) will be collected as possible for 
development of hypoglycemia, tumor, pancreatitis, edema, angioedema-related symptom, 
immune system disorder, skin disorder and subcutaneous tissue disorder, cardiovascular 
system event (symptomatic coronary artery disease, cerebrovascular disorder, 
arteriosclerosis obliterans, cardiovascular death, sudden death, etc.) 
2) Survey period 
Period from the start of Nesina treatment to 36 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 in infants breastfed by a Nesina taking mother 
• Symptoms in children who received the relevant drug 
• Symptoms in patients who received the relevant drug at a higher dose than approved or who took by 
themselves 
 

 
7 
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. (e.g., bronchospasm and 
the like, requiring a short-term intensive care in an emergency room and the like) 
 
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 
 
Table 3 Criteria for causality assessment between adverse events and Nesina 
Assessment 
Assessment criterion 
Related 
(Suspectedly related) 
Temporally evident 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 
(Unlikely related) 
No temporally evident 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. 

 
8 
 
10.0 
Analysis Parameters and Methods 
10.1 Patient Component Parameters 
The following will be tabulated: number of registered patients, number of survey sheet 
(electronic) collected patients, number of survey completer, number of survey discontinuations 
and the reason for discontinuation, 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 
The following patient demographics will be tabulated: age, sex, disease period, severity of 
renal impairment (including severity) (yes or no), concurrent disease, past medical history, 
alcohol history, smoking history, etc. 
 
10.3 Details of Treatment 
The following will be tabulated: status of Nesina treatment, status of concomitant medications 
(including the status of diabetic drugs at the start of 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 and summarized by Preferred Term (PT) and System Organ Class 
(SOC). 
 Occurrence of Adverse Drug Reactions 
10.4.1
The type, seriousness, onset period, and the like for adverse drug reactions reported in the 
observation period will be tabulated. 
 
 Factors Probably Affecting Safety 
10.4.2
For adverse drug reactions reported in the observation period, the frequency of patient 
demographics (e.g., age, sex), 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: 
 Changes in HbA1c over Time 
10.5.1
The HbA1c values at each time point and the changes (values at each time point − values at 
the start of Nesina treatment) will be tabulated. The achieving percent in glycemic control 
for HbA1c will be tabulated for each time point. 
 
 Factors Probably Affecting Efficacy 
10.5.2
For the changes in HbA1c and the achieving percent in glycemic control for HbA1c at 36 
months after the start of treatment, the following will be stratified: patients demographics 

 
9 
(e.g., age, sex, 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 
For the safety and efficacy in patients with moderate or higher renal impairment, the 
relationship between the severity of renal impairment and Nesina doses (each will be 
stratified) will be thoroughly evaluated. 
 
10.7 Interim Analysis 
After 1-year observation period is completed in all patients, the interim analysis for the 
parameters described in Sections 10.1 to 10.6 will be performed to confirm the early safety 
and efficacy of Nesina in patients with mild type 2 diabetes mellitus, based on the data entered 
in “Patient Data and Details of Treatment by 12 Months of Treatment.” 
 
11.0 
Surveillance Organizations 
11.1 Investigator 
 Takeda Pharmaceutical Company Limited. 
 
12.0 
Name and address of CRO and Scope of the CRO Task 
 
13.0 
Other Necessary Matters 
13.1 Revision of the Protocol 
During the surveillance period, the protocol can be reviewed and revised, if the following are 
necessary to be changed after monitored: the survey progress, number of dropouts, 
development of 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 surveillance period, if partly changes of dosage and 
administration and indications are approved, the protocol revision will be also considered and 
performed as necessary. 
 
13.2 Measures for Issues or Questions 
If any question about the safety or efficacy is arisen, data will be thoroughly investigated and 
the relevant persons will take measures for the question. 
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Appendix Surveillance Schedule 
 
Survey/data 
entry 
time 
point 
 
 
 
 
Parameters 
Observation period 
At patient registration 
 
At start of treatment 
 
3 months after treatment 
 
6 months after treatment 
 
12 months after treatment 
 
18 months after treatment 
 
24 months after treatment 
 
30 months after treatment 
 
36 months after treatment 
 
 
At treatment 
discontinuation 
Patient registration data 
Start date of Nesina treatment 
○ 
 
 
 
 
 
 
 
 
 
Patient ID Number 
○ 
Patients initial 
○ 
Sex 
○ 
Birth date 
○ 
HbA1c within 3 months prior to Nesina 
treatment 
○ 
 
 
 
 
 
 
 
 
 
Inclusion criteria / exclusion criteria 
○ 
 
 
 
 
 
 
 
Patient demographic data 
Diagnosis period of type 2 diabetes 
mellitus 
 
○ 
 
 
 
 
 
 
 
 
Height 
○ 
 
 
 
 
 
 
 
Category of clinical practice (at start of 
survey) 
 
○ 
 
 
 
 
 
 
 
 
Pregnancy (yes or no) (females only) 
○ 
 
 
 
 
 
 
 
Week of pregnancy (if applicable) 
○ 
 
 
 
 
 
 
 
Severity of renal impairment 
○ 
 
 
 
 
 
 
 
Rationale for severity assessment of renal 
impairment 
 
○ 
 
 
 
 
 
 
 
 
Concurrent disease 
○ 
 
 
 
 
 
 
 
Past medical history 
○ 
 
 
 
 
 
 
Alcohol history 
○ 
 
 
 
 
 
 
Smoking history 
○ 
 
 
 
 
 
 
Dietary/exercise intervention (yes or no) 
 
○ 
 
 
 
 
 
 
 
Details of 
treatment 
Status of Nesina treatment 
 
○ 
○ 
Status of other diabetic drug 
 
○ 
○ 
Status of concomitant medication (other
than diabetic drugs) 
 
○ 
○ 
Laboratory/Observation Parameters, etc 
Laboratory values 
• HbA1c (JDS, international standard 
value, or NGSP) 
• Fasting glucose 
• Fasting insulin 
• Fasting triglyceride 
• Total cholesterol 
• HDL-cholesterol 
• LDL-cholesterol 
 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
Weight 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
Blood pressure 
○  
○ 
○ 
○ 
○ 
○ 
○ 
○ 
○ 
Adverse event 
 
○ 
○ 
○ 
Performed 
○ 
Performed throughout the period 
* Including the diabetic drugs discontinued within 3 months prior to the start of Nesina 

 
 
 
 
 
Protocol for 
Nesina Tablets Special Drug Use Surveillance: Mild 
Type 2 Diabetes Mellitus 
 
 
 
 
 
 
 
 
 
 
Version 
Third version 
Creation date 
April 1, 2015 
Sponsor 
Takeda Pharmaceutical Company Limited. 
 

 
Table of Contents 
1.0 
Surveillance Background ............................................................................................................................... 1 
2.0 
Objectives of Surveillance.............................................................................................................................. 1 
3.0 
Number of Planned Patients for Surveillance and the Rationales .................................................................. 2 
3.1 
Number of Planned Patients for Surveillance......................................................................................... 2 
3.2 
Rationales ............................................................................................................................................... 2 
4.0 
Patients for Surveillance ................................................................................................................................. 2 
4.1 
Inclusion Criteria .................................................................................................................................... 2 
4.2 
Exclusion Criteria ................................................................................................................................... 2 
5.0 
Dosage and Administration for Patients to be Surveyed ................................................................................ 3 
6.0 
Number of To-be Survey Sites by Department .............................................................................................. 3 
7.0 
Survey Methods.............................................................................................................................................. 3 
7.1 
Observation Period ................................................................................................................................. 3 
7.2 
Request for Sites and Agreement ........................................................................................................... 3 
7.3 
Methods for Registration of Patients to be Surveyed ............................................................................. 3 
7.4 
Entry on Survey Sheet (Electronic) and Electronic Signature................................................................ 3 
7.5 
Measures for Development of Adverse Events ...................................................................................... 4 
8.0 
Scheduled Survey Period ............................................................................................................................... 4 
9.0 
Matters to be Surveyed ................................................................................................................................... 4 
9.1 
Patient Registration Data ........................................................................................................................ 4 
9.2 
Survey sheet: patient demographic data ................................................................................................. 5 
9.3 
Survey sheet: details of treatment........................................................................................................... 5 
9.4 
Laboratory/Observation Parameters ....................................................................................................... 5 
9.5 
Adverse Event ........................................................................................................................................ 5 
10.0 
Analysis Parameters and Methods ................................................................................................................. 8 
10.1 
Patient Component Parameters .............................................................................................................. 8 
10.2 
Patient Demographics............................................................................................................................. 8 
10.3 
Details of Treatment ............................................................................................................................... 8 
10.4 
Safety Parameters ................................................................................................................................... 8 
 
Occurrence of Adverse Drug Reactions ............................................................................................. 8 
10.4.1
 
Factors Probably Affecting Safety ...................................................................................................... 8 
10.4.2
10.5 
Efficacy Parameters ................................................................................................................................ 8 
 
Changes in HbA1c over Time ............................................................................................................ 8 
10.5.1
 
Factors Probably Affecting Efficacy .................................................................................................. 8 
10.5.2
10.6 
Parameters in Patients with Special Demographics ............................................................................... 9 
10.7 
Interim Analysis ..................................................................................................................................... 9 
11.0 
Surveillance Organizations ............................................................................................................................. 9 
11.1 
Investigator ............................................................................................................................................. 9 
12.0 
Name and address of CRO and Scope of the CRO Task ................................................................................ 9 
13.0 
Other Necessary Matters ................................................................................................................................ 9 

 
13.1 
Revision of the Protocol ......................................................................................................................... 9 
13.2 
Measures for Issues or Questions ........................................................................................................... 9 
 
Appendix Surveillance Schedule.............................................................................................................................. 11 
 

 
1 
1.0 
Surveillance Background 
The goal of diabetes mellitus treatment is to maintain patients’ QOLs as those in healthy 
people and to secure their lifetimes through management for a favorable blood glucose level 
for a long time. In particular, early drug treatment is considered important for patients with 
mild type 2 diabetes mellitus, which maintains a favorable blood glucose level and inhibits the 
diabetes progress, along with prevention of microangiopathy. 
As an oral drug started to be administered early to patients with mild type 2 diabetes mellitus, 
the desirable drug should have a low risk of hypoglycemia, be well tolerable, and not exhaust 
pancreatic function. 
DPP-4 inhibitors selectively inhibit DPP-4, increase blood GLP-1 levels, and prompt the 
pancreas to secrete insulin in a glucose level-dependent manner. Taken together, DPP-4 
inhibitors are expected to be highly effective for patients with mild type 2 diabetes mellitus. 
As a DPP-4 inhibitor, Nesina tablets (generic name: alogliptin benzoate) are confirmed to be 
highly effective and safe when administered alone and combined with various oral diabetic 
drugs in clinical studies conducted in Japan. The following are approved indications for 
Nesina: 
 
Indications for Nesina tablets 
Type 2 diabetes mellitus 
However, this indication is limited only for patients who had an insufficient response to the 
following therapies: 
(1) Only diet and exercise therapies. 
(2) α-glucosidase inhibitors used in addition to diet and exercise therapies. 
(3) Thiazolidines used in addition to diet and exercise therapies. 
(4) Sulfonylureas used in addition to diet and exercise therapies. 
(5) Biguanides used in addition to diet and exercise therapies. 
 
However, the efficacy and safety of Nesina has not been well evaluated for patients with mild 
type 2 diabetes mellitus because Nesina tablets have been administered to type 2 diabetes 
mellitus patients with HbA1c of ≥ 6.5% (for patients treated with sulfonylureas, HbA1c of ≥ 
7.0%) in clinical studies conducted before drug approval. 
Therefore, this Special Drug Use Surveillance (hereinafter, the Surveillance) was planned to 
evaluate the long-term safety and efficacy of Nesina tablets (hereinafter, Nesina) for patients 
with mild type 2 diabetes mellitus patients in a daily clinical practice. 
 
2.0 
Objectives of Surveillance 
To examine the safety and efficacy of long-term treatment with alogliptin (Nesina) in patients 
with mild type 2 diabetes mellitus in the routine clinical setting. 
 

 
2 
3.0 
Number of Planned Patients for Surveillance and the Rationales 
3.1 Number of Planned Patients for Surveillance 
20000 patients 
 
3.2 Rationales 
According to database of 16 hospitals in Japan, supplied by 
 of 
142358 patients documented as visited from October to December 2010, 15141 were patients 
with type 2 diabetes mellitus. Of these, 4165 patients had HbA1c (JDS) of ≤ 7.0%, which 
were the target population in this Surveillance. For patients with indications for Nesina, in 
addition, 1864 patients (70.4%) received only diet and exercise therapies (no diabetic drugs); 
226 patients (8.5%) received α-glucosidase inhibitors; 175 patients (6.6%) received 
thiazolidines; 273 patients (10.3%) received sulfonylureas; 109 patients (4.1%) received 
biguanides (each drug was administered alone). 
 
In order to identify adverse drug reactions with a frequency of ≥ 0.5% using ≥ a 95% 
confidence level, 600 patients will be required. Assuming that the proportion of drugs in 
patients with mild type 2 diabetes mellitus is same as the above, if data in 20000 patients with 
mild type 2 diabetes mellitus are collected in this Surveillance, 14084 patients will be required 
for Nesina treatment alone; 1708 patients will be required for combination with α-glucosidase 
inhibitors; 1322 patients will be required for combination with thiazolidines; 2063 patients 
will be required for combination with sulfonylureas; 824 patients will be required for 
combination with biguanides. Since any combination can identify the adverse drug reactions 
with a frequency of ≥ 0.5% using ≥ a 95% confidence level, the number of planned patients 
for surveillance was established as 20000. 
 
4.0 
Patients for Surveillance 
Patients with mild type 2 diabetes mellitus will be evaluated for this Surveillance. However, 
patients must meet the inclusion criteria and none of the exclusion criteria, described below. 
Refer to the Precaution with Respect to Indication in the package insert. 
4.1 Inclusion Criteria 
Patients who meet the following criterion will be included in this Surveillance: 
(1) Patients with HbA1c (JDS value) ≤7.0% at the time of enrolment (within 3 months 
before initiation of Nesina therapy) 
* Regardless of the use of antidiabetic medication 
 
4.2 Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from this Surveillance: 
(1) Patients with severe ketosis, diabetic coma or precoma, or type 1 diabetes mellitus 
(2) Patients with severe infection, pre- or post-operative patients, or patients with serious 
traumatic injury 
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(3) Patients with a history of hypersensitivity to any ingredient of Nesina 
 
5.0 
Dosage and Administration for Patients to be Surveyed 
The usual adult dose of alogliptin is 25 mg administered orally once daily. Refer to the 
Precaution with Respect to Dosage and Administration in the package insert. 
 
6.0 
Number of To-be Survey Sites by Department 
Internal medicine or other department: Approximately 1000 sites 
 
7.0 
Survey Methods 
7.1 Observation Period 
The observation period will be 36 months after the start date of Nesina treatment. 
If Nesina treatment is discontinued for any reason, the survey will be ended at the 
discontinuation. 
 
7.2 Request for Sites and Agreement 
This surveillance will be conducted using the electronic data collection system via web 
(
). Before asking survey, MRs of Takeda Takeda Pharmaceutical Company Limited. 
(Hereinafter, Takeda MRs) will fully explain to the Investigator about the objectives, details, 
handling methods for 
 and handling of electronic signature, user ID, and 
passwords, based on “Request for Cooperation of Special Drug Use Surveillance,” “Summary 
for Surveillance,” “Entry Screen Images,” and “Brief Manual for Handling of 
 and 
will finalize written agreement with survey sites to ask requests for surveillance within the 
specified period. 
 
7.3 Methods for Registration of Patients to be Surveyed 
This Surveillance will be conducted using Central Registration System with 
 The 
Investigator will enter registration data on 
 (refer to Section 9.1) for patients who 
start Nesina treatment after the start date of agreement with a survey site, before 14 days after 
the start date of Nesina treatment (define the start date of treatment as “0 day” and one day 
after the start date of treatment as “1 day”). 
 
7.4 Entry on Survey Sheet (Electronic) and Electronic Signature 
The Investigator will enter patient demographic data and details of treatment on 
 at 
each data entry time point (at the start of Nesina treatment, 3 months, 6 months, 12 months, 18 
months, 24 months, 30 months, and 36 months after the start of Nesina treatment or treatment 
discontinuation). In addition, the Investigator will sign electronically on the survey sheet in 
 for “Patient Demographic Data and Details of Treatment by 12 Months of 
Treatment” after 12 months of treatment  and for Patient Demographic Data and Details of 
Treatment by 36 Months of Treatment” after 36 months of treatment. 
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For patients who discontinue treatment with Nesina during the observation period for any 
reason, the Investigator will enter the patient demographic data and details of treatment on 
 and will sign electronically in the survey sheet around within 1 month after the end 
of necessary observation.  However, for patients who discontinue treatment with Nesina due 
to an adverse event, the Investigator will continue observation after treatment discontinuation, 
wherever possible, until the adverse event resolve or is resolving and will enter the 
observation results on 
 as well as sign electronically in the survey sheet. 
In case that additional survey is required after Takeda checked the details, Takeda will ask 
request for re-survey on 
 The Investigator will check the details of request for 
re-survey and enter the re-survey results on 
 as well as sign electronically in the 
survey sheet. 
 
7.5 Measures for Development of Adverse Events 
In case of development of an adverse event, the Investigator will contact the person in charge 
of Takeda Pharmaceutical Company Limited (hereinafter, the person in charge of Takeda). If 
the person in charge of Takeda requests additional detailed information, the Investigator will 
provide it. 
 
8.0 
Scheduled Survey Period 
Survey period: July 2011 to January 31, 2017 
Patient registration period: July 2011 to July 31, 2013Note) 
Due date for entry of “Patient Data and Details of Treatment by 12 Months of Treatment:” 
August 31, 2014 
Due date for entry of “Patient Data and Details of Treatment by 36 Months of Treatment:” 
August 31, 2016 
 
Note) Patients who will be treated with Nesina by July 31, 2013 can be registered. 
In case that the registered patients reach the scheduled number of patients to be surveyed 
before July 31 2013, the registration will close earlier than scheduled. 
 
9.0 
Matters to be Surveyed 
The Investigator will enter data of the parameters described below on 
 The 
schedule of this surveillance is shown in the Appendix. 
9.1 Patient Registration Data 
1) Matters to be surveyed 
Start date of Nesina treatment, Patient ID Number, patient initial, sex, birth date, HbA1c 
(JDS) within 3 months prior to Nesina treatment, inclusion criteria assessment, and 
exclusion criteria assessment 
2) Survey period 
At patient registration 
 
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5 
9.2 Survey sheet: patient demographic data 
1) Matters to be surveyed 
Diagnosis period of type 2 diabetes mellitus, height, practice category (at the start of 
survey), presence or absence of pregnancy (females only), pregnancy week (if applicable), 
severity of renal impairment, rationale for assessment of the severity of renal impairment, 
concurrent disease, prior medical history, alcohol history, smoking history, and presence or 
absence of dietary intervention / exercise intervention 
2) Survey period 
At the start of Nesina treatment 
 
9.3 Survey sheet: details of treatment 
1) Matters to be surveyed 
Details of Nesina treatment (daily dose and administration period), status of end of Nesina 
treatment, reason for Nesina discontinuation (if applicable), details of other diabetic drug 
treatment* (drug name, daily dose, route of administration, and administration period), and 
status of concomitant medications (other than diabetic drugs) (drug name, route of 
administration, administration period, and objectives of administration) 
* Diabetic drugs which are discontinued within 3 months prior to Nesina treatment are 
included. 
2) Survey period 
Period from the start of Nesina treatment to 36 months after treatment (or treatment 
discontinuation) 
 
9.4 Laboratory/Observation Parameters 
1) Matters to be surveyed 
HbA1c (JDS, international standard value, or NGSP), fasting glucose, fasting insulin, 
fasting triglyceride, total cholesterol,” HDL-cholesterol, LDL-cholesterol, weight, and 
blood pressure 
2) Survey period 
At the start of Nesina treatment, 3 months , 6 months, 12 months, 18 months, 24 months, 
30 months, and 36 months of treatment (or treatment discontinuation) 
 
9.5 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), procedures related to Nesina, outcome, causal 
relationship to Nesina (refer to Table 3), presence or absence of diabetic complication 
(diabetic retinopathy, diabetic neuropathy, or diabetic nephropathy), change over time in 
clinically important laboratory values related to adverse events 
If the outcome is assessed as Not resolved or Unknown and if the causal relationship cannot 

 
6 
be assessed, the patient will be followed up, wherever possible. The detailed information 
(clinical course, laboratory tests for diagnosis, etc.) will be collected as possible for 
development of hypoglycemia, tumor, pancreatitis, edema, angioedema-related symptom, 
immune system disorder, skin disorder and subcutaneous tissue disorder, cardiovascular 
system event (symptomatic coronary artery disease, cerebrovascular disorder, 
arteriosclerosis obliterans, cardiovascular death, sudden death, etc.) 
2) Survey period 
Period from the start of Nesina treatment to 36 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 in infants breastfed by a Nesina taking mother 
• Symptoms in children who received the relevant drug 
• Symptoms in patients who received the relevant drug at a higher dose than approved or who took by 
themselves 
 

 
7 
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. (e.g., bronchospasm and 
the like, requiring a short-term intensive care in an emergency room and the like) 
 
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 
 
Table 3 Criteria for causality assessment between adverse events and Nesina 
Assessment 
Assessment criterion 
Related 
(Suspectedly related) 
Temporally evident 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 
(Unlikely related) 
No temporally evident 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. 

 
8 
 
10.0 
Analysis Parameters and Methods 
10.1 Patient Component Parameters 
The following will be tabulated: number of registered patients, number of survey sheet 
(electronic) collected patients, number of survey completer, number of survey discontinuations 
and the reason for discontinuation, 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 
The following patient demographics will be tabulated: age, sex, disease period, severity of 
renal impairment (including severity) (yes or no), concurrent disease, past medical history, 
alcohol history, smoking history, etc. 
 
10.3 Details of Treatment 
The following will be tabulated: status of Nesina treatment, status of concomitant medications 
(including the status of diabetic drugs at the start of 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 and summarized by Preferred Term (PT) and System Organ Class 
(SOC). 
 Occurrence of Adverse Drug Reactions 
10.4.1
The type, seriousness, onset period, and the like for adverse drug reactions reported in the 
observation period will be tabulated. 
 
 Factors Probably Affecting Safety 
10.4.2
For adverse drug reactions reported in the observation period, the frequency of patient 
demographics (e.g., age, sex), 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: 
 Changes in HbA1c over Time 
10.5.1
The HbA1c values at each time point and the changes (values at each time point − values at 
the start of Nesina treatment) will be tabulated. The achieving percent in glycemic control 
for HbA1c will be tabulated for each time point. 
 
 Factors Probably Affecting Efficacy 
10.5.2
For the changes in HbA1c and the achieving percent in glycemic control for HbA1c at 36 
months after the start of treatment, the following will be stratified: patients demographics 

 
9 
(e.g., age, sex, 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 
For the safety and efficacy in patients with moderate or higher renal impairment, the 
relationship between the severity of renal impairment and Nesina doses (each will be 
stratified) will be thoroughly evaluated. 
 
10.7 Interim Analysis 
After 1-year observation period is completed in all patients, the interim analysis for the 
parameters described in Sections 10.1 to 10.6 will be performed to confirm the early safety 
and efficacy of Nesina in patients with mild type 2 diabetes mellitus, based on the data entered 
in “Patient Data and Details of Treatment by 12 Months of Treatment.” 
 
11.0 
Surveillance Organizations 
11.1 Investigator 
 Takeda Pharmaceutical Company Limited. 
 
12.0 
Name and address of CRO and Scope of the CRO Task 
 
13.0 
Other Necessary Matters 
13.1 Revision of the Protocol 
During the surveillance period, the protocol can be reviewed and revised, if the following are 
necessary to be changed after monitored: the survey progress, number of dropouts, 
development of 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 surveillance period, if partly changes of dosage and 
administration and indications are approved, the protocol revision will be also considered and 
performed as necessary. 
 
13.2 Measures for Issues or Questions 
If any question about the safety or efficacy is arisen, data will be thoroughly investigated and 
the relevant persons will take measures for the question. 
PPD
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10 
Appendix Surveillance Schedule 
 
Survey/data entry time point 
 
 
Parameters 
Observation period 
At patient 
registration 
At start of 
treatment 
3 months after 
treatment 
6 months after 
treatment 
12 months 
after treatment 
18 months 
after treatment 
24 months 
after treatment 
30 months 
after treatment 
36 months 
after treatment 
At treatment 
discontinuation 
Patient registration data 
Start date of Nesina tablets 
X 
 
 
 
 
 
 
 
 
 
Patient ID Number 
X 
Patients initial 
X 
Sex 
X 
Birth date 
X 
HbA1c within 3 months prior to Nesina 
treatment 
X 
 
 
 
 
 
 
 
 
 
Inclusion criteria / exclusion criteria 
X 
 
 
 
 
 
 
 
Patient demographic data 
Diagnosis period of type 2 diabetes 
mellitus 
 
X 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
Category of clinical practice (at start of 
survey) 
 
X 
 
 
 
 
 
 
 
 
Pregnancy (yes or no) (females only) 
X 
 
 
 
 
 
 
 
Week of pregnancy (if applicable) 
X 
 
 
 
 
 
 
 
Severity of renal impairment 
X 
 
 
 
 
 
 
 
Rationale for severity assessment of renal 
impairment 
 
X 
 
 
 
 
 
 
 
 
Concurrent disease 
X 
 
 
 
 
 
 
 
Past medical history 
X 
 
 
 
 
 
 
Alcohol history 
X 
 
 
 
 
 
 
Smoking history 
X 
 
 
 
 
 
 
Dietary/exercise intervention (yes or no) 
 
X 
 
 
 
 
 
 
 
Details of 
treatment 
Status of Nesina tablet treatment 
X 
Other diabetic drug 
X 
Concomitant medication (other than diabetic
drugs) 
 
X 
Laboratory/Observation Parameters, 
etc 
Laboratory values 
• HbA1c (JDS, international standard 
value, or NGSP) 
• Fasting glucose 
• Fasting insulin 
• Fasting triglyceride 
• Total cholesterol 
• HDL-cholesterol 
• LDL-cholesterol 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood pressure 
X  
X 
X 
X 
X 
X 
X 
X 
X 
Adverse event 
X 

 
 
 
 
 
Protocol for 
Nesina Tablets Special Drug Use Surveillance: Mild 
Type 2 Diabetes Mellitus 
 
 
 
 
 
 
 
 
 
 
Version 
Second version 
Creation date 
February 24, 2012 
Sponsor 
Takeda Pharmaceutical Company Limited. 
 

 
Table of Contents 
1.0 
Surveillance Background ............................................................................................................................... 1 
2.0 
Objectives of Surveillance.............................................................................................................................. 1 
3.0 
Number of Planned Patients for Surveillance and the Rationales .................................................................. 2 
3.1 
Number of Planned Patients for Surveillance......................................................................................... 2 
3.2 
Rationales ............................................................................................................................................... 2 
4.0 
Patients for Surveillance ................................................................................................................................. 2 
4.1 
Inclusion Criteria .................................................................................................................................... 2 
4.2 
Exclusion Criteria ................................................................................................................................... 2 
5.0 
Dosage and Administration for Patients to be Surveyed ................................................................................ 3 
6.0 
Number of To-be Survey Sites by Department .............................................................................................. 3 
7.0 
Survey Methods.............................................................................................................................................. 3 
7.1 
Observation Period ................................................................................................................................. 3 
7.2 
Request for Sites and Agreement ........................................................................................................... 3 
7.3 
Methods for Registration of Patients to be Surveyed ............................................................................. 3 
7.4 
Entry on Survey Sheet (Electronic) and Electronic Signature................................................................ 3 
7.5 
Measures for Development of Adverse Events ...................................................................................... 4 
8.0 
Scheduled Survey Period ............................................................................................................................... 4 
9.0 
Matters to be Surveyed ................................................................................................................................... 4 
9.1 
Patient Registration Data ........................................................................................................................ 4 
9.2 
Survey sheet: patient demographic data ................................................................................................. 4 
9.3 
Survey sheet: details of treatment........................................................................................................... 5 
9.4 
Laboratory/Observation Parameters ....................................................................................................... 5 
9.5 
Adverse Event ........................................................................................................................................ 5 
10.0 
Analysis Parameters and Methods ................................................................................................................. 8 
10.1 
Patient Component Parameters .............................................................................................................. 8 
10.2 
Patient Demographics............................................................................................................................. 8 
10.3 
Details of Treatment ............................................................................................................................... 8 
10.4 
Safety Parameters ................................................................................................................................... 8 
 
Occurrence of Adverse Drug Reactions ............................................................................................. 8 
10.4.1
 
Factors Probably Affecting Safety ...................................................................................................... 8 
10.4.2
10.5 
Efficacy Parameters ................................................................................................................................ 8 
 
Changes in HbA1c over Time ............................................................................................................ 8 
10.5.1
 
Factors Probably Affecting Efficacy .................................................................................................. 9 
10.5.2
10.6 
Parameters in Patients with Special Demographics ............................................................................... 9 
10.7 
Interim Analysis ..................................................................................................................................... 9 
11.0 
Surveillance Organizations ............................................................................................................................. 9 
11.1 
Investigator ............................................................................................................................................. 9 
11.2 
Medical Expert ....................................................................................................................................... 9 
12.0 
Name and address of CRO and Scope of the CRO Task ................................................................................ 9 

 
13.0 
Other Necessary Matters ................................................................................................................................ 9 
13.1 
Revision of the Protocol ......................................................................................................................... 9 
13.2 
Measures for Issues or Questions ......................................................................................................... 10 
 
Appendix Surveillance Schedule.............................................................................................................................. 11 
 

 
1 
1.0 
Surveillance Background 
The goal of diabetes mellitus treatment is to maintain patients’ QOLs as those in healthy 
people and to secure their lifetimes through management for a favorable blood glucose level 
for a long time. In particular, early drug treatment is considered important for patients with 
mild type 2 diabetes mellitus, which maintains a favorable blood glucose level and inhibits the 
diabetes progress, along with prevention of microangiopathy. 
As an oral drug started to be administered early to patients with mild type 2 diabetes mellitus, 
the desirable drug should have a low risk of hypoglycemia, be well tolerable, and not exhaust 
pancreatic function. 
DPP-4 inhibitors selectively inhibit DPP-4, increase blood GLP-1 levels, and prompt the 
pancreas to secrete insulin in a glucose level-dependent manner. Taken together, DPP-4 
inhibitors are expected to be highly effective for patients with mild type 2 diabetes mellitus. 
As a DPP-4 inhibitor, Nesina tablets (generic name: alogliptin benzoate) are confirmed to be 
highly effective and safe when administered alone and combined with various oral diabetic 
drugs in clinical studies conducted in Japan. The following are approved indications for 
Nesina: 
 
Indications for Nesina tablets 
Type 2 diabetes mellitus 
However, this indication is limited only for patients who had an insufficient response to the 
following therapies: 
(1) Only diet and exercise therapies. 
(2) α-glucosidase inhibitors used in addition to diet and exercise therapies. 
(3) Thiazolidines used in addition to diet and exercise therapies. 
(4) Sulfonylureas used in addition to diet and exercise therapies. 
(5) Biguanides used in addition to diet and exercise therapies. 
 
However, the efficacy and safety of Nesina has not been well evaluated for patients with mild 
type 2 diabetes mellitus because Nesina tablets have been administered to type 2 diabetes 
mellitus patients with HbA1c of ≥ 6.5% (for patients treated with sulfonylureas, HbA1c of ≥ 
7.0%) in clinical studies conducted before drug approval. 
Therefore, this Special Drug Use Surveillance (hereinafter, the Surveillance) was planned to 
evaluate the long-term safety and efficacy of Nesina tablets (hereinafter, Nesina) for patients 
with mild type 2 diabetes mellitus patients in a daily clinical practice. 
 
2.0 
Objectives of Surveillance 
To examine the safety and efficacy of long-term treatment with alogliptin (Nesina) in patients 
with mild type 2 diabetes mellitus in the routine clinical setting. 
 

 
2 
3.0 
Number of Planned Patients for Surveillance and the Rationales 
3.1 Number of Planned Patients for Surveillance 
20000 patients 
 
3.2 Rationales 
According to database of 16 hospitals in Japan, supplied by 
 of 
142358 patients documented as visited from October to December 2010, 15141 were patients 
with type 2 diabetes mellitus. Of these, 4165 patients had HbA1c (JDS) of ≤ 7.0%, which 
were the target population in this Surveillance. For patients with indications for Nesina, in 
addition, 1864 patients (70.4%) received only diet and exercise therapies (no diabetic drugs); 
226 patients (8.5%) received α-glucosidase inhibitors; 175 patients (6.6%) received 
thiazolidines; 273 patients (10.3%) received sulfonylureas; 109 patients (4.1%) received 
biguanides (each drug was administered alone). 
 
In order to identify adverse drug reactions with a frequency of ≥ 0.5% using ≥ a 95% 
confidence level, 600 patients will be required. Assuming that the proportion of drugs in 
patients with mild type 2 diabetes mellitus is same as the above, if data in 20000 patients with 
mild type 2 diabetes mellitus are collected in this Surveillance, 14084 patients will be required 
for Nesina treatment alone; 1708 patients will be required for combination with α-glucosidase 
inhibitors; 1322 patients will be required for combination with thiazolidines; 2063 patients 
will be required for combination with sulfonylureas; 824 patients will be required for 
combination with biguanides. Since any combination can identify the adverse drug reactions 
with a frequency of ≥ 0.5% using ≥ a 95% confidence level, the number of planned patients 
for surveillance was established as 20000. 
 
4.0 
Patients for Surveillance 
Patients with mild type 2 diabetes mellitus will be evaluated for this Surveillance. However, 
patients must meet the inclusion criteria and none of the exclusion criteria, described below. 
Refer to the Precaution with Respect to Indication in the package insert. 
4.1 Inclusion Criteria 
Patients who meet the following criterion will be included in this Surveillance: 
(1) Patients with HbA1c (JDS value) ≤7.0% at the time of enrolment (within 3 months 
before initiation of Nesina therapy) 
* Regardless of the use of antidiabetic medication 
 
4.2 Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from this Surveillance: 
(1) Patients with severe ketosis, diabetic coma or precoma, or type 1 diabetes mellitus 
(2) Patients with severe infection, pre- or post-operative patients, or patients with serious 
traumatic injury 
PPD

 
3 
(3) Patients with a history of hypersensitivity to any ingredient of Nesina 
 
5.0 
Dosage and Administration for Patients to be Surveyed 
The usual adult dose of alogliptin is 25 mg administered orally once daily. Refer to the 
Precaution with Respect to Dosage and Administration in the package insert. 
 
6.0 
Number of To-be Survey Sites by Department 
Internal medicine or other department: Approximately 1000 sites 
 
7.0 
Survey Methods 
7.1 Observation Period 
The observation period will be 36 months after the start date of Nesina treatment. 
If Nesina treatment is discontinued for any reason, the survey will be ended at the 
discontinuation. 
 
7.2 Request for Sites and Agreement 
This surveillance will be conducted using the electronic data collection system via web 
. Before asking survey, MRs of Takeda Takeda Pharmaceutical Company Limited. 
(Hereinafter, Takeda MRs) will fully explain to the Investigator about the objectives, details, 
handling methods for 
 and handling of electronic signature, user ID, and 
passwords, based on “Request for Cooperation of Special Drug Use Surveillance,” “Summary 
for Surveillance,” “Entry Screen Images,” and “Brief Manual for Handling of 
 and 
will finalize written agreement with survey sites to ask requests for surveillance within the 
specified period. 
 
7.3 Methods for Registration of Patients to be Surveyed 
This Surveillance will be conducted using Central Registration System with 
 The 
Investigator will enter registration data on 
 (refer to Section 9.1) for patients who 
start Nesina treatment after the start date of agreement with a survey site, before 14 days after 
the start date of Nesina treatment (define the start date of treatment as “0 day” and one day 
after the start date of treatment as “1 day”). 
 
7.4 Entry on Survey Sheet (Electronic) and Electronic Signature 
The Investigator will enter patient demographic data and details of treatment on 
 at 
each data entry time point (at the start of Nesina treatment, 3 months, 6 months, 12 months, 18 
months, 24 months, 30 months, and 36 months after the start of Nesina treatment or treatment 
discontinuation). In addition, the Investigator will sign electronically on the survey sheet in 
 for “Patient Demographic Data and Details of Treatment by 12 Months of 
Treatment” after 12 months of treatment and for Patient Demographic Data and Details of 
Treatment by 36 Months of Treatment” after 36 months of treatment. 
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4 
For patients who discontinue treatment with Nesina during the observation period for any 
reason, the Investigator will enter the patient demographic data and details of treatment on 
 and will sign electronically in the survey sheet around within 1 month after the end 
of necessary observation. However, for patients who discontinue treatment with Nesina due to 
an adverse event, the Investigator will continue observation after treatment discontinuation, 
wherever possible, until the adverse event resolve or is resolving and will enter the 
observation results on 
 as well as sign electronically in the survey sheet. 
In case that additional survey is required after Takeda checked the details, Takeda will ask 
request for re-survey on 
 The Investigator will check the details of request for 
re-survey and enter the re-survey results on 
 as well as sign electronically in the 
survey sheet. 
 
7.5 Measures for Development of Adverse Events 
In case of development of an adverse event, the Investigator will contact the Takeda MR. If 
the Takeda MR requests additional detailed information, the Investigator will provide it. 
 
8.0 
Scheduled Survey Period 
Survey period: July 2011 to January 31, 2017 
Patient registration period: July 2011 to July 31, 2013Note) 
Due date for entry of “Patient Data and Details of Treatment by 12 Months of Treatment:” 
August 31, 2014 
Due date for entry of “Patient Data and Details of Treatment by 36 Months of Treatment:” 
August 31, 2016 
 
Note) Patients who will be treated with Nesina by July 31, 2013 can be registered. 
In case that the registered patients reach the scheduled number of patients to be surveyed 
before July 31 2013, the registration will close earlier than scheduled. 
 
9.0 
Matters to be Surveyed 
The Investigator will enter data of the parameters described below on 
 The 
schedule of this surveillance is shown in the Appendix. 
9.1 Patient Registration Data 
1) Matters to be surveyed 
Start date of Nesina treatment, Patient ID Number, patient initial, sex, birth date, HbA1c 
(JDS) within 3 months prior to Nesina treatment, inclusion criteria assessment, and 
exclusion criteria assessment 
2) Survey period 
At patient registration 
 
9.2 Survey sheet: patient demographic data 
1) Matters to be surveyed 
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5 
Diagnosis period of type 2 diabetes mellitus, height, practice category (at the start of 
survey), presence or absence of pregnancy (females only), pregnancy week (if applicable), 
severity of renal impairment, rationale for assessment of the severity of renal impairment, 
concurrent disease, prior medical history, alcohol history, smoking history, and presence or 
absence of dietary intervention / exercise intervention 
2) Survey period 
At the start of Nesina treatment 
 
9.3 Survey sheet: details of treatment 
1) Matters to be surveyed 
Details of Nesina treatment (daily dose and administration period), status of end of Nesina 
treatment, reason for Nesina discontinuation (if applicable), details of other diabetic drug 
treatment* (drug name, daily dose, route of administration, and administration period), and 
status of concomitant medications (other than diabetic drugs) (drug name, route of 
administration, administration period, and objectives of administration) 
* Diabetic drugs which are discontinued within 3 months prior to Nesina treatment are 
included. 
2) Survey period 
Period from the start of Nesina treatment to 36 months after treatment (or treatment 
discontinuation) 
 
9.4 Laboratory/Observation Parameters 
1) Matters to be surveyed 
HbA1c (JDS, international standard value, or NGSP), fasting glucose, fasting insulin, 
fasting triglyceride, total cholesterol,” HDL-cholesterol, LDL-cholesterol, weight, and 
blood pressure 
2) Survey period 
At the start of Nesina treatment, 3 months , 6 months, 12 months, 18 months, 24 months, 
30 months, and 36 months of treatment (or treatment discontinuation) 
 
9.5 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), procedures related to Nesina, outcome, causal 
relationship to Nesina (refer to Table 3), presence or absence of diabetic complication 
(diabetic retinopathy, diabetic neuropathy, or diabetic nephropathy), change over time in 
clinically important laboratory values related to adverse events 
If the outcome is assessed as Not resolved or Unknown and if the causal relationship cannot 
be assessed, the patient will be followed up, wherever possible. The detailed information 
(clinical course, laboratory tests for diagnosis, etc.) will be collected as possible for 

 
6 
development of hypoglycemia, tumor, pancreatitis, edema, angioedema-related symptom, 
immune system disorder, skin disorder and subcutaneous tissue disorder, cardiovascular 
system event (symptomatic coronary artery disease, cerebrovascular disorder, 
arteriosclerosis obliterans, cardiovascular death, sudden death, etc.) 
2) Survey period 
Period from the start of Nesina treatment to 36 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 in infants breastfed by a Nesina taking mother 
• Symptoms in children who received the relevant drug 
• Symptoms in patients who received the relevant drug at a higher dose than approved or who took by 
themselves 
 

 
7 
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. (e.g., bronchospasm and 
the like, requiring a short-term intensive care in an emergency room and the like) 
 
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 
 
Table 3 Criteria for causality assessment between adverse events and Nesina 
Assessment 
Assessment criterion 
Related 
(Suspectedly related) 
Temporally evident 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 
(Unlikely related) 
No temporally evident 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 

 
8 
disease, concomitant medication, other factor, etc. 
 
10.0 
Analysis Parameters and Methods 
10.1 Patient Component Parameters 
The following will be tabulated: number of registered patients, number of survey sheet 
(electronic) collected patients, number of survey completer, number of survey discontinuations 
and the reason for discontinuation, 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 
The following patient demographics will be tabulated: age, sex, disease period, severity of 
renal impairment (including severity) (yes or no), concurrent disease, past medical history, 
alcohol history, smoking history, etc. 
 
10.3 Details of Treatment 
The following will be tabulated: status of Nesina treatment, status of concomitant medications 
(including the status of diabetic drugs at the start of 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 and summarized by Preferred Term (PT) and System Organ Class 
(SOC). 
 Occurrence of Adverse Drug Reactions 
10.4.1
The type, seriousness, onset period, and the like for adverse drug reactions reported in the 
observation period will be tabulated. 
 
 Factors Probably Affecting Safety 
10.4.2
For adverse drug reactions reported in the observation period, the frequency of patient 
demographics (e.g., age, sex), 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: 
 Changes in HbA1c over Time 
10.5.1
The HbA1c values at each time point and the changes (values at each time point − values at 
the start of Nesina treatment) will be tabulated. The achieving percent in glycemic control 
for HbA1c will be tabulated for each time point. 
 

 
9 
 Factors Probably Affecting Efficacy 
10.5.2
For the changes in HbA1c and the achieving percent in glycemic control for HbA1c at 36 
months after the start of treatment, the following will be stratified: patients demographics 
(e.g., age, sex, 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 
For the safety and efficacy in patients with moderate or higher renal impairment, the 
relationship between the severity of renal impairment and Nesina doses (each will be 
stratified) will be thoroughly evaluated. 
 
10.7 Interim Analysis 
After 1-year observation period is completed in all patients, the interim analysis for the 
parameters described in Sections 10.1 to 10.6 will be performed to confirm the early safety 
and efficacy of Nesina in patients with mild type 2 diabetes mellitus, based on the data entered 
in “Patient Data and Details of Treatment by 12 Months of Treatment.” 
 
11.0 
Surveillance Organizations 
11.1 Investigator 
Takeda 
Pharmaceutical Company Limited. 
 
 
11.2 Medical Expert 
 
12.0 
Name and address of CRO and Scope of the CRO Task 
 
13.0 
Other Necessary Matters 
13.1 Revision of the Protocol 
During the surveillance period, the protocol can be reviewed and revised, if the following are 
necessary to be changed after monitored: the survey progress, number of dropouts, 
development of 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 surveillance period, if partly changes of dosage and 
PPD
PPD
PPD
PPD

 
10 
administration and indications are approved, the protocol revision will be also considered and 
performed as necessary. 
 
13.2 Measures for Issues or Questions 
If any question about the safety or efficacy is arisen, data will be thoroughly investigated and 
the relevant persons will take measures for the question. 
 

 
11 
Appendix Surveillance Schedule 
 
Survey/data entry time point 
 
 
Parameters 
Observation period 
At patient 
registration 
At start of 
treatment 
3 months after 
treatment 
6 months after 
treatment 
12 months 
after treatment 
18 months 
after treatment 
24 months 
after treatment 
30 months 
after treatment 
36 months 
after treatment 
At treatment 
discontinuation 
Patient registration data 
Start date of Nesina tablets 
X 
 
 
 
 
 
 
 
 
 
Patient ID Number 
X 
Patients initial 
X 
Sex 
X 
Birth date 
X 
HbA1c within 3 months prior to Nesina 
treatment 
X 
 
 
 
 
 
 
 
 
 
Inclusion criteria / exclusion criteria 
X 
 
 
 
 
 
 
 
Patient demographic data 
Diagnosis period of type 2 diabetes 
mellitus 
 
X 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
Category of clinical practice (at start of 
survey) 
 
X 
 
 
 
 
 
 
 
 
Pregnancy (yes or no) (females only) 
X 
 
 
 
 
 
 
 
Week of pregnancy (if applicable) 
X 
 
 
 
 
 
 
 
Severity of renal impairment 
X 
 
 
 
 
 
 
 
Rationale for severity assessment of renal 
impairment 
 
X 
 
 
 
 
 
 
 
 
Concurrent disease 
X 
 
 
 
 
 
 
 
Past medical history 
X 
 
 
 
 
 
 
Alcohol history 
X 
 
 
 
 
 
 
Smoking history 
X 
 
 
 
 
 
 
Dietary/exercise intervention (yes or no) 
 
X 
 
 
 
 
 
 
 
Details of 
treatment 
Status of Nesina tablet treatment 
X 
Other diabetic drug 
X 
Concomitant medication (other than diabetic
drugs) 
 
X 
Laboratory/Observation Parameters, 
etc 
Laboratory values 
• HbA1c (JDS, international standard 
value, or NGSP) 
• Fasting glucose 
• Fasting insulin 
• Fasting triglyceride 
• Total cholesterol 
• HDL-cholesterol 
• LDL-cholesterol 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood pressure 
X  
X 
X 
X 
X 
X 
X 
X 
X 
Adverse event 
X 

 
 
 
 
 
Protocol for 
Nesina Tablets Special Drug Use Surveillance: Mild 
Type 2 Diabetes Mellitus 
 
 
 
 
 
 
 
 
 
 
Version 
First version 
Creation date 
June 22, 2011 
Sponsor 
Takeda Pharmaceutical Company Limited. 
 

 
Table of Contents 
1.0 
Surveillance Background ............................................................................................................................... 1 
2.0 
Objectives of Surveillance.............................................................................................................................. 1 
3.0 
Number of Planned Patients for Surveillance and the Rationales .................................................................. 2 
3.1 
Number of Planned Patients for Surveillance......................................................................................... 2 
3.2 
Rationales ............................................................................................................................................... 2 
4.0 
Patients for Surveillance ................................................................................................................................. 2 
4.1 
Inclusion Criteria .................................................................................................................................... 2 
4.2 
Exclusion Criteria ................................................................................................................................... 2 
5.0 
Dosage and Administration for Patients to be Surveyed ................................................................................ 3 
6.0 
Number of To-be Survey Sites by Department .............................................................................................. 3 
7.0 
Survey Methods.............................................................................................................................................. 3 
7.1 
Observation Period ................................................................................................................................. 3 
7.2 
Request for Sites and Agreement ........................................................................................................... 3 
7.3 
Methods for Registration of Patients to be Surveyed ............................................................................. 3 
7.4 
Entry on Survey Sheet (Electronic) and Electronic Signature................................................................ 3 
7.5 
Measures for Development of Adverse Events ...................................................................................... 4 
8.0 
Scheduled Survey Period ............................................................................................................................... 4 
9.0 
Matters to be Surveyed ................................................................................................................................... 4 
9.1 
Patient Registration Data ........................................................................................................................ 4 
9.2 
Survey sheet: patient demographic data ................................................................................................. 4 
9.3 
Survey sheet: details of treatment........................................................................................................... 5 
9.4 
Laboratory/Observation Parameters ....................................................................................................... 5 
9.5 
Adverse Event ........................................................................................................................................ 5 
10.0 
Analysis Parameters and Methods ................................................................................................................. 8 
10.1 
Patient Component Parameters .............................................................................................................. 8 
10.2 
Patient Demographics............................................................................................................................. 8 
10.3 
Details of Treatment ............................................................................................................................... 8 
10.4 
Safety Parameters ................................................................................................................................... 8 
 
Occurrence of Adverse Drug Reactions ............................................................................................. 8 
10.4.1
 
Factors Probably Affecting Safety ...................................................................................................... 8 
10.4.2
10.5 
Efficacy Parameters ................................................................................................................................ 8 
 
Changes in HbA1c over Time ............................................................................................................ 8 
10.5.1
 
Factors Probably Affecting Efficacy .................................................................................................. 8 
10.5.2
10.6 
Parameters in Patients with Special Demographics ............................................................................... 9 
10.7 
Interim Analysis ..................................................................................................................................... 9 
11.0 
Surveillance Organizations ............................................................................................................................. 9 
11.1 
Investigator ............................................................................................................................................. 9 
11.2 
Medical Expert ....................................................................................................................................... 9 
12.0 
Name and address of CRO and Scope of the CRO Task ................................................................................ 9 

 
13.0 
Other Necessary Matters ................................................................................................................................ 9 
13.1 
Revision of the Protocol ......................................................................................................................... 9 
13.2 
Measures for Issues or Questions ......................................................................................................... 10 
 
Appendix Surveillance Schedule.............................................................................................................................. 11 
 

 
1 
1.0 
Surveillance Background 
The goal of diabetes mellitus treatment is to maintain patients’ QOLs as those in healthy 
people and to secure their lifetimes through management for a favorable blood glucose level 
for a long time. In particular, early drug treatment is considered important for patients with 
mild type 2 diabetes mellitus, which maintains a favorable blood glucose level and inhibits the 
diabetes progress, along with prevention of microangiopathy. 
As an oral drug started to be administered early to patients with mild type 2 diabetes mellitus, 
the desirable drug should have a low risk of hypoglycemia, be well tolerable, and not exhaust 
pancreatic function. 
DPP-4 inhibitors selectively inhibit DPP-4, increase blood GLP-1 levels, and prompt the 
pancreas to secrete insulin in a glucose level-dependent manner. Taken together, DPP-4 
inhibitors are expected to be highly effective for patients with mild type 2 diabetes mellitus. 
As a DPP-4 inhibitor, Nesina tablets (generic name: alogliptin benzoate) are confirmed to be 
highly effective and safe when administered alone and combined with various oral diabetic 
drugs in clinical studies conducted in Japan. The following are approved indications for 
Nesina: 
 
Indications for Nesina tablets 
Type 2 diabetes mellitus 
However, this indication is limited only for patients who had an insufficient response to the 
following therapies: 
(1) Only diet and exercise therapies. 
(2) α-glucosidase inhibitors used in addition to diet and exercise therapies. 
(3) Thiazolidines used in addition to diet and exercise therapies. 
(4) Sulfonylureas used in addition to diet and exercise therapies. 
(5) Biguanides used in addition to diet and exercise therapies. 
 
However, the efficacy and safety of Nesina has not been well evaluated for patients with mild 
type 2 diabetes mellitus because Nesina tablets have been administered to type 2 diabetes 
mellitus patients with HbA1c of ≥ 6.5% (for patients treated with sulfonylureas, HbA1c of ≥ 
7.0%) in clinical studies conducted before drug approval. 
Therefore, this Special Drug Use Surveillance (hereinafter, the Surveillance) was planned to 
evaluate the long-term safety and efficacy of Nesina tablets (hereinafter, Nesina) for patients 
with mild type 2 diabetes mellitus patients in a daily clinical practice. 
 
2.0 
Objectives of Surveillance 
To examine the safety and efficacy of long-term treatment with alogliptin (Nesina) in patients 
with mild type 2 diabetes mellitus in the routine clinical setting. 
 

 
2 
3.0 
Number of Planned Patients for Surveillance and the Rationales 
3.1 Number of Planned Patients for Surveillance 
20000 patients 
 
3.2 Rationales 
According to database of 16 hospitals in Japan, supplied by 
 of 
142358 patients documented as visited from October to December 2010, 15141 were patients 
with type 2 diabetes mellitus. Of these, 4165 patients had HbA1c (JDS) of ≤ 7.0%, which 
were the target population in this Surveillance. For patients with indications for Nesina, in 
addition, 1864 patients (70.4%) received only diet and exercise therapies (no diabetic drugs); 
226 patients (8.5%) received α-glucosidase inhibitors; 175 patients (6.6%) received 
thiazolidines; 273 patients (10.3%) received sulfonylureas; 109 patients (4.1%) received 
biguanides (each drug was administered alone). 
 
In order to identify adverse drug reactions with a frequency of ≥ 0.5% using ≥ a 95% 
confidence level, 600 patients will be required. Assuming that the proportion of drugs in 
patients with mild type 2 diabetes mellitus is same as the above, if data in 20000 patients with 
mild type 2 diabetes mellitus are collected in this Surveillance, 14084 patients will be required 
for Nesina treatment alone; 1708 patients will be required for combination with α-glucosidase 
inhibitors; 1322 patients will be required for combination with thiazolidines; 2063 patients 
will be required for combination with sulfonylureas; 824 patients will be required for 
combination with biguanides. Since any combination can identify the adverse drug reactions 
with a frequency of ≥ 0.5% using ≥ a 95% confidence level, the number of planned patients 
for surveillance was established as 20000. 
 
4.0 
Patients for Surveillance 
Patients with mild type 2 diabetes mellitus will be evaluated for this Surveillance. However, 
patients must meet the inclusion criteria and none of the exclusion criteria, described below. 
Refer to the Precaution with Respect to Indication in the package insert. 
4.1 Inclusion Criteria 
Patients who meet the following criterion will be included in this Surveillance: 
(1) Patients with HbA1c (JDS value) ≤7.0% at the time of enrolment (within 3 months 
before initiation of Nesina therapy) 
* Regardless of the use of antidiabetic medication 
 
4.2 Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from this Surveillance: 
(1) Patients with severe ketosis, diabetic coma or precoma, or type 1 diabetes mellitus 
(2) Patients with severe infection, pre- or post-operative patients, or patients with serious 
traumatic injury 
PPD

 
3 
(3) Patients with a history of hypersensitivity to any ingredient of Nesina 
 
5.0 
Dosage and Administration for Patients to be Surveyed 
The usual adult dose of alogliptin is 25 mg administered orally once daily. Refer to the 
Precaution with Respect to Dosage and Administration in the package insert. 
 
6.0 
Number of To-be Survey Sites by Department 
Internal medicine or other department: Approximately 1000 sites 
 
7.0 
Survey Methods 
7.1 Observation Period 
The observation period will be 36 months after the start date of Nesina treatment. 
If Nesina treatment is discontinued for any reason, the survey will be ended at the 
discontinuation. 
 
7.2 Request for Sites and Agreement 
This surveillance will be conducted using the electronic data collection system via web 
 Before asking survey, MRs of Takeda Takeda Pharmaceutical Company Limited. 
(Hereinafter, Takeda MRs) will fully explain to the Investigator about the objectives, details, 
handling methods for 
, and handling of electronic signature, user ID, and 
passwords, based on “Request for Cooperation of Special Drug Use Surveillance,” “Summary 
for Surveillance,” “Entry Screen Images,” and “Brief Manual for Handling of 
 and 
will finalize written agreement with survey sites to ask requests for surveillance within the 
specified period. 
 
7.3 Methods for Registration of Patients to be Surveyed 
This Surveillance will be conducted using Central Registration System with 
. The 
Investigator will enter registration data on 
 (refer to Section 9.1) for patients who 
start Nesina treatment after the start date of agreement with a survey site, before 14 days after 
the start date of Nesina treatment (define the start date of treatment as “0 day” and one day 
after the start date of treatment as “1 day”). 
 
7.4 Entry on Survey Sheet (Electronic) and Electronic Signature 
The Investigator will enter patient demographic data and details of treatment on 
 at 
each data entry time point (at the start of Nesina treatment, 3 months, 6 months, 12 months, 18 
months, 24 months, 30 months, and 36 months after the start of Nesina treatment or treatment 
discontinuation). In addition, the Investigator will sign electronically on the survey sheet in 
 for “Patient Demographic Data and Details of Treatment by 12 Months of 
Treatment” after 12 months of treatment and for Patient Demographic Data and Details of 
Treatment by 36 Months of Treatment” after 36 months of treatment. 
CCI
CCI
CCI
CCI
CCI
CCI
CCI

 
4 
For patients who discontinue treatment with Nesina during the observation period for any 
reason, the Investigator will enter the patient demographic data and details of treatment on 
 and will sign electronically in the survey sheet around within 1 month after the end 
of necessary observation. However, for patients who discontinue treatment with Nesina due to 
an adverse event, the Investigator will continue observation after treatment discontinuation, 
wherever possible, until the adverse event resolve or is resolving and will enter the 
observation results on 
 as well as sign electronically in the survey sheet. 
In case that additional survey is required after Takeda checked the details, Takeda will ask 
request for re-survey on 
. The Investigator will check the details of request for 
re-survey and enter the re-survey results on 
 as well as sign electronically in the 
survey sheet. 
 
7.5 Measures for Development of Adverse Events 
In case of development of an adverse event, the Investigator will contact the Takeda MR. If 
the Takeda MR requests additional detailed information, the Investigator will provide it. 
 
8.0 
Scheduled Survey Period 
Survey period: July 2011 to January 31, 2017 
Patient registration period: July 2011 to July 31, 2013Note) 
Due date for entry of “Patient Data and Details of Treatment by 12 Months of Treatment:” 
August 31, 2014 
Due date for entry of “Patient Data and Details of Treatment by 36 Months of Treatment:” 
August 31, 2016 
 
Note) Patients who will be treated with Nesina by July 31, 2013 can be registered. 
In case that the registered patients reach the scheduled number of patients to be surveyed 
before July 31 2013, the registration will close earlier than scheduled. 
 
9.0 
Matters to be Surveyed 
The Investigator will enter data of the parameters described below on 
 The 
schedule of this surveillance is shown in the Appendix. 
9.1 Patient Registration Data 
1) Matters to be surveyed 
Start date of Nesina treatment, Patient ID Number, patient initial, sex, birth date, HbA1c 
(JDS) within 3 months prior to Nesina treatment, inclusion criteria assessment, and 
exclusion criteria assessment 
2) Survey period 
At patient registration 
 
9.2 Survey sheet: patient demographic data 
1) Matters to be surveyed 
CCI
CCI
CCI
CCI
CCI

 
5 
Diagnosis period of type 2 diabetes mellitus, height, practice category (at the start of 
survey), presence or absence of pregnancy (females only), pregnancy week (if applicable), 
severity of renal impairment, rationale for assessment of the severity of renal impairment, 
concurrent disease, prior medical history, alcohol history, smoking history, and presence or 
absence of dietary intervention / exercise intervention 
2) Survey period 
At the start of Nesina treatment 
 
9.3 Survey sheet: details of treatment 
1) Matters to be surveyed 
Details of Nesina treatment (daily dose and administration period), status of end of Nesina 
treatment, reason for Nesina discontinuation (if applicable), details of other diabetic drug 
treatment* (drug name, daily dose, route of administration, and administration period), and 
status of concomitant medications (other than diabetic drugs) (drug name, route of 
administration, administration period, and objectives of administration) 
* Diabetic drugs which are discontinued within 3 months prior to Nesina treatment are 
included. 
2) Survey period 
Period from the start of Nesina treatment to 36 months after treatment (or treatment 
discontinuation) 
 
9.4 Laboratory/Observation Parameters 
1) Matters to be surveyed 
HbA1c (JDS or international standard value), fasting glucose, fasting insulin, fasting 
triglyceride, total cholesterol,” HDL-cholesterol, LDL-cholesterol, weight, and blood 
pressure 
2) Survey period 
At the start of Nesina treatment, 3 months , 6 months, 12 months, 18 months, 24 months, 
30 months, and 36 months of treatment (or treatment discontinuation) 
 
9.5 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), procedures related to Nesina, outcome, causal 
relationship to Nesina (refer to Table 3), presence or absence of diabetic complication 
(diabetic retinopathy, diabetic neuropathy, or diabetic nephropathy), change over time in 
clinically important laboratory values related to adverse events 
If the outcome is assessed as Not resolved or Unknown and if the causal relationship cannot 
be assessed, the patient will be followed up, wherever possible. The detailed information 
(clinical course, laboratory tests for diagnosis, etc.) will be collected as possible for 

 
6 
development of hypoglycemia, tumor, pancreatitis, edema, angioedema-related symptom, 
immune system disorder, skin disorder and subcutaneous tissue disorder, cardiovascular 
system event (symptomatic coronary artery disease, cerebrovascular disorder, 
arteriosclerosis obliterans, cardiovascular death, sudden death, etc.) 
2) Survey period 
Period from the start of Nesina treatment to 36 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 in infants breastfed by a Nesina taking mother 
• Symptoms in children who received the relevant drug 
• Symptoms in patients who received the relevant drug at a higher dose than approved or who took by 
themselves 
 

 
7 
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. (e.g., bronchospasm and 
the like, requiring a short-term intensive care in an emergency room and the like) 
 
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 
 
Table 3 Criteria for causality assessment between adverse events and Nesina 
Assessment 
Assessment criterion 
Related 
(Suspectedly related) 
Temporally evident 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 
(Unlikely related) 
No temporally evident 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. 

 
8 
 
10.0 
Analysis Parameters and Methods 
10.1 Patient Component Parameters 
The following will be tabulated: number of registered patients, number of survey sheet 
(electronic) collected patients, number of survey completer, number of survey discontinuations 
and the reason for discontinuation, 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 
The following patient demographics will be tabulated: age, sex, disease period, severity of 
renal impairment (including severity) (yes or no), concurrent disease, past medical history, 
alcohol history, smoking history, etc. 
 
10.3 Details of Treatment 
The following will be tabulated: status of Nesina treatment, status of concomitant medications 
(including the status of diabetic drugs at the start of 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 and summarized by Preferred Term (PT) and System Organ Class 
(SOC). 
 Occurrence of Adverse Drug Reactions 
10.4.1
The type, seriousness, onset period, and the like for adverse drug reactions reported in the 
observation period will be tabulated. 
 
 Factors Probably Affecting Safety 
10.4.2
For adverse drug reactions reported in the observation period, the frequency of patient 
demographics (e.g., age, sex), 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: 
 Changes in HbA1c over Time 
10.5.1
The HbA1c values at each time point and the changes (values at each time point − values at 
the start of Nesina treatment) will be tabulated. The achieving percent in glycemic control 
for HbA1c will be tabulated for each time point. 
 
 Factors Probably Affecting Efficacy 
10.5.2
For the changes in HbA1c and the achieving percent in glycemic control for HbA1c at 36 
months after the start of treatment, the following will be stratified: patients demographics 

 
9 
(e.g., age, sex, 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 
For the safety and efficacy in patients with moderate or higher renal impairment, the 
relationship between the severity of renal impairment and Nesina doses (each will be 
stratified) will be thoroughly evaluated. 
 
10.7 Interim Analysis 
After 1-year observation period is completed in all patients, the interim analysis for the 
parameters described in Sections 10.1 to 10.6 will be performed to confirm the early safety 
and efficacy of Nesina in patients with mild type 2 diabetes mellitus, based on the data entered 
in “Patient Data and Details of Treatment by 12 Months of Treatment.” 
 
11.0 
Surveillance Organizations 
11.1 Investigator 
Takeda 
Pharmaceutical Company Limited. 
 
 
11.2 Medical Expert 
 
12.0 
Name and address of CRO and Scope of the CRO Task 
 
13.0 
Other Necessary Matters 
13.1 Revision of the Protocol 
During the surveillance period, the protocol can be reviewed and revised, if the following are 
necessary to be changed after monitored: the survey progress, number of dropouts, 
development of 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 surveillance period, if partly changes of dosage and 
administration and indications are approved, the protocol revision will be also considered and 
performed as necessary. 
 
PPD
PPD
PPD
PPD

 
10 
13.2 Measures for Issues or Questions 
If any question about the safety or efficacy is arisen, data will be thoroughly investigated and 
the relevant persons will take measures for the question. 
 

 
11 
Appendix Surveillance Schedule 
 
Survey/data entry time point 
 
 
Parameters 
Observation period 
At patient 
registration 
At start of 
treatment 
3 months after 
treatment 
6 months after 
treatment 
12 months 
after treatment 
18 months 
after treatment 
24 months 
after treatment 
30 months 
after treatment 
36 months 
after treatment 
At treatment 
discontinuation 
Patient registration data 
Start date of Nesina tablets 
X 
 
 
 
 
 
 
 
 
 
Patient ID Number 
X 
Patients initial 
X 
Sex 
X 
Birth date 
X 
HbA1c within 3 months prior to Nesina 
treatment 
X 
 
 
 
 
 
 
 
 
 
Inclusion criteria / exclusion criteria 
X 
 
 
 
 
 
 
 
Patient demographic data 
Diagnosis period of type 2 diabetes 
mellitus 
 
X 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
Category of clinical practice (at start of 
survey) 
 
X 
 
 
 
 
 
 
 
 
Pregnancy (yes or no) (females only) 
X 
 
 
 
 
 
 
 
Week of pregnancy (if applicable) 
X 
 
 
 
 
 
 
 
Severity of renal impairment 
X 
 
 
 
 
 
 
 
Rationale for severity assessment of renal 
impairment 
 
X 
 
 
 
 
 
 
 
 
Concurrent disease 
X 
 
 
 
 
 
 
 
Past medical history 
X 
 
 
 
 
 
 
Alcohol history 
X 
 
 
 
 
 
 
Smoking history 
X 
 
 
 
 
 
 
Dietary/exercise intervention (yes or no) 
 
X 
 
 
 
 
 
 
 
Details of 
treatment 
Status of Nesina tablet treatment 
X 
Other diabetic drug 
X 
Concomitant medication (other than diabetic
drugs) 
 
X 
Laboratory/Observation Parameters, 
etc 
Laboratory values 
• HbA1c (JDS or international standard 
value) 
• Fasting glucose 
• Fasting insulin 
• Fasting triglyceride 
• Total cholesterol 
• HDL-cholesterol 
• LDL-cholesterol 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood pressure 
X  
X 
X 
X 
X 
X 
X 
X 
X 
Adverse event 
X