Conditions: Type 2 Diabetes Mellitus
Keywords: Type 2, Diabetes, Diabetes Mellitus
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 27
Healthy volunteers: no

Brief summary:
This is a multi-center, randomized, open-label, parallel-group comparative, exploratory study to evaluate the effect of trelagliptin administered at a dose of 100 mg once weekly or alogliptin administered at a dose of 25 mg once daily for 4 weeks on glycemic variation in patients with type 2 diabetes mellitus using continuous glucose monitoring (CGM).

Detailed description:
The purpose of this study is to evaluate the effect of trelagliptin administered orally at a dose of 100 mg once weekly or alogliptin administered orally at a dose of 25 mg once daily for 4 weeks on glycemic variation in an exploratory manner as a primary objective and to evaluate the effect of difference method of administration of Dipeptidyl-peptidase (DPP)-4 on glycemic variation as secondary objective.

Arms:
arm 1: Trelagliptin 100 mg once weekly taken orally before breakfast arm 2: Alogliptin 25 mg once daily taken orally before breakfast

Interventions: intervention 1: Trelagliptin intervention 2: Alogliptin
Intervention descriptions: intervention 1: Trelagliptin 100 mg tablet intervention 2: Alogliptin 25 mg tablet

Protocol document:
Prot_000.pdf: 
Certain information within this clinical study report has been redacted (ie, specific content is masked 
irreversibly from view with a black 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 and the language in original document was Japanese.


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CONFIDENTIAL 
 
PROTOCOL 
 
 
An exploratory study to evaluate the effects of Trelagliptin and Alogliptin by CGM 
on glucose variability for one week with type 2 diabetes mellitus (TRACK) 
 
 
 
 
 
Sponsor 
Takeda Pharmaceutical Company Limited 
2-12-10 Nihonbashi, Chuo-ku, Tokyo 
Protocol number 
Trelagliptin-4001 
Version number 
3rd Version 
Study drug: 
Trelagliptin 
Alogliptin 
Creation date 
February 16, 2017 
 
 
CONFIDENTIAL PROPERTY 
This document is a confidential communication of Takeda. Acceptance of this document constitutes 
agreement by the potential recipient of the drug to be administered that no information contained herein 
will be published or disclosed without written authorization from Takeda except to the extent necessary to 
obtain informed consent from those research subjects to whom the drug may be administered. 
Furthermore, the information is only intended for review and compliance by the recipient, his or her staff, 
and applicable institutional review committee and regulatory agencies to enable conduction of the study. 


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1.0 
CLINICAL STUDY PRINCIPLES AND CLINICAL STUDY 
MANAGEMENT INFORMATION 
1.1 
Clinical Study Principals 
This study will be conducted with the highest respect for the individual participants in accordance 
with the requirements of this clinical study protocol and also in accordance with the following: 
• 
The ethical principles that have their origin in the Declaration of Helsinki. 
• 
Ethical Guideline for Clinical Research (the Ministry of Education, Culture, Sports, Science and 
Technology and the Ministry of Health, Labour and Welfare, December 22, 2014). 
• 
Good Clinical Practice: Consolidated Guideline (ICH. E6) 
• 
All applicable laws and regulations, including, without limitation, data privacy laws and conflict 
of interest guidelines. 
1.2 
CLINICAL STUDY ADMINISTRATIVE STRUCTURE 
This study will be conducted under the administrative structure described in the attached sheet 1 in 
accordance with the protocol prepared and planned by the sponsor.  
 


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Table of Contents 
1.0 
CLINICAL STUDY PRINCIPLES AND CLINICAL STUDY 
MANAGEMENT INFORMATION ....................................................................... 2 
1.1 
Clinical Study Principals ................................................................................... 2 
1.2 
CLINICAL STUDY ADMINISTRATIVE STRUCTURE ............................... 2 
2.0 
STUDY SUMMARY .............................................................................................. 8 
3.0 
ABBREVIATION ................................................................................................. 14 
4.0 
INTRODUCTION ................................................................................................. 15 
4.1 
Background ...................................................................................................... 15 
4.2 
Rationale for the proposed research ................................................................ 15 
5.0 
RESEARCH OBJECTIVES AND ENDPOINTS ................................................. 17 
5.1 
Objectives ........................................................................................................ 17 
5.2 
Definition of endpoints .................................................................................... 17 
5.2.1 Primary endpoints ...................................................................................... 17 
5.2.2 Secondary endpoints .................................................................................. 17 
5.2.3 Other endpoints ......................................................................................... 18 
6.0 
CLINICAL RESEARCH DESIGN ....................................................................... 19 
6.1 
Clinical research design ................................................................................... 19 
6.2 
Rationale for the clinical research design ........................................................ 20 
6.3 
Premature termination of entire clinical research or premature 
termination of clinical research at a research implementing entity ................. 21 
6.3.1 Premature termination criteria of entire clinical research ......................... 21 
6.3.2 Criteria for premature termination of research implementing entities ...... 22 
6.3.3 Procedures of clinical study suspension and premature termination of 
entire clinical study or study at a research implementing entity ............... 22 
6.4 
Procedures for protocol revision ..................................................................... 22 
7.0 
SELECTION AND WITHDRAWAL CRITERIA OF RESEARCH 
SUBJECTS ............................................................................................................ 23 
7.1 
Inclusion criteria .............................................................................................. 23 
7.2 
Exclusion criteria ............................................................................................. 24 
7.3 
Prohibited concomitant drugs and restricted concomitant drugs..................... 27 


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7.3.1 Prohibited concomitant drugs .................................................................... 27 
7.3.2 Restricted concomitant drugs .................................................................... 27 
7.4 
Research Subject Management ........................................................................ 27 
7.5 
Criteria for discontinuation or withdrawal of a research subject .................... 28 
7.6 
Procedures for discontinuation of individual research subjects ...................... 29 
8.0 
RESEARCH TREATMENT ................................................................................. 30 
8.1 
Treatment with the study drug ......................................................................... 30 
8.1.1 Study drug ................................................................................................. 30 
8.1.2 Dose and administration method ............................................................... 30 
8.1.3 Overdose .................................................................................................... 31 
8.2 
Medication other than the study drug .............................................................. 31 
8.3 
Allocation and prescription of the study drug and administration 
procedure ......................................................................................................... 31 
8.4 
Preparation and storage of allocation list ........................................................ 32 
9.0 
CLINICAL STUDY PROTOCOL ........................................................................ 33 
9.1 
Research procedures ........................................................................................ 33 
9.1.1 Informed consent procedure ...................................................................... 33 
9.1.2 Demographic data, medical history, and previous therapeutic drugs ........ 33 
9.1.3 Physical examination ................................................................................. 33 
9.1.4 Weight, height and BMI ............................................................................ 33 
9.1.5 Concomitant drugs ..................................................................................... 34 
9.1.6 Concurrent disease ..................................................................................... 34 
9.1.7 Laboratory tests ......................................................................................... 34 
9.1.8 HbA1c (NGSP value) ................................................................................ 35 
9.1.9 Continuous glucose monitoring (CGM) .................................................... 35 
9.1.10 Contraception ............................................................................................ 36 
9.1.11 Pregnancy .................................................................................................. 37 
9.1.12 Record of cases withdrawn before randomization .................................... 37 
9.1.13 Record of randomization ........................................................................... 37 
9.2 
Drug-taking status of the research subjects ..................................................... 38 
9.3 
Implementation time point of the test and observation items .......................... 38 


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9.3.1 Start of observation period (Visit 1: Day -2) ............................................. 38 
9.3.2 At start of treatment period (Visit 2: Day 1) ............................................. 39 
9.3.3 Treatment period (Visit 3: Day 21) ........................................................... 39 
9.3.4 Treatment period (Visit 4: Day 24) ........................................................... 40 
9.3.5 At end of treatment period (Visit 5: Day 29) or discontinuation 
during treatment period ............................................................................. 40 
10.0 
ADVERSE EVENT ............................................................................................... 42 
10.1 
Definitions ....................................................................................................... 42 
10.1.1 Adverse event ............................................................................................ 42 
10.1.2 Considerations for adverse events ............................................................. 42 
10.1.3 Serious adverse event ................................................................................ 44 
10.1.4 Adverse events of special interest (specific adverse events) ..................... 45 
10.1.5 Severity of adverse events ......................................................................... 46 
10.1.6 Causality of adverse events ....................................................................... 46 
10.1.7 Relationship to study procedures ............................................................... 47 
10.1.8 Date of onset .............................................................................................. 47 
10.1.9 Date of resolution ...................................................................................... 47 
10.1.10Actions taken for the study drug................................................................ 47 
10.1.11Outcome .................................................................................................... 48 
10.2 
Procedures ....................................................................................................... 49 
10.2.1 Collection and reporting of adverse events ............................................... 49 
10.2.2 Collection and reporting of serious adverse events ................................... 50 
10.2.3 Reporting of additional information concerning adverse events ............... 51 
10.3 
Follow-up of serious adverse events ............................................................... 51 
10.3.1 Reporting of serious adverse events to Ethics Review Committee, 
etc., and regulatory authorities .................................................................. 51 
11.0 
COMMITTEES ESTABLISHED FOR THIS STUDY ........................................ 53 
12.0 
DATA MANAGEMENT AND STORAGE OF RECORDS ............................... 54 
12.1 
Case report form .............................................................................................. 54 
12.2 
Timing of data entry into the electronic CRF system ...................................... 55 
12.3 
Storage of records ............................................................................................ 55 


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13.0 
STATISTICAL ANALYSIS METHODS ............................................................. 56 
13.1 
Statistical and analytical plans ......................................................................... 56 
13.1.1 Analysis set ................................................................................................ 56 
13.1.2 Analysis of demographic and other baseline characteristics ..................... 56 
13.1.3 Efficacy analysis ........................................................................................ 56 
13.1.4 Conversion method of data and handling of missing data ........................ 58 
13.1.5 Significance level and confidence coefficient ........................................... 58 
13.1.6 Safety analysis ........................................................................................... 59 
13.2 
Criteria for interim analysis and premature discontinuation ........................... 59 
13.3 
Determination of the number of planned research subject .............................. 59 
14.0 
QUALITY CONTROL AND QUALITY ASSURANCE .................................... 60 
14.1 
Monitoring of the research implementing entity ............................................. 60 
14.2 
Deviation from the Ethical Guidelines for Medical and Health Research 
Involving Human Subjects and the research protocol. .................................... 60 
14.3 
Quality assurance audits and regulatory agency inspections........................... 60 
15.0 
ETHICAL CONDUCT OF CLINICAL RESEARCH .......................................... 62 
15.1 
Approval of the Ethical Review Board, etc. .................................................... 62 
15.2 
Conflict of interest ........................................................................................... 63 
15.3 
Informed consent and information sheet, and the agreement of the 
research subjects .............................................................................................. 63 
15.4 
Personal information of the research subjects ................................................. 64 
15.5 
Consultation windows for the research subjects or persons related to the 
research concerned .......................................................................................... 65 
15.6 
Financial burden or reward to the research subjects........................................ 65 
15.7 
Benefits and inconveniences to the research subjects ..................................... 65 
15.7.1 Benefits to research subjects...................................................................... 65 
15.7.2 Inconveniences to research subjects .......................................................... 65 
15.8 
Attribution of research results and access rights ............................................. 65 
15.8.1 Attribution of research results ................................................................... 65 
15.8.2 Data access rights ...................................................................................... 65 
15.9 
Reporting of results, publication, disclosure, and clinical research 
registration policy ............................................................................................ 66 


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15.9.1 Reporting of results, publication and disclosure ....................................... 66 
15.9.2 Clinical research registration ..................................................................... 66 
15.9.3 Clinical trial results disclosure .................................................................. 66 
15.10 Insurance and compensation for injury ........................................................... 66 
16.0 
REFERENCES ...................................................................................................... 68 
LIST OF IN-TEXT TABLES 
Table8.a 
Administration group and administration method ..................................... 31 
Table 9.a 
Laboratory tests ......................................................................................... 35 
Table 10.a 
Takeda Medically Significant AE List ...................................................... 45 
LIST OF IN-TEXT FIGURES 
Figure6.a 
Outline of clinical research design ............................................................ 20 
LIST OF APPENDICES 
Appendix A 
Schedule of Research Procedures .............................................................. 69 
Appendix B 
Responsibilities of the sponsor .................................................................. 71 
 


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2.0 
STUDY SUMMARY 
Sponsor: 
Takeda Pharmaceutical Company Limited 
Study drug: 
Trelagliptin 
Alogliptin 
Study title: 
An exploratory study of the effects of trelagliptin and alogliptin on glycemic variation 
in patients with type 2 diabetes mellitus 
Protocol number: Trelagliptin-4001 (122/NRP-001) 
Clinical study design: 
This is a multi-center, randomized, open-label, parallel-group comparative, exploratory study to evaluate 
the effect of trelagliptin administered at a dose of 100 mg once weekly or alogliptin administered at a 
dose of 25 mg once daily for 4 weeks on glycemic variation in patients with type 2 diabetes mellitus using 
continuous glucose monitoring (CGM). 
After informed consent, patients determined to be eligible for this study based on the eligibility 
assessment will be randomized to either the trelagliptin 100 mg group or the alogliptin 25 mg group (at a 
ratio of 1:1), using "HbA1c at the start of the observation period (< 7.5% or ≥ 7.5%)" and age (< 65 or ≥ 
65) as a stratification factor for randomization. 
The total duration of evaluation will be 31 days, consisting of the observation period for 2 days and a 
treatment period for 29 days (4 weeks). CGM will be performed on research subjects on an outpatient 
basis (in 2 assessments) for 2 days from the start of the observation period (Day -2) and for 9 days from 
Day 21 of the treatment period. 
Objective:  
To evaluate the effect of trelagliptin administered orally at a dose of 100 mg once weekly or alogliptin 
administered orally at a dose of 25 mg once daily for 4 weeks on glycemic variation in an exploratory 
manner and as preliminary to examine the influence of the once-weekly administration and blood glucose 
fluctuations due to the difference in the daily administration in patients with type 2 diabetes mellitus 
Study population:  
Patients with type 2 diabetes mellitus 
Planned number of research subjects: 
The planned minimum number of research subjects evaluable 
for the primary endpoint in each group is as follows: 
Trelagliptin 100 mg group: 15 
Alogliptin 25 mg group: 15 
Number of study research 
implementing entities: 
3 medical institutions 


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Total: 30 
Dose and method of administration: 
Trelagliptin 100 mg once weekly or alogliptin 25 mg once 
daily, taken orally before breakfast 
Route of administration: 
Oral 
Duration of treatment: 
4 weeks 
Duration of evaluation: 
31 days (observation period for 2 days 
and treatment period for 4 weeks [29 
days]) 
Inclusion criteria 
1. 
Research subjects who, in the opinion of the principal investigator or the investigator, are capable of 
understanding the content of the clinical research and complying with the research protocol 
requirements. 
2. 
Patients who are able to sign and date the informed consent form and information sheet prior to the 
start of study procedures 
3. 
Patients diagnosed with type 2 diabetes mellitus 
4. 
Patients with an HbA1c (NGSP value) value ≥ 6.5% and < 8.5% at the start of the observation 
period (Day -2) 
5. 
Patients who experience a ≤ ±1.0% change in HbA1c (NGSP value) at the start of the observation 
period (Day -2) as compared with an HbA1c value obtained during the preceding 6 weeks 
6. 
Patients receiving stable dietetic therapy and exercise therapy (if performed) for ≥ 4 weeks before 
the start of the observation period 
7. 
Patients, who in the opinion of the principal investigator or the investigator, does not have to change 
(including discontinuation or interruption) HMG-CoA reductase inhibitors or add new HMG-CoA 
reductase inhibitors during treatment period. 
8. 
Men or women aged 20 years or older at the time of informed consent 
Exclusion criteria:  
1. 
Patients who received anti-diabetic medications within 4 weeks prior to the start of the observation 
period 
2. 
Patients who have changed (including discontinuation or interruption) HMG-CoA reductase 
inhibitors or received new HMG-CoA reductase inhibitors ≤ 4 weeks before the start of the 
observation period.  
3. 
Patients with clinically evident hepatic dysfunction (e.g., AST or ALT ≥ 2.5-fold the upper limit of 
normal at the start of the observation period [Day -2]) 


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4. 
Patients with moderate renal dysfunction, severe renal dysfunction or renal failure (e.g., creatinine 
clearance < 50 mL/min or serum creatinine > 1.4 mg/dL in men or > 1.2 mg/dL in women 
[equivalent to the creatinine clearance for persons aged 60 years with a body weight of 65 kg] at the 
start of the observation period [Day -2]) 
5. 
Patients with severe heart disease, cerebrovascular disorder, or severe pancreatic, hematologic or 
other diseases 
6. 
Patients with a history of gastric or small intestinal resection 
7. 
Patients with proliferative diabetic retinopathy 
8. 
Patients warranting insulin therapy for glycemic control (e.g., patients with severe ketosis, diabetic 
coma or precoma, type 1 diabetes mellitus, severe infection, perioperative patients, or serious 
trauma) 
9. 
Patients with a history of hypersensitivity or allergy to DPP-4 inhibitors 
10. Patients who experience an allergic reaction to metal during CGM at the start of the observation 
period (Day -2) 
11. Patients with any malignant tumors 
12. Habitual drinkers whose average daily alcohol consumption is > 100 mL 
13. Patients who have any contraindications for the study drug or are taking any contraindicated 
concomitant drugs listed in the package insert 
14. Patients anticipated to require any prohibited concomitant medications during the study period 
15. Patients who are day and night lifestyle reversal 
16. Patients participating in any other clinical studies at the time of informed consent for this study 
17. Pregnant women, nursing mothers, women who are possible pregnant, or women who plan to 
become pregnant 
18. Other patients who are considered inappropriate for participation in this study in the opinion of the 
principal investigator or investigator 
Endpoints: 
<Primary endpoints> 
• 
Changes in the standard deviation (SD) of 24-hour blood glucose values (mg/dL) for each 7-day 
period between Week 3 and Week 4 (between Day 22 and Day 28) of the treatment period, calculated 
from the value at the start of the observation period 
<Secondary endpoints> 
Efficacy endpoints: 
• 
Changes in AUC over time when specific blood glucose levels ( 110, 140, 160, or 180 mg/dL) are 
observed during the 3 hour time period after breakfast, lunch and evening meal*1, 2 
• 
Change in AUC over time during periods when blood glucose 140, 160, or 180 mg/dL 


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(hyperglycemia) is observed*1, 2 
• 
Changes in blood glucose 140, 160, or 180 mg/dL (hyperglycemia) over time*1, 2 
• 
Changes in AUC over time during periods when blood glucose < 70 mg/dL (hypoglycemia) is 
observed*1,2  
• 
Change in peak postprandial glucose levels over time 3 hours after breakfast, lunch, and evening 
meal*1,2 
• 
 Change in maximum variation of blood glucose levels over time between before and after breakfast, 
lunch, and evening meal*1,2  
• 
Changes in MAGE*1, 2 
• 
Changes in mean 24-hour blood glucose levels*1, 2 
• 
Changes in mean daytime blood glucose levels*1, 2 
• 
Changes in mean nocturnal  blood glucose levels*1, 2 
• 
Changes in AUC*1, 2 
• 
Changes in AUC over time during periods when blood glucose 110 mg/dL (hypoglycemia) is 
observed*1,2 
• 
Changes in the SD of 24-hour blood glucose values*1,2 
• 
Changes in the SD of daytime blood glucose values*1,2 
• 
Changes in the SD of nocturnal blood glucose values*1,2 
*1: Measured value and percent changes for each 7-day period between Week 3 and Week 4 (between 
Day 22 and Day 28) of the treatment period calculated from the value at the start of the observation 
period (however changes in the SD of 24-hour blood glucose values shall be measured value only)  
*2: Measured value and percent change from the value at the start of the observation period to the mean 
value during the 7-day period between Week 3 and Week 4 (between Day 22 and Day 28) of the 
treatment period 
[Safety endpoint] 
• 
Adverse events 
<Other endpoints> 
• 
Glycoalbumin 
• 
1,5-AG 
• 
Fasting blood glucose 
• 
Fasting insulin 
• 
Fasting glucagon 
• 
Fasting proinsulin 


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• 
Fasting GLP-1 
• 
Fasting GIP 
• 
DPP-4 activity 
• 
Inhibitory rate of DPP-4 activity 
Statistical method 
(1) Analysis set 
Two analysis sets, “full analysis set” and “safety data analysis set” are used in this study. "The Full 
Analysis Set" used as a primary analysis set in the efficacy analysis shall be defined as "the research 
subjects who were randomized and given at least one dose of the study drug." The safety data 
analysis set shall be defined as “the research subjects who were given at least one dose of the study 
drug”. 
(2) Efficacy analysis 
<Primary endpoints> 
• 
For the “full analysis set”, summary statistics (number of subjects, mean, SDs, maximum values, 
minimum values, quartiles [same apply hereafter]) and 95% confidence interval (two sides) of mean 
shall be calculated for each treatment group at each evaluation point (each day), and illustrating 
changes in mean and SD in order to evaluate changes in the SD of 24-hour blood glucose values 
(mg/dL) for each 7-day period between Week 3 and Week 4 (between Day 22 and Day 28) of the 
treatment period, calculated from the value at the start of the observation period for trelagliptin or 
alogliptin separately. Preliminary, for the “full analysis set”, calculate point estimation and 95% 
confidence interval (two sides) in difference of mean in treatment groups (trelagliptin 100 mg group 
– alogliptin 25 mg group) in order to examine the influence of the once-weekly administration and 
blood glucose fluctuations due to the difference in the daily administration exploratory. 
• 
As well, for the “full analysis set ,” conduct analysis of covariance at each evaluation point with 
changes in the SD of 24-hour blood glucose values between Week 3 and Week 4 from the value at 
the start of the observation period as dependent variable, treatment groups as independent variable, 
HbA1c (NGSP value) at the start of the observation period, changes in the SD of 24-hour blood 
glucose values at the start of the observation period, and age as covariates, and calculate point 
estimation and 95% confidence interval (two sides) in difference of adjusted mean for each group. 
• 
Preliminary, “full analysis set ,” calculate point estimation and 95% confidence interval (two sides) 
in difference of adjusted mean in treatment groups (trelagliptin 100 mg group – alogliptin 25 mg 
group) 
<Secondary endpoints> 
• 
Conduct the same analysis as the primary endpoints for *1 and *2 of the each endpoint section. 


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However, for changes in mean/SD, only measured values of *1 and *2 shall be illustrated. 
<Additional endpoints> 
• For the “full analysis set”, while calculating summary statistics and 95% confidence interval (two 
sides) of mean at each evaluation point (the start of the observation period by each treatment group, 
first day, 1 point during third to fifth day, and ninth day of CGM which is to be performed for 9 days 
from Day 21) in measured values and changes from the start of the observation period, and illustrate 
changes in mean and SD. 
(3) Safety analysis 
• Adverse events shall be reported using MedDRA terminology and summarized using the Preferred 
Term (PT) and System Organ Class (SOC) of the MedDRA. For the “safety data analysis set”, 
frequency tabulation shall be conducted for adverse events after start of treatment with study drug by 
each treatment group: 
 
Frequency tabulation of all adverse events 
 
Frequency tabulation of adverse events that causal relationship is “related” to study drug. 
 
Frequency tabulation of the degree of all adverse events 
 
Frequency tabulation of degree of adverse events that causal relationship is “related” to study 
drug. 
 
Frequency tabulation of adverse events that were “discontinued” as a measurement concerning 
study drug. 
 
Frequency tabulation of serious adverse events 
Rationale for the number of planned research subjects: 
The planned minimum number of research subjects evaluable for the primary endpoint in each group is as 
follows: 
Trelagliptin 100 mg group: 15 
Alogliptin 25 mg group: 15 
Set in consideration with the feasibility of the number of research subjects for exploring the effects of 
trelagliptin 100 mg and alogliptin 25 mg on glycemic variation. It is not based on statistical power 
calculation. 


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3.0 
ABBREVIATION 
AE 
adverse event 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AUC 
Area under the curve 
1,5-AG 
1,5-anhydroglucitol 
BMI 
body mass index 
CGM 
continuous glucose monitoring 
COI 
conflict of interest 
CRO 
contract research organization 
DPP-4 
dipeptidyl-peptidase-4 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GIP 
glucose-dependent insulinotropic 
polypeptide 
GLP-1 
glucagon like peptide-1 
HbA1c 
hemoglobin A1c 
ICH 
International Conference on 
Harmonisation 
MAGE 
Mean Amplitude Glycemic Excursions 
MedDRA 
Medical Dictionary for Regulatory 
Activities 
PT 
preferred term  
SAE 
serious adverse event 
SD 
standard deviation 
SMBG 
Self Monitoring of Blood Glucose 
SOC 
system organ class 
WHO 
World Health Organization 
 


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4.0 
INTRODUCTION 
4.1 
Background 
Conventionally, although HbA1c has been used as an indicator for glycemic control for patients with 
diabetes mellitus, it has been indicated that it is insufficient for inhibiting cardiovascular events by 
only controlling HbA1c which reflects the long term glycemic variation 1-3) On the other hand, it has 
been reported that persistent hyperglycemia and the range of glycemic variation is related to 
oxidative stress and cardiovascular events, and it has been indicated that treatment is necessary in 
consideration of daily glycemic variation 4-6). Also, it is anticipated that the glycemic variation of 
patients with diabetes mellitus and the characteristics of each anti-diabetic medications may be 
revealed and to be able to make a choice for a more appropriate treatment. 
Self-measurement of blood glucose (SMBG) is used frequently for measuring glycemic variation 
and although one may understand the blood glucose level at the time of measurement, it is difficult 
to know if the blood glucose level has an upward trend or not changing or a downward trend at that 
time point, and it is reported that 80% hypoglycemia or hyperglycemia may be missed 7,8). That is 
why the continuous glucose monitor (CGM) was developed and it became possible to accurately 
evaluate variance of blood glucose which was difficult and planning of treatment course according to 
each patient’s condition is anticipated. Actually, in many researches that was conducted to collect 
various glycemic variation patterns to verify the optimization of treatment of diabetes mellitus, the 
benefits of various indicators of glycemic variation obtained from CGM has been reported 9). 
Dipeptidyl-peptidase-4 (DPP-4) inhibitors are used widely as oral treatment drug for type 2 diabetes 
mellitus and it has an effect to promote insulin secretion blood glucose dependently by raising blood 
concentration of glucagon like peptide-1 (GLP-1). Conventionally, although DPP-4 inhibitors are 
taken once to twice daily commonly, once weekly trelagliptin was developed for a new treatment 
option as good glycemic control from improvement of drug compliance rate and flexibility of timing 
of taking drug according to lifestyle and further improvement of Quality Of Life(QOL) from less 
number of doses was in need. The phase III clinical study conducted at the development stage has 
shown that trelagliptin, when administered for 24 weeks, was not inferior to alogliptin, a DPP-4 
inhibitor used as control, in terms of the change in HbA1c at the end of the treatment period 10). 
However, effect on glycemic variation of trelagliptin and alogliptin has not been clarified efficiently, 
and it is anticipated that understanding the characteristics of once weekly DPP-4 inhibitors and once 
daily DPP-4 inhibitors may be an efficient rational for therapeutic use. 
 
4.2 
Rationale for the proposed research 
 


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Because there is no enough evidence assayed for glycemic variation of not only once weekly DPP-4 
inhibitors but also once daily DPP-4 inhibitor, Trelagliptin, once weekly DPP-4 inhibitor, and 
Alogliptin, once daily DPP -4 inhibitor, were set as study drugs to collect the consecutive data of 
glycemic variation obtained from CGM and to evaluate difference of DPP-4 inhibitors.  
Although trelagliptin was non-inferior to alogliptin, once daily DPP-4 inhibitor, in terms of the 
change from baseline in HbA1c at the phase III clinical study conducted during the development 
period, the effect on glycemic variation of alogliptin have to be clarified when the effect of different 
dose and method of administration of DPP-4 inhibitors on glycemic variation would like to be 
evaluated. 
In this present study, therefore, the effect of once weekly trelagliptin or once daily alogliptin on 
glycemic variation will be evaluated in patients with type 2 diabetes mellitus in an exploratory 
manner as a primary objective, and the effect by difference of dose and method of administration on 
glycemic variation will be evaluated as secondary as far as possible. 


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5.0 
RESEARCH OBJECTIVES AND ENDPOINTS 
5.1 
Objectives 
 
To evaluate the effect of trelagliptin administered orally at a dose of 100 mg once weekly or 
alogliptin orally administered at a dose of 25 mg once daily for 4 weeks on glycemic variation in an 
exploratory manner as a primary objective and to evaluate, as far as possible, the effect of difference 
method of administration of DPP-4 on glycemic variation as secondary objective. 
 
5.2 
Definition of endpoints 
5.2.1 Primary endpoints 
Changes in the standard deviation (SD) of 24-hour blood glucose values (mg/dL) for each 7-day 
period between Week 3 and Week 4 (between Day 22 and Day 28) of the treatment period, 
calculated from the value at the start of the observation period 
5.2.2 Secondary endpoints 
(1) Efficacy: 
 
Changes in AUC over time when specific blood glucose levels ( 110, 140, 160, or 180 
mg/dL) are observed during the 3 hour time period after breakfast, lunch and evening meal 
 
Change in AUC over time during periods when blood glucose 140, 160, or 180 mg/dL 
(hyperglycemia) is observed 
 
Changes in blood glucose 140, 160, or 180 mg/dL (hyperglycemia) over time 
 
Changes in AUC over time during periods when blood glucose < 70 mg/dL 
(hypoglycemia) is observed 
 
Change in peak postprandial glucose levels over time 3 hours after breakfast, lunch, and 
evening meal 
 
Change in maximum variation of blood glucose levels over time between before and after 
breakfast, lunch, and evening meal 
 
Changes in MAGE  
 
Changes in mean 24-hour blood glucose levels  
 
Changes in mean daytime blood glucose levels 
 
Changes in mean nocturnal blood glucose levels 


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 
Changes in AUC 
 
Changes in AUC over time during periods when blood glucose 110 mg/dL is observed 
 
Changes in the SD of 24-hour blood glucose values 
 
Changes in the SD of daytime blood glucose values 
 
Changes in the SD of nocturnal blood glucose values 
(2) Safety: Adverse events 
5.2.3 Other endpoints 
(1) Efficacy: 
 
Glycoalbumin 
 
1,5-AG 
 
Fasting blood glucose 
 
Fasting insulin 
 
Fasting glucagon 
 
Fasting proinsulin 
 
Fasting GLP-1 
 
Fasting GIP 
 
DPP-4 activity 
 
Inhibitory rate of DPP-4 activity 


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6.0 
CLINICAL RESEARCH DESIGN 
6.1 
Clinical research design 
<Clinical study design> 
This is a multi-center, randomized, open-label, parallel-group comparative, exploratory study to 
evaluate the effect of trelagliptin administered at a dose of 100 mg once weekly or alogliptin at a 
dose of 25 mg once daily for 4 weeks on glycemic variation in patients with type 2 diabetes mellitus 
using continuous glucose monitoring (CGM). 
 
<Research TREATMENT> 
After informed consent, patients determined to be eligible for this study based on the eligibility 
assessment will be randomized to either the trelagliptin 100 mg group or the alogliptin 25 mg group 
(at a ratio of 1:1), using "HbA1c at the start of the observation period (< 7.5% or ≥ 7.5%)" and age 
(< 65 or ≥ 65) as a stratification factor for randomization. 
The principal investigator or investigator shall prescribe trelagliptin 100 mg/week or alogliptin 25 
mg/day according to the allocation results notified from the enrollment center. 
Trelagliptin 100 mg once weekly or alogliptin 25 mg once daily, taken orally before breakfast 
Planned number of research subjects: 
The planned minimum number of research subjects evaluable for the primary endpoint in each group 
is as follows: 
Trelagliptin 100 mg group: 15 
Alogliptin 25 mg group: 15 
Number of study research implementing entities: 
3 medical institutions 
<Duration of evaluation and number of visits of research subjects> 
Duration of evaluation: 31 days, consisting of the observation period for 2 days and a treatment 
period for 29 days (4 weeks). 
Number of visits: a total of 5 visits. Research subjects shall visit the study site at the start of the 
observation period (VISIT 1: Day-2), at the start of the treatment period (VISIT 2: Day 1), during 
the treatment period for CGM insertion (VISIT 3: Day 21) and for CGM sensor exchange (VISIT 4: 
Day 24), and at the end of the treatment period (VISIT 5: Day 29). 
Figure 6 (a) shows a schematic of the clinical research design. Refer to Appendix A for schedule of 
examinations, observations, and assessments. 


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Figure 6.a Outline of clinical research design 
< Outline of clinical research > 
 
 
 
Week 0 
 
 
 
 
 
Week 3 
 
Week 4 
 
 
 
(Randomizati
on) 
 
 
 
 
 
 
 
 
 
 
Day -2 
（Day 1） 
 
 
 
 
Day 21 
Day 22 
Day 24 
Day 29 
 
 
VISIT 1 
（VISIT 2） 
 
 
 
 
VISIT 3 
 
VISIT 4 
VISIT 5 
 
 
Insert CGM 
sensor 
Laborator
y tests 
Remove CGM 
sensor 
Start study 
medication 
 
 
 
 
Insert CGM sensor 
Laboratory 
tests 
 
 
Exchange 
CGM sensor 
 
Remove CGM 
sensor 
Laboratory 
tests 
Informed 
consent 
procedure 
Assess eligibility 
 
 
 
 
 
 
 
     ←Observation period→ 
←      Treatment period     → 
 
Trelagliptin 100 mg 
 
Alogliptin 25 mg 
Stable dietetic therapy and exercise therapy 
 
6.2 
Rationale for the clinical research design 
(1) Rationale for the clinical research design 
  
Because there is no enough evidence assayed for glycemic variation of not only once weekly 
DPP-4 inhibitors but also once daily DPP-4 inhibitor, Trelagliptin, once weekly DPP-4 inhibitor, 
and Alogliptin, once daily DPP -4 inhibitor, were set as study drugs to collect the consecutive 
data of glycemic variation obtained from CGM and to evaluate difference of DPP-4 inhibitors.  
Although trelagliptin was non-inferior to alogliptin, once daily DPP-4 inhibitor, in terms of the 
change from baseline in HbA1c at the phase III clinical study conducted during the development 
period,  the effect on glycemic variation of alogliptin have to be clarified when the effect of 
different dose and method of administration of DPP-4 inhibitors on glycemic variation would like 
to be evaluated.  
In this present study, therefore, the effect of once weekly trelagliptin or once daily alogliptin on 
glycemic variation will be evaluated in patients with type 2 diabetes mellitus in an exploratory 
manner as a primary objective, and the effect by difference of dose and method of administration 
on glycemic variation will be evaluated as secondary as far as possible. 


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Therefore this unblind study was designed to objectively evaluate the effect on glycemic variation of 
trelagliptin 100 mg and alogliptin 25 mg administered in patients with type 2 diabetes mellitus. And 
also to evaluate the effect of different method of administration on glycemic variation, stratified 
randomization comparison method between 2 groups was adopted with “HbA1c at the start of the 
observation period (< 7.5% or ≥ 7.5%) and age (< 65 or ≥ 65)” as a stratification factor for 
randomization. 
Also, to exclude effect on glycemic variation from other anti-diabetic medications, research 
subjects who were taking anti-diabetic medications ≤ 4 weeks before start of observation period 
were excluded. 
(2) Rationale for dosage 
The dosages of trelagliptin and alogliptin were set at 100 mg/week and 25 mg/day, respectively, 
to evaluate glycemic variation at the usual dosage in clinical settings.  
(3) Rationale for dosage 
Study drugs show the glucose lowering effect by increasing incretin which are secreted by food 
intake. Thus, in order to eliminate the influence on the blood glucose by food intake. To further 
unify the administration timing of the research subjects prior to breakfast in terms of evaluating 
their glycemic variation. 
(4) Rationale for duration of treatment 
From the results of trelagliptin and alogliptin in phase II and III trials, duration was set at 4 
weeks taking into account that the effect on blood glucose levels stabilize after 2 to 4 weeks 
with either drugs. 
(5) Rationale for the number of planned research subjects: 
Refer section 13.3 
6.3 
Premature termination of entire clinical research or premature termination 
of clinical research at a research implementing entity 
6.3.1 Premature termination criteria of entire clinical research 
The sponsor should immediately discontinue the study when at least one of the following criteria is 
applicable: 
 
When new information or other evaluation on the safety or efficacy of the study drug becomes 
available that shows a change in the known risk/benefit profile of the concerned compound, and 
risks/benefits are no longer tolerable for research subject participation in the study. 


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 
When there is serious deviation from ethical guidelines or ICH-GCP that may threaten safety of 
the research subjects. 
6.3.2 Criteria for premature termination of research implementing entities 
A study site may be notified by the sponsor to discontinue clinical study if the site (including the 
principal investigator) is found in significant violation of Ethical Guideline for Clinical Research, 
protocol, or contractual agreement, is unable to ensure adequate performance of the study, or as 
otherwise permitted by the contractual agreement. 
6.3.3 Procedures of clinical study suspension and premature termination of 
entire clinical study or study at a research implementing entity 
In the event that the sponsor or a research implementing entity committee such as an ethics review 
committee decides to prematurely suspend or terminate the entire clinical study or clinical study at a 
research implementing entity, a study-specific procedure shall be provided by the sponsor. The 
procedure shall be followed by applicable research implementing entities during the course of 
clinical study suspension or premature termination. 
6.4 
Procedures for protocol revision 
If the protocol needs to be revised, the sponsor shall consider and decide whether to revise the 
protocol. 
The principal investigator of each research implementing entity shall be informed of the details of 
each protocol revision. Also, principal investigators shall confirm the content of the revision of the 
protocol and submit a letter of agreement to the sponsor as evidence of agreement with the protocol 
revision. 
Upon notification, the principal investigator at each research implementing entity shall submit the 
revised contents to committees such as the IEC, as necessary according to institutional regulations 
for review, and obtain approval from the director of the entity. 


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7.0 
SELECTION AND WITHDRAWAL CRITERIA OF RESEARCH 
SUBJECTS 
7.1 
Inclusion criteria 
Research subjects shall fulfill all of the following criteria to be included in this clinical study: 
1. Research subjects who, in the opinion of the principal investigator or the investigator, are 
capable of understanding the content of the clinical research and complying with the 
research protocol requirements. 
2. Patients who are able to sign and date the informed consent form and information sheet 
prior to the start of study procedures 
3. Patients diagnosed with type 2 diabetes mellitus 
4. Patients with an HbA1c (NGSP value) value ≥ 6.5% and < 8.5% at the start of the 
observation period (Day -2) 
5. Patients who experience a ≤ ±1.0% change in HbA1c (NGSP value) at the start of the 
observation period (Day -2) as compared with an HbA1c value obtained during the 
preceding 6 weeks 
6. Patients receiving stable dietetic therapy and exercise therapy (if performed) for ≥ 4 weeks 
before the start of the observation period 
7. Patients who in the opinion of the principal investigator or the investigator, does not have to 
change (including discontinuation or interruption) HMG-CoA reductase inhibitors or 
addition of new HMG-CoA reductase inhibitors during treatment period.  
8. Men or women aged 20 years or older at the time of informed consent 
[Rational for the inclusion criteria] 
1.2. These were set as essential conditions for the clinical research. 
3. 
Set as target disease for this study. 
4. 
To evaluate the glycemic variation caused by the study drug accurately, the upper limit 
value was set at 8.5% (NGSP value) to exclude research subject with insufficient glycemic 
control. 
5. 
To evaluate the glycemic variation accurately, the change variation of HbA1c was set to 
exclude research subject with unstable glycemic control 
6. 
Set in consideration of the possibility of change in dietetic/exercise therapy may affect 
evaluation of glycemic variation. 


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7. This was set in consideration of the possibility that HMG-CoA reductase inhibitors may 
affect glycemic variation. 
8. 
This was set to allow for separate assessment of men/women. The lower age limit was set 
to 20 years to allow patients to make a voluntary decision regarding their participation in 
this clinical research. 
 
7.2 
Exclusion criteria 
Research subjects meeting any of the criteria below shall not be included in this research. 
1. Patients who received anti-diabetic medications within 4 weeks prior to the start of the 
observation period. 
2. Patients who have changed (including discontinuation or interruption) HMG-CoA reductase 
inhibitors or received new HMG-CoA reductase inhibitors ≤ 4 weeks before the start of the 
observation period. 
3. Patients with clinically evident hepatic dysfunction (e.g., AST or ALT ≥ 2.5-fold the upper 
limit of normal at the start of the observation period [Day -2]) 
4. Patients with moderate renal dysfunction, severe renal dysfunction or renal failure (e.g., 
creatinine clearance < 50 mL/min or serum creatinine > 1.4 mg/dL in men or > 1.2 mg/dL in 
women [equivalent to the creatinine clearance for persons aged 60 years with a body weight 
of 65 kg] at the start of the observation period [Day -2]) 
5. Patients with severe heart disease, cerebrovascular disorder, or severe pancreatic, 
hematologic or other diseases 
6. Patients with a history of gastric or small intestinal resection 
7. Patients with proliferative diabetic retinopathy 
8. Patients warranting insulin therapy for glycemic control (e.g., patients with severe ketosis, 
diabetic coma or precoma, type 1 diabetes mellitus, severe infection, perioperative patients, 
or serious trauma) 
9. Patients with a history of hypersensitivity or allergy to DPP-4 inhibitors 
10. Patients who experience an allergic reaction to metal during CGM at the start of the 
observation period (Day -2) 
11. Patients with any malignant tumors 
12. Habitual drinkers whose average daily alcohol consumption is > 100 mLNote 1) 


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13. Patients who have any contraindications for the study drug or are taking any contraindicated 
concomitant drugs listed in the package insert 
14. Patients anticipated to require any prohibited concomitant medications during the study 
period 
15. Patients who are day and night lifestyle reversal 
16. Patients participating in any other clinical studies at the time of informed consent for this 
study 
17. Pregnant women, nursing mothers, women who are possible pregnant, or women who plan 
to become pregnant 
18. Other patients who are considered inappropriate for participation in this study in the opinion 
of the principal investigator or investigator 


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Note 1: Alcohol conversion table (for reference) 
Alcohol type 
Variation 
Alcohol strength (%) 
Amount equivalent to alcohol 100 mL 
Brewed alcohol 
Sake 
15% 
670 mL (about 3 gos, 1 go=180 mL) 
Beer 
5% 
2,000 mL (about 3 large bottles) 
Happoshu 
(low-malt beer –
like beverage) 
5% 
2,000 mL 
Wine 
12% 
830 mL 
Shaoxing rice 
wine 
18% 
560 mL 
Spirits 
Shochu  
(group ko) 
35% 
290 mL 
Shochu  
(group otsu) 
25% 
400 mL 
Whisky 
40% 
250 mL (about 3 double glasses) 
Brandy 
40% 
250 mL (about 3 double glasses) 
Vodka 
40% 
250 mL (about 3 double glasses) 
Combined alcohol 
Plum wine 
13% 
770 mL 
Combined sake 
16% 
630 mL 
[Rationale for the exclusion criteria] 
1, 2. Set in order to evaluate drug efficacy accurately. 
3, 5, 7, 10, 11, 13. These were set in consideration of safety of research subjects. 
4. Severe renal dysfunction and renal failure shall be excluded because trelagliptin is 
contraindicated for these conditions. Moderate renal dysfunction shall be excluded in 
consideration of safety of research subjects. 
6, 12, 14. Set in order to take in consideration of safety of research subjects and to evaluate drug 
efficacy accurately. 
8, 9. Set as contraindication for trelagliptin and alogliptin treatment. 
15..,16 Set in order to establish rational for evaluation of this study. 
17. Set as safety of trelagliptin and alogliptin in pregnant women has not been established. Also, 
set as excretion of trelagliptin and alogliptin in breast milk was confirmed in non-clinical 
trials. 
18. These were set as fundamental items for the research. 


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7.3 
Prohibited concomitant drugs and restricted concomitant drugs 
7.3.1 Prohibited concomitant drugs 
The following drugs are prohibited from the start of observation period to end of treatment period. 
1. Anti-diabetic medications other than the allocated oral hypoglycemic drug 
2. Glucocorticoids (medications for local effect such as external preparations are excluded) 
3. Estrogen preparations 
4. HMG-CoA reductase inhibitors* other than those used at the time of informed consent 
*Dosage of HMG-CoA reductase inhibitors those used at the time of informed consent may 
not be changed.  
5. Acetaminophen 
 [Rational for prohibited concomitant drugs] 
1 to 5. Set as it may affect evaluation of drug efficacy. 
7.3.2 Restricted concomitant drugs 
The following drugs those used at the time of informed consent are permitted from the start of 
observation period to end of treatment period. However, change of dosage, addition of or change to a 
new drug for those drugs is prohibited unless the principal investigator and investigator consider 
necessary due to adverse events. 
1. Lipid lowering agents other than HMG-CoA reductase inhibitors 
2. Anti-hypertensive drug 
7.4 
Research Subject Management 
The principal investigator and investigator shall instruct the research subject the items below. 
(1) Give instructions to take allocated oral hypoglycemic drug as directed. If poor compliance with 
study treatment (e.g., < 75% of the prescribed dose) after the previous visit has been found and 
does not improve, the research subject may be withdrawn from the research if appropriate for 
the circumstances. 
(2) If hypoglycemia symptom (hunger abnormal, feeling of weakness, trembling of hands and 
fingers, cold sweat, palpitations, etc.) is observed, take glucose or sucrose (sugar), and if it does 
not improve give instructions to visit promptly. 
(3) For dietetic therapy and exercise therapy (if performed), the principal investigator and 
investigator shall make sure prescriptions (instructions for calories, etc.) are consistent 
throughout the research period, and instruct the research subject to adhere to the dietetic therapy 
and exercise therapy (if performed). 


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(4) When CGM is being conducted, the principal investigator and investigator shall instruct 
exercise therapy (if performed) that may be performed under the same conditions every day, 
and instruct the research subject to adhere to it. 
(5) When CGM is being conducted, give instruction to photograph every meal contents. 
(6) Instruct the research subject not to eat high-sugar, high-calorie food or beverage between meals 
during CGM. 
(7) When CGM is being conducted, give instructions to note necessary items into the research 
subject diary. 
(8) On visit days for planned laboratory tests, give instructions not to take oral hypoglycemic drug 
scheduled to be taken on that day. Further, at each visit, have the research subject report if drug 
has been taken or not the day before, and on the day of visit. 
(9) On visit days for planned laboratory tests, give instructions for fasting ≥ 10 hours before visit. 
(10) For research subjects of childbearing potential, give instructions to use adequate contraception. 
If pregnancy is discovered, have the research subject report promptly, and discontinue the 
research immediately. 
(11) The principal investigator and investigator shall instruct the research subject to adhere to 
instructed prohibited concomitant drugs. When drugs are taken other than the drugs prescribed 
by the principal investigator and investigator, have the research subject report its content. 
(12) Regarding subjective symptoms/objective findings, have the research subject report at visit the 
necessary items from its contents, onset date, degree, outcome and date of outcome. 
7.5 
Criteria for discontinuation or withdrawal of a research subject 
The principal investigator or investigator shall record the main reason for discontinuation of protocol 
treatment on the case report form according to the classification described below. Refer section 
9.1.12 for discontinuation case before randomization. 
1. Adverse event 
When the research subject had an adverse event that requires withdrawal of the research subject 
from the study because continued participation in the study would impose an unacceptable risk 
to the research subject’s health, or when the research subject is unwilling to continue study 
participation because of the pretreatment event or adverse event. 
2. Major protocol deviation 
When it is discovered after randomization that a research subject does not meet the eligibility 
criteria or is not adhering to the protocol, and continued participation in the research would 
impose an unacceptable risk to the research subject’s health.  
3. Lost to follow-up 
When the research subject failed to make visits and could not be contacted. The attempts that 
were made to contact the research subject shall be recorded in the source documents. 


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4. Voluntary termination 
When the research subject wishes to withdraw from the research. The reason for discontinuation 
shall be recorded on the CRF when it is clarified. 
5. Research termination 
When the sponsor or a committee such as the IEC or regulatory authority has decided to 
terminate the study. Refer to Section 6.3.1 for details. 
6. Pregnancy 
When a female research subject is found to be pregnant. 
Note: Research participation shall be immediately discontinued when pregnancy is known. 
Refer to Section 9.1.11 for procedure. 
7. Others 
Note: The specific reasons should be recorded on the CRF. 
7.6 
Procedures for discontinuation of individual research subjects 
The principal investigator or investigator shall terminate a research subject’s research participation 
when the research subject meets the criteria described in Section 7.5. Individual research subjects 
may discontinue their research participation without giving a reason at any time during the research. 
Should a research subject’s participation be discontinued, the primary reason for termination shall be 
recorded on the CRF by the principal investigator or investigator. In addition, efforts shall be made 
to perform all tests/observations/evaluations scheduled at the time of discontinuation. 


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8.0 
RESEARCH TREATMENT 
This section indicates the treatment regimen of this clinical research. See the latest package insert for 
details and handling of each drug. 
8.1 
Treatment with the study drug 
8.1.1 Study drug 
(1) Study drug: 
Generic name: Trelagliptin Succinate 
Chemical name: 2- ({6- [（3R）-3-Aminopiperidin-1-yl] -3-methyl-2, 4-dioxo-3, 4- 
dihydropyrimidin -1 (2H)-yl} )methyl-4-fluorobenzonitrile monosuccinate 
Generic name: Alogliptin benzonate 
Chemical name:2- ({6- [(3R) -3-Aminopiperidin-1-yl] 
-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1 (2H) –yl} methyl) benzonitrile 
monobenzoate 
8.1.2 Dose and administration method 
Trelagliptin 100 mg (once weekly) or alogliptin 25 mg (once daily) shall be administered orally 
before breakfast. However, the drug shall be administered as described below at the start of the 
treatment period (VISIT 2: Day 1) or during the treatment period (VISIT 3: Day 21). 
At the start of the treatment period (VISIT 2: Day 1): The drug shall be administered after required 
tests/observations, etc. 
During the treatment period (from VISIT 3 to VISIT 5):  
Trelagliptin 100 mg/week group shall insert the sensor on a day between 3day and a day 
before Trelagliptin administration day.  Trelagliptin 100 mg/week shall be administered 
before breakfast on the day of the drug administration. The next administration of 
Trelagliptin 100 mg is after the sensor removal.  
Alogliptin 25 mg/day shall be administered after required tests/observations, etc at every 
VISIT without taking study drug. Research subjects shall take study drug prior to the every 
breakfast at home.  
Duration of treatment shall be start of treatment period (Day 1) to end of treatment period (Day 29). 
Dose and administration method for each administration group are shown in table 8.a. 
 


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Table8.a Administration group and administration method 
Administration group 
Dose 
Route of 
administration: 
Administration method 
Trelagliptin group 
Trelagliptin 100 mg 
Oral 
administration 
Once weekly, before 
breakfast  
Alogliptin group 
Alogliptin 25 mg  
Oral 
administration 
Once daily, before 
breakfast 
8.1.3 Overdose 
Overdose is defined as intentional or accidental administration of the study drug at a higher dose 
than that specified in the protocol, either by a health professional or by the research subject. 
To consistently collect important safety information about overdose, the principal investigator or 
investigator(s) shall record all cases of overdose on the “Overdose” page of the CRF, 
irrespective of the presence or absence of accompanying adverse event. Adverse events associated 
with overdose shall be recorded on the “Adverse events” page of the CRF, in accordance with the 
procedures described in Section 10.0, “ADVERSE EVENTS.” 
In addition, serious adverse events associated with overdose shall be recorded in accordance with the 
procedures described in Section 10.2.2, “Collection and reporting of SAEs.” 
In the event of overdose, the principal investigator or investigator shall treat the subject as required 
based on symptoms. 
8.2 
Medication other than the study drug 
Prohibited concomitant drugs (refer to Section 7.3.1) may not be used. Also, restricted drugs (refer 
to Section 7.3.2) may be used if used at the time of informed consent. However, dose change for 
those restricted drugs or addition of or change to a new drug shall be prohibited unless the principal 
investigator and investigator consider necessary due to adverse events. Other treatments shall be 
conducted under normal medical practice 
8.3 
Allocation and prescription of the study drug and administration procedure 
The principal investigator or its designee shall access the web case enrollment system to allocate 
research subjects. In addition the principal investigator or its designee shall notify information 
necessary for allocation such as the research subject ID number. Thereafter, the drug to be 
administered to the research subjects shall be notified by the web case enrollment system. The 
principal investigator and investigator shall prescribe the study drug according to the notification and 
record the drug information into the CRF of each research subject. 


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8.4 
Preparation and storage of allocation list 
The person responsible for allocation (designated by the sponsor) shall create an allocation list. 
Allocation shall be conducted at the enrollment center using web case enrollment system at start of 
treatment period (Day 1) with "HbA1c at the start of the observation period (< 7.5% or ≥ 7.5%)" and 
age (< 65 or ≥ 65) as a stratification factor for randomization. The enrollment center shall use the 
allocation list for stratified randomization created by the allocation responsible person. 
Information on the allocation shall be kept in a safe place and shall not be available to anyone other 
than authorized persons, to secure independency from the clinical research. 


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9.0 
CLINICAL STUDY PROTOCOL 
9.1 
Research procedures 
The principal investigator or investigator shall collect data in accordance with the procedure below. 
The same principal investigator or investigator shall perform tests/observations/evaluation of 
research subjects, in principle. The study schedule is provided in Appendix A. 
9.1.1 Informed consent procedure 
The procedures for obtaining informed consent are described in Section 15.3. 
Consent shall be obtained from the research subject before initiation of research procedures. 
Research subject ID code is given to each research subject from whom informed consent was 
acquired and who was randomized. The research subject ID code shall be used throughout the 
research period and shall not be changed. 
9.1.2 Demographic data, medical history, and previous therapeutic drugs 
(1) Demographic information 
Demographic data shall be collected regarding birth, gender, smoking history, drinking history, 
time (year/month) of onset (or diagnosis of diabetes). 
(2) Medical history 
Medical history data shall be collected regarding clinically problematic diseases or symptoms 
that disappeared within 1 year or were terminated from the start of observation period. When 
the symptoms or disease continues, it shall be considered as a concurrent disease (Refer to 
Section 9.1.6). 
(3) Pre-treatment 
Regarding pre-treatment, name of drug, route of administration and date of final administration 
shall be collected for all anti-diabetic medication (including injections) that ended use ≤ 12 
weeks before start of observation period. 
9.1.3 Physical examination 
All subsequent physical examinations after the start of the treatment period shall be assessed for 
clinically significant changes from the baseline examination. 
9.1.4 Weight, height and BMI 
Body weight shall be measured to one decimal place in kilograms.  


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Height shall be measured or asked to the nearest whole number in centimeters.  
BMI shall be calculated by the sponsor using the following formula and shown to one decimal place:  
Body Mass Index:  BMI = weight (kg) / (height (m))2 
Example: 
Height = 176 cm, weight = 79.2 kg, BMI = 79.2/1.762 = 25.6 kg/m2  
9.1.5 Concomitant drugs 
Concomitant drugs are all drugs to be given in addition to the study drug. Drugs prescribed by 
doctors or the over-the-counter medicines purchased by the research subjects shall be included. At 
every hospital visit of the research subject, the status of use of drugs (name of drug, route of 
administration) other than the allocated oral hypoglycemic drug, from start of observation period to 
the completion of the clinical research shall be monitored. 
9.1.6 Concurrent disease 
A concurrent disease is defined as a disease or symptom that is present at the start of the observation 
period or that develops between the start of the observation period and the start of study treatment. 
Clinically significant abnormalities, including laboratory test data and physical examination findings, 
observed in tests and physical examinations at the start of study treatment shall be considered as a 
concurrent disease at the discretion of the principal investigator or investigator. The content of 
concurrent disease (diagnosis) shall be investigated. 
9.1.7 Laboratory tests 
Laboratory tests in table 9.a shall be measured at clinical laboratory institutions according to the 
observation schedule (Appendix A). Regarding tests at fasting, blood sampling shall be conducted 
after ≥ 10 hours of fasting. The principal investigator and investigator shall evaluate and keep the 
reported laboratory test results. 
Inhibitory rate of DPP-4 activity will be calculated by the sponsor using formula below: 
Inhibitory rate of DPP-4 activity (%) = (DPP-4 activity at start of observation period – DPP-4 
activity at each visit of treatment period) / DPP-4 activity at start of observation period x 100 


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Table 9.a 
Laboratory tests 
Serum chemistry 
 
Fasting blood glucose 
Fasting insulin 
Fasting glucagon 
Fasting proinsulin 
FastingGLP-1 
Fasting GIP 
DPP-4 activity 
Glycoalbumin 
1,5-AG 
 
The principal investigator shall keep laboratory test reference values, including the historical data. 
9.1.8 HbA1c (NGSP value) 
Measured at research implementing entities to confirm eligibility of research subject at start of 
observation period. The principal investigator and investigator shall evaluate and keep the reported 
laboratory test results. 
9.1.9 Continuous glucose monitoring (CGM)  
Conducted according to Schedule of Research Procedures (Appendix A) Details shall be specified 
separately in the operation procedures manual. 
(1) Device used in this study 
, leased from the sponsor. 
(2) Self-measurement of blood glucose (SMBG)  
Use device leased from sponsor 
Research subjects shall measure blood glucose levels every day during CGM in the observation 
and treatment periods. At least, blood glucose levels shall be measured at three time points on 
the first day of CGM ([1] at least 2 hours after the recorder is connected and [2] 2 hours after 
the first is measured. [3] at bedtime) and at four time points from the second day onward ([1] 
before breakfast, (2) before lunch, (3) before evening meal, and (4) at bedtime).  
The glucose levels from SMBG shall be used for correction of glucose levels obtained from 
CGM. 
(3) Observation period 


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A sensor shall be inserted at the start of the observation period (Day -2) and removed at the start 
of treatment (Day 1) 
(4) Treatment period 
A sensor shall be inserted (VISIT 3: Day 21), exchanged (VISIT 4: Days 24 to 26), and 
removed (VISIT 5: Day 29) during the treatment period. 
(5) Dietetic therapy and exercise therapy 
Research subjects shall present photographs of all meals to the principal investigator or 
investigator during CGM. Also, the meal provided by the sponsor shall be taken according to 
the calories prescribed by the sponsor for each research subject at the meal times shown below. 
Time point of provision of meals: evening meal at start of observation period (Day-2), evening 
meal on first and seventh of CGM to be performed from Day 21 for 9 days.  
Research subjects shall only conduct exercise therapy feasible (if performed) under the same 
conditions every day during CGM. 
The principal investigator or investigator shall prescribe consistent dietetic therapy and exercise 
therapy (if performed) throughout the research period. Compliance with dietetic therapy and 
exercise therapy(if performed) shall be investigated and rated on a four-point scale as follows: 
1. 
Compliant (compliance rate ≥ 90%)  
2. 
Almost compliant (compliance rate ≥ 70%)  
3. 
Generally compliant (compliance rate ≥ 50%)  
4. 
Minimally compliant (compliance rate < 50%) 
(6) Research subject diary 
Research subjects shall complete the subject diary every day during CGM and submit the diary 
to the principal investigator or investigator. 
The following information shall be recorded in the subject diary: date and time of dosing, time 
of SMBG and blood glucose levels, meal time and contents, exercise time, wake-up time, 
bedtime, etc.  
9.1.10 Contraception 
Women of childbearing potential (e.g., women who have not undergone surgical sterilization, 
women who have not reached menopause) shall use appropriate contraception during participation in 
this clinical research from the time of informed consent. During the informed consent process, 
appropriate contraceptive methods and the necessity of avoiding pregnancy during participation in 


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the clinical research shall be fully explained to women of childbearing potential with the use of the 
informed consent form and information sheet, and the research subjects shall fully understand these 
explanations before providing consent. 
9.1.11 Pregnancy 
When a study subject or a partner of study subject was found to be pregnant during the study period, 
the principal investigator or investigator notify the monitoring staff of the sponsor. The principal 
investigator or investigator provide detailed information using the Follow-up Form for Pregnancy 
separately wherever possible. 
9.1.12 Record of cases withdrawn before randomization 
The consent form shall be signed, and a CRF shall be created for all research subjects who are 
withdrawn before randomization. 
The following items are to be described on the CRF. 
• 
Informed consent procedure 
• 
<MMM/DD/YYYY> 
• 
Sex 
• 
Eligibility 
• 
Reason for discontinuation 
The primary reason for withdrawal before randomization shall be recorded on the CRF according to 
the following classification: 
• 
Not meeting inclusion criteria or meeting exclusion criteria 
• 
Serious deviation from protocol 
• 
Lost to follow-up 
• 
Voluntary discontinuation (specify the reason) 
• 
Premature termination criteria of entire clinical research 
• 
Others (specify the reason) 
Research subject ID numbers assigned to research subjects withdrawn from the research before 
randomization shall not be reused. 
9.1.13 Record of randomization 
Research subjects to be randomized shall meet all of the inclusion criteria and shall not meet any of 
the exclusion criteria according to Section 8.2. The principal investigator or investigator shall 
specify the reason why the subject cannot be randomized to the treatment period. 


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9.2 
Drug-taking status of the research subjects 
The principal investigator or investigator shall confirm the treatment compliance and the date and 
time of dosing during CGM with the research subject at every visit. At the end of study drug 
administration, Treatment compliance shall be rated on a two-point scale as follows: 
1. Compliant (compliance rate ≥ 75%) 
2. Not compliant (compliance rate < 75%) 
Medication instruction shall be given to research subjects throughout the clinical research period. If 
poor compliance with study treatment (e.g., < 75% of the prescribed dose) after the previous visit 
has been found and does not improve, the research subject may be withdrawn from the research if 
appropriate for the circumstances. 
9.3 
Implementation time point of the test and observation items 
The schedule for all tests, observations, and evaluations is shown in Appendix A. The principal 
investigator or investigator shall perform the tests, observations, and evaluations at the time points 
shown below. 
9.3.1 Start of observation period (Visit 1: Day -2)  
After consent is obtained, physical examination/tests are to be conducted for research enrollment. 
Eligibility of research subjects shall be determined in accordance with the inclusion and exclusion 
criteria as described in section 7.0. Refer to section 9.1.12 for the recording of research subjects who 
are withdrawn before randomization. 
Tests and observations to be performed and endpoints to be assessed during the observation period 
(VISIT 1: Day -2) are shown below. 
• 
Informed consent procedure 
• 
Demographic information 
• 
Medical history, pre-treatment 
• 
Physical examination 
• 
Height 
• 
Concomitant drugs 
• 
Concurrent disease 
• 
Prescription of and compliance with dietetic therapy and exercise therapy 


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Tests and observations to be performed and endpoints to be assessed during the observation period 
VISIT 1(Day -2) are shown below. 
• 
Physical examination 
• 
Body weight 
• 
Laboratory tests 
• 
HbA1c 
• 
CGM  (remove sensor) 
• 
Self-measurement of blood glucose (self-measured by research subject) 
9.3.2 At start of treatment period (Visit 2: Day 1) 
Research subjects whose eligibility has been confirmed shall be randomized according to section 8.3 
following the results of test, observation and endpoints implemented before start of treatment period. 
Randomization is performed at the visit when the principal investigator or investigator is considered 
as necessity. 
The test, observation, and endpoints to be implemented at the start of treatment period (Visit 2: Day 
1) are shown below. 
• 
Physical examination 
• 
Concomitant drugs 
• 
Compliance with dietetic therapy and exercise therapy 
• 
CGM (remove sensor) 
• 
SMBG (research subject perform by own) 
• 
Adverse Event 
9.3.3 Treatment period (Visit 3: Day 21) 
The test, observation, and endpoints to be implemented during the treatment period (Visit 3: Day 21) 
are shown below. 
• 
Physical examination 
• 
Body weight 
• 
Concomitant drugs 
• 
Laboratory tests 


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• 
Treatment status 
• 
Compliance with dietetic therapy and exercise therapy 
• 
CGM (remove) 
• 
Self-measurement of blood glucose (self-measured by research subject) 
• 
Adverse event 
9.3.4 Treatment period (Visit 4: Day 24) 
The test, observation, and endpoints to be implemented during the treatment period (Visit 4: Day 24) 
are shown below. 
• 
Physical examination 
• 
Concomitant drugs 
• 
Laboratory tests Drug-taking status 
• 
Compliance with dietetic therapy and exercise therapy 
• 
CGM (exchange sensor) 
• 
Self-measurement of blood glucose (self-measured by research subject) 
• 
Adverse event 
9.3.5 At end of treatment period (Visit 5: Day 29) or discontinuation during 
treatment period 
The test, observation, and evaluation items to be implemented during at the end of treatment period 
(Visit 5: Day 29) are shown below. 
• 
Physical examination 
• 
Body weight 
• 
Concomitant drugs 
• 
Laboratory tests 
• 
Drug-taking status 
• 
Compliance with dietetic therapy and exercise therapy 
• 
CGM (remove sensor) 
• 
Self-measurement of blood glucose (self-measured by research subject until removal of 
CGM sensor) 


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• 
Adverse event 
The test, observation, and endpoints to be implemented at discontinuation of treatment period are 
shown below. 
• 
Physical examination 
• 
Body weight 
• 
Concomitant drugs 
• 
Laboratory tests 
• 
Drug-taking status 
• 
Compliance with dietetic therapy and exercise therapy 
• 
Adverse event 
• 
Reason of discontinuation  
The status of all randomized research subjects at the end of the clinical research shall be recorded on 
the CRF. 


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10.0 
ADVERSE EVENT 
10.1 
Definitions 
10.1.1 Adverse event 
An adverse event is defined as any untoward medical occurrence in a patient or a research subject 
receiving a pharmaceutical product (including the study drug). It does not necessarily have an 
apparent causal relationship with this pharmaceutical product (including study drug). 
An adverse event can therefore be any unfavorable or unintended sign (e.g., clinically significant 
laboratory abnormality), symptom, or disease temporally associated with the use of a pharmaceutical 
product (including the study drug), regardless of whether it is considered related to the 
pharmaceutical product (including the study drug) or not. 
10.1.2 Considerations for adverse events 
Generally unfavorable findings are described below: 
• 
Newly diagnosed disease or unexpected aggravation of existing symptom (intermittent 
event of an existing symptom is not considered an adverse event) 
• 
Requiring action or medical practice 
• 
Requiring invasive diagnostic treatment 
• 
Requiring discontinuation or a change in the dose of the study drug or a concomitant 
medication 
• 
Considered unfavorable by the principal investigator or the investigator 
Diagnosis name and signs/symptoms: 
Adverse events shall be recorded by diagnosis name. Accompanying signs (including abnormal 
laboratory values, abnormal ECG findings) and symptoms shall not be recorded as adverse events. If 
an adverse event could not be expressed by a diagnosis name, the signs or symptoms shall be 
recorded as the adverse event. 
Laboratory test values and ECG findings: 
Abnormal laboratory values and ECG findings shall be recorded as adverse events when the 
principal investigator or investigator judges the results are clinically problematic (in other words, 
when certain action or medical practice is required, or when the principal investigator or the 
investigator judges the change has exceeded the normal physiological variation range of the research 
subject). Retest and/or continued monitoring of an abnormality are not considered medical practice. 


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Also, repeated or additional conduction of non-invasive tests for verification, evaluation, and 
monitoring of an abnormality are not considered medical practice. 
However, when abnormal laboratory values and ECG findings are the accompanying symptoms of a 
disease diagnosed as an adverse event (e.g., increased creatinine due to renal dysfunction, etc.), the 
adverse event shall be handled by its diagnosis name. 
Pre-existing conditions (disease or symptom that has been present since before the start of study 
treatment): Pre-existing disease or symptom that has been present since before the start of study 
treatment shall be regarded as a concurrent disease and not an adverse event. When a concurrent 
medical condition is aggravated, the aggravation shall be determined as an adverse event and the 
principal investigator or the investigator shall record on the CRF that the adverse event is an 
aggravation of the concurrent disease (e.g., “aggravation of hypertension,” etc.). 
If a research subject has a pre-existing episodic condition (e.g., asthma, epilepsy), each episode shall 
be recorded as an adverse event if the episodes become more frequent, serious, or severe in nature. If 
a research subject has a chronic concurrent condition (e.g., cataracts, rheumatoid arthritis), 
worsening of the condition shall be recorded as adverse event if the degree of the worsening exceeds 
that which would be expected. The principal investigator or investigator shall ensure that the adverse 
event term to be recorded represents the change in the condition from baseline (e.g. “worsening 
of…”). 
Worsening of adverse events:  
If a research subject experiences a worsening of the adverse event after a change to the study drug, 
or secondary signs and symptoms are caused by the adverse event, the worsening or the secondary 
signs and symptoms shall be recorded as a new adverse event on the CRF. The principal investigator 
or investigator shall use an adverse event term that explicitly means a change of the condition (e.g., 
“worsening of…”). 
Change of severity of adverse events:  
If the research subject experiences changes in the severity of an adverse event, the event shall be 
recorded once, at its peak severity. 
Previously planned surgery or treatment:  
Preplanned surgeries or interventions that were scheduled before study treatment shall not be 
considered adverse events. However, when the existing symptom is aggravated to a degree requiring 
emergency surgery or treatment, the condition or the event shall be considered an adverse event. A 
concurrent disease that resulted from previously planned surgery shall be reported as an adverse 
event. 


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Non-urgent surgery or treatment:  
Non-urgent surgery or treatment that does not induce a change in the condition of a research subject 
(cosmetic surgery, etc.) shall not be considered an adverse event; However, it shall be recorded in 
the source documents. Concurrent diseases due to a non-urgent surgery shall be reported as an 
adverse event. 
The insufficient clinical response (lack of efficacy): insufficient clinical response, efficacy, or 
pharmacological action shall not be recorded as an adverse event. The principal investigator or 
investigator shall make the distinction between worsening of a pre-existing condition and lack of 
therapeutic efficacy. 
Overdose of the study drug:  
Overdose of any medication without onset of event shall not be recorded as an adverse event, but the 
overdose shall be recorded on the “Overdose” page of the CRF. Any onset of event shall be recorded 
as adverse events on the “Adverse events” of the CRF. 
10.1.3 Serious adverse event 
Of all unfavorable medical events that develop after administration of a pharmaceutical product 
(including the study drug) (irrespective of dose), a serious adverse event is an event that: 
1. results in death, 
2. is life threatening*, 
3. requires inpatient hospitalization or prolongation of existing hospitalization, 
4. results in persistent or significant disability/incapacity, 
5. leads to a congenital anomaly/birth defect, or 
6. Medically important event that causes a risk to the research subject even if it is not 
immediately life-threatening and does not result in death or hospitalization, or requires an 
action or treatment to prevent the results described in 1 to 5 above. Points described in the 
Takeda Medically Significant Adverse Event List (Table 10.a 
) are included in this 
section. 
* The term “life threatening” refers to an event in which the research subject was at risk of death at 
the time of the event; it does not refer to an event that hypothetically might have caused death if it 
were more severe. 


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Table 10.a 
Takeda Medically Significant AE List 
Acute respiratory failure/acute respiratory 
distress syndrome (ARDS) 
Torsades de pointes/ ventricular 
fibrillation/ventricular tachycardia 
Malignant hypertension 
Convulsive seizure (including convulsion 
and epilepsy) 
Agranulocytosis 
Aplastic anemia 
Toxic epidermal necrolysis/ 
Oculomucocutaneous syndrome 
(Stevens-Johnson syndrome) 
Hepatic necrosis 
Acute hepatic failure 
Anaphylactic shock 
Acute renal failure  
Pulmonary hypertension 
Pulmonary fibrosis (including interstitial 
pneumonia) 
Neuroleptic malignant syndrome/ malignant 
hyperpyrexia 
Spontaneous abortion/ stillbirth and fetal death 
Confirmed or suspected transmission of 
infection by a medicinal product 
Confirmed or suspected endotoxin shock 
10.1.4 Adverse events of special interest (specific adverse events) 
An AE of Special Interest (AESI) (serious or non-serious) is one of scientific and medical concern 
specific to the study drug, for which ongoing monitoring and rapid communication by the principal 
investigator or investigator to Takeda may be appropriate. Such events may require further 
investigation in order to establish assessment, and instructions provided to investigators on how and 
when they should be reported to the sponsor are described in Section 10.2.1.3. 
AESIs: Hypoglycemia-related AEs, intestinal obstruction-related AEs and acute pancreatitis-related 
AEs (for both Trelagliptin and Alogliptin), QT/QTc interval prolongation-related AEs (for 
Trelagliptin), and Liver dysfunction or jaundice-related AEs (for Alogliptin). 
<For both Trelagliptin and Alogliptin> 
[Hypoglycemia-related AEs] 
Hypoglycemia-related AEs are designated as AESIs because, in general, attention should be paid to 
the events in the treatment of diabetes mellitus. 
[Intestinal obstruction-related AEs] 
Intestinal obstruction-related AEs are designated as AESIs because there are accumulated reports of 
intestinal obstruction as an adverse reaction to similar incretin-related drugs (GLP-1 receptor 
agonists and other DPP-4 inhibitors). 
[Acute pancreatitis-related AEs] 


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Acute pancreatitis-related AEs are designated as AESIs because there are accumulated reports of 
acute pancreatitis as an adverse reaction to similar incretin-related drugs. 
<For Trelagliptin> 
[QT/QTc interval prolongation-related AEs] 
QT/QTc interval prolongation-related AEs are designated as AESIs because, in the QT/QTc 
assessment study conducted during the development, QT/QTc interval prolongation was reported in 
the trelagliptin 800 mg group although it did not occur in the trelagliptin 200 mg group. 
<For Alogliptin> 
【Liver dysfunction or jaundice-related AEs】 
Liver dysfunction or jaundice-related AEs are designated as AESIs because there are accumulated 
reports as serious adverse reaction. 
10.1.5 Severity of adverse events 
The severity of adverse events shall be classified and defined as shown below. 
Mild 
The event is transient and easily 
tolerated by the subject. 
Moderate 
The event interrupts the subject’s usual 
activities. 
Severe 
The 
event 
causes 
considerable 
interference with the subject’s usual 
activities. 
10.1.6 Causality of adverse events 
The causal relationship of each adverse event to the study drug shall be classified and defined as 
shown below. 
Related 
An adverse event that follows an apparent temporal sequence (including clinical course 
after discontinuation). An adverse event the causal relationship could not be denied and 
there is reasonable possibility due to the study drug, although other factors such as 
underlying disease, concurrent diseases, or concomitant drugs/treatment are also 
suspected. 
Not 
related 
An adverse event that does not follow an apparent temporal sequence from 
administration of the study drug. Very likely due to other factors such as underlying 


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disease, concurrent diseases, or concomitant drugs/treatment. 
10.1.7 Relationship to study procedures 
The relationship shall be recorded as “Yes” if the principal investigator or investigator considers that 
there is reasonable possibility that an adverse event is due to a study procedure. Otherwise, the 
relationship shall be recorded as “No.” 
10.1.8 Date of onset 
The date of onset of adverse events shall be determined according to the following rules: 
Adverse event 
Date of onset 
Signs, symptoms, diseases 
(diagnoses) 
The date on which the first signs/symptoms were noted by the 
research subject and/or the principal investigator or investigator. 
Asymptomatic diseases 
The date on which a diagnosis was confirmed through a test(s). 
The date on which a diagnosis was confirmed, even when the test 
results indicate an old sign(s) of the disease or an approximate time 
of its onset. 
Exacerbation of concurrent 
diseases 
The date on which the first worsening of diseases/symptoms was 
noted by the research subject and/or the principal investigator or 
investigator. 
Onset of a test abnormality after 
the start of the study drug 
administration 
The date on which a clinically significant laboratory abnormality 
was detected. 
Worsening of a baseline test 
abnormality after initiation of 
study treatment 
The date on which a clear increase/decrease in a laboratory 
parameter was clinically confirmed based on the time profile of the 
parameter. 
10.1.9 Date of resolution 
The date of resolution of an adverse event is the date on which the research subject recovered 
(including resolution with sequelae). If a research subject died due to the adverse event concerned, it 
shall be the date of death. The adverse event shall be recorded as “ongoing” if the research subject 
has not yet recovered by the end of the study. 
10.1.10 Actions taken for the study drug 
Actions taken for the study drug shall be classified or defined as shown below. 
Drug withdrawn 
The study drug is discontinued because of an adverse event (including withdrawal 
by the research subject at his/her own discretion). 
When the treatment with the study drug is continued after withdrawal from the 
study, it shall be defined as “Dose not changed.” 


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Dose not changed 
If the dose was unchanged after the onset of the adverse event it shall be defined 
as “Dose not changed.” 
If the study drug was discontinued, reduced, or increased because of another 
adverse event it shall be defined as “Dose not changed.” 
If the study drug was discontinued or reduced for a reason other than for the 
adverse event, e.g., inadvertence of the research subject, it shall be defined as 
“Dose not changed”. 
Unknown 
It has not been possible to determine what action has been taken because the 
research subject is lost to follow-up. 
Not Applicable 
The study treatment had already been completed or discontinued before the onset 
of the adverse event. 
Dose reduced 
The dose of the study drug was reduced because of the adverse event (including 
dose reduction by the research subject at his/her own discretion). 
Dose increased 
The dose of the study drug was increased because of the adverse event (including 
dose increase by the research subject at his/her discretion). 
Washout 
If the study treatment is suspended (i.e., interrupted) (including 
suspension/interruption by the research subject at his/her discretion) because of 
the adverse event but resumed thereafter, shall be defined as “washout”. 
10.1.11 Outcome 
Outcome of adverse events is classified as follows: 
Category 
Criteria 
Recovered 
Disappearance or recovery of symptoms and findings 
Laboratory values returned to normal or baseline 
Improved 
The intensity is lowered by one or more stages 
Symptoms or findings mostly disappeared 
Laboratory values improved, but have not returned to normal or baseline 
The research subject died from a cause other than the concerned adverse event while 
the condition was resolving (recording of the date of death unnecessary) 
Not recovered 
No change in symptoms, findings, or laboratory data 
The symptoms, findings, or laboratory data on the final day of observable period 
were aggravated compared with the date of onset 
Irreversible congenital anomaly 
The research subject died from another cause before resolution of the concerned 
adverse event (recording of the date of death unnecessary) 
Recovered 
with sequelae 
Disability that disturbs daily life 


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Death 
Direct relationship between death and the concerned adverse event 
“Direct relationship” means that the concerned adverse event was the cause of 
death, or the concerned adverse event was clearly responsible for death. 
Outcome of an adverse event which was not determined (judged, presumed) a direct 
cause of death observed in the same research subject is not considered as death. 
If outcome is death, the date of death shall be recorded. 
Unknown 
Follow-up specified in the protocol after the date of onset was not possible due to 
change of hospitals or relocation, etc. 
10.2 
Procedures 
10.2.1 Collection and reporting of adverse events 
10.2.1.1 Adverse event collection period 
Collection of the adverse events shall commence at the start of administration of the study drug (Day 
1) and shall continue until end of treatment (Day 29). 
10.2.1.2 Reporting of adverse events 
At each study visit, the principal investigator or investigator shall check for the presence of any 
onset of subjective symptoms. A neutral question, such as “How have you been feeling since your 
last visit?” may be asked to collect any adverse events that occurred between the previous and 
present visits. 
The principal investigator or investigator shall follow up all research subjects experiencing an 
adverse event irrespective of the causal relationship with the study drug, until the symptom resolves, 
or any clinically significant abnormal laboratory values have returned to baseline or there is a 
satisfactory explanation for the change (permanent or irreversible adverse events). All adverse 
events shall be entered on the CRF. Adverse event term, onset date, resolution date, severity, causal 
relationship with the study drug (i.e. "Unrelated" or "Related"), action taken for the study drug, 
outcome, causal relationship with any study procedure (with specific procedure if assessed to be 
causally related), and seriousness shall be entered. 
Follow-up period of adverse events shall be until recovery of the adverse events, or the time when 
the principal investigator or investigator judges that further follow-up would be unnecessary. 
10.2.1.3 Reporting of adverse events of special interest (specific adverse events) 
If AESI occurring during the AE collection period is considered to be clinically significant based on 
the criteria below, it should be reported to the sponsor (refer to the attachment  for contact 
information) within 1 business day of first onset, or subject’s notification of the event by the 


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principal investigator or investigator. AESI Form should be completed and signed (or signed and 
sealed) by the principal investigator and reported to the sponsor within 10 business days. 
The criteria for AESIs (hypoglycemia-related AEs, intestinal obstruction-related AEs, acute 
pancreatitis-related AEs, and QT/QTc interval prolongation-related AEs) are as shown below. If any 
other AEs potentially related to the study drug occur, it will be considered whether to include them 
in the AESIs. 
[Hypoglycemia-related AEs] 
AEs related to hypoglycemia 
[Intestinal obstruction-related AEs] 
Intestinal obstruction, ileus, subileus, obstruction of the digestive tract, gastrointestinal motility 
disorder, impaired gastric emptying, and AEs related to these conditions 
[Acute pancreatitis-related AEs] 
AEs related to pancreatitis or acute pancreatitis 
[QT/QTc interval prolongation-related AEs] 
Torsade de pointes, sudden death, ventricular tachycardia, ventricular fibrillation, ventricular flutter, 
consciousness disturbed, convulsion, ECG QT prolonged, and AEs related to these conditions 
【Liver dysfunction or jaundice-related AEs】 
Adverse events corresponding to ' Liver dysfunction related to drug - comprehensive search' in 
MedDRA standard search formula.  
The AESIs have to be recorded as AEs in the CRF. A report along with all other required 
documentation must be submitted to the sponsor. 
10.2.2 Collection and reporting of serious adverse events 
When a serious adverse event develops during the period of collecting adverse events, it shall be 
reported according to the following procedures. At the time of onset of a serious adverse event or 
notification of the onset by the research subject, the principal investigator shall report the serious 
adverse event to the chief executive of the research implementing entity immediately, and the 
sponsor or CRO to whom the sponsor has entrusted responsibility shall notify the principal 
investigator of the research implementing entity. 
The principal investigator shall then report the serious adverse event to the sponsor (for the contact 
information, refer to the attachment) within 1 day of notification of the event onset. Further, the 
principal investigator shall submit a formal report within 10 calendar days to the sponsor. 


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Furthermore, it shall be mandatory to include the contents below in the report to be submitted to the 
sponsor within 1 working day, and other items shall be reported as far as possible. 
• 
Brief description of adverse event and the reason for why it was determined as serious 
• 
Research subject ID number 
• 
Name of principal investigator or the investigator 
• 
Name of the study drug 
• 
Determined causal relationship 
The principal investigator or investigator shall report spontaneously reported serious adverse events 
that are collected even after the adverse event collection period to the sponsor. 
10.2.3 Reporting of additional information concerning adverse events 
If the sponsor requests provision of additional information concerning adverse events for reporting 
to regulatory authorities, the principal investigator or the investigator shall confirm the necessary 
additional information and enter in the EDC system or submit a report within the period specified by 
the sponsor. 
10.3 
Follow-up of serious adverse events 
When information that was not included in the detailed report was obtained later, the principal 
investigator or investigator shall state it in the copy of the report on serious adverse events, or create 
another document and submit it to the contact address shown on the attached sheet within 1 working 
day. Relevant data collected at the research implementing entity (e.g., ECG charts, laboratory test 
values, discharge summary, postmortem results) shall be sent to the sponsor or the committee such 
as the IEC upon request. 
The principal investigator or the investigator shall follow-up all serious adverse events, etc., until 
recovery is confirmed, or the final outcome is determined. 
10.3.1 Reporting of serious adverse events to Ethics Review Committee, etc., and 
regulatory authorities 
When the chief executive of the research implementing entity receives a report of a serious adverse 
event from the principal investigator, the chief shall consult the Ethics Review Committee, etc., and 
notify the research implementing entities that are conducting the clinical research through the 
sponsor or the CRO consigned by the sponsor. 
If the serious adverse event reported by the principal investigator in which direct causal relationship 
cannot be denied with this study (the study drug) and is unexpected, the chief executive of the 


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research implementing entity shall prepare a written report of the unexpected serious adverse event 
containing the information reported by the principal investigator plus the information below, and 
submit the report to the Minister of Health, Labour and Welfare, and notify other clinical research 
implementing entities. (Reporting to the Minister of Health, Labour and Welfare via the sponsor, or 
notification to other clinical research implementing entities via the sponsor may also be possible) 
• 
Actions taken for serious adverse events (discontinuation of new enrollment, revision of 
informed consent form, re-consents to other research subjects, etc.) 
• 
Date of review, summery of review, result, necessary action, etc., related to Ethics Review 
Committee, etc. 
• 
Notification to other research implementing entities 
The sponsor shall report, in accordance with regulations, unexpected serious adverse drug reactions 
and other serious adverse events that are subject to emergency reporting to regulatory authorities, the 
principal investigators, and chief executives of the research implementing entities. 
From the time point of first acknowledging the event or receiving additional information, the 
sponsor or the CRO consigned by the sponsor shall comply with regulatory required time frames for 
reporting, and make emergency reports concerning unexpected serious adverse drug reactions and 
expected serious adverse drug reactions to regulatory authorities. Also, the sponsor shall, in the same 
way, make an emergency report of other critical safety information that may have a major effect on 
the study drug risk-benefit, continuation of study drug administration, or continuation of clinical 
research. The research implementing entity shall submit copies of emergency report documents to 
the Ethics Review Committee, etc. 


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11.0 
COMMITTEES ESTABLISHED FOR THIS STUDY 
In this clinical research, none of Clinical Research Steering Committee, Data and Safety Monitoring 
Committee, or Central Assessment Committee shall be established. 


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12.0 
DATA MANAGEMENT AND STORAGE OF RECORDS 
Data management operations shall be performed according to the standard operating procedure by 
the data management department of the sponsor independent from the medical affairs department. 
Adverse events, medical history, and concurrent conditions shall be coded using MedDRA. Drugs 
shall be translated using the WHO Drug Dictionary. 
12.1 
Case report form 
The principal investigator or investigator shall complete a CRF for each research subject who has 
signed the informed consent form. 
The sponsor or its designee shall provide research implementing entities with access authorization to 
the electronic CRF. Before use of the electric CRF system, the sponsor shall provide training to the 
principal investigator, investigators, and study collaborators. The CRF shall be used to report the 
information collected during the study period to the sponsor. The CRF shall be made in Japanese. 
Data shall be directly entered in preparing the CRF. 
A change or correction of the CRF shall be recorded as an audit trail that records the information 
before and after the change or correction, the person who made the change or correction, date of 
change or correction, and its reason. 
The principal investigator shall ensure the accuracy and completeness of the CRF, and provide an 
electronic signature on the relevant page of the case report form. The principal investigator shall bear 
full responsibility for the accuracy and reliability of all data entered on the CRF. 
The following data shall be recorded on the CRF directly. (Except if there is a description in the 
source material) 
• 
Eligibility, end state, reason of termination, severity, degree, the causal relationship with the 
study drug or the study procedures, outcome of the adverse event. 
The following data shall not be recorded on the CRF directly. 
• 
Measurement results of CGM 
• 
Laboratory result tested at central. 
When the principal investigator or the investigator makes a change or correction in the data entered 
on the CRF after fixation of clinical data base, a record (Data Clarification Form) of change or 
correction on the CRF provided by the sponsor shall be used. The principal investigator shall 
confirm that the record of change or correction on the CRF is accurate and complete, and sign or 
write name/ affix a seal, and date it. 


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The sponsor or its designee shall confirm that CRFs have been made appropriately according to the 
procedures defined for each study. The sponsor or its designee shall have access to the medical 
records of the research subjects and in-house records to ensure the accuracy of the CRF as necessary. 
The completed CRF is the property of the sponsor, and the principal investigator or investigator shall 
not disclose the information to a third party without a written permission from the sponsor. 
12.2 
Timing of data entry into the electronic CRF system 
The sponsor or its designee shall request the principal investigator and investigator to promptly enter 
data into the EDC at enrollment of the research subject, each visit during study treatment, 
completion/discontinuation of study treatment, and follow-up period. Details of deadlines for data 
entry shall be specified separately in a procedure manual. 
12.3 
Storage of records 
The principal investigator or the chief executive of research implementing entity shall store the 
following materials, including those specified in section 12.1, and study-specific documents to be 
used by the regulatory authority and the sponsor or its designee for investigation and audit. The 
documents include research subject ID code, medical records, clinical study worksheets (if used), 
original signed and dated informed consent forms, the change and fix record of CRF (copy) and 
electric copies of electronic CRF including audit trail. The principal investigator and the chief 
executive of the research implementing entity shall appropriately retain the material/information 
related to this study for at least 5 years from the date of reporting the end of the research by the 
principal investigator, or for 3 years from the date of reporting final publication of the study result, 
whichever date is later. However, when the sponsor requires a longer storage period, the chief 
executive of the research implementing entity shall discuss the period and methods of storage with 
the sponsor. 
 


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13.0 
STATISTICAL ANALYSIS METHODS 
The person responsible for statistical analysis and the designee (a person employed by a CRO 
independent of the sponsor; the person in charge of analysis) shall conduct analyses. The sponsor will 
not be involved in statistical analyses. 
13.1 
Statistical and analytical plans 
The person in charge of analysis shall prepare a statistical analysis plan (hereinafter referred to as 
SAP) before the acquisition of the informed consent of the earliest research subject, and issue the 
first edition. Detailed definition of endpoints and analysis methods should be specified in the SAP to 
deal with all the purposes of the research. 
13.1.1 Analysis set 
Two analysis sets, “full analysis set” and “Safety data analysis set” are used in this study. The “full 
analysis set" used as a primary analysis set in the efficacy analysis shall be defined as "the research 
subjects who were randomized and given at least one dose of the study drug." The “Safety data 
analysis set” shall be defined as "the research subjects who are given at least one dose of the study 
drug." 
13.1.2 Analysis of demographic and other baseline characteristics 
From the “full analysis set” primary research subject background items will be tabulated by each 
treatment group and by merging the treatment groups. 
13.1.3 Efficacy analysis 
[Primary endpoints] 
• 
Changes in the SD of 24-hour blood glucose values (mg/dL) for each 7-day period between 
Week 3 and Week 4 (between Day 22 and Day 28) of the treatment period, calculated from the 
value at the start of the observation period  
(Analysis method) 
•For the “full analysis set”, summary statistics (number of subjects, mean, SDs, maximum values, 
minimum values, quartiles [same apply hereafter]) and 95% confidence interval (two sides) of mean 
shall be calculated for each treatment group at each evaluation point (each day), and illustrating 
changes in mean and SD in order to evaluate changes in the SD of 24-hour blood glucose values 
(mg/dL) for each 7-day period between Week 3 and Week 4 (between Day 22 and Day 28) of the 
treatment period, calculated from the value at the start of the observation period for trelagliptin or 
alogliptin separately. 
•Preliminary, for the “full analysis set”, calculate point estimation and 95% confidence interval (two 


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sides) in difference of mean in treatment groups (trelagliptin 100 mg group – alogliptin 25 mg 
group) in order to examine the influence of the once-weekly administration and blood glucose 
fluctuations due to the difference in the daily administration exploratory. 
•As well, for the “full analysis set ,” conduct analysis of covariance at each evaluation point with 
changes in the SD of 24-hour blood glucose values between Week 3 and Week 4 from the value at 
the start of the observation period as dependent variable, treatment groups as independent variable, 
HbA1c (NGSP value) at the start of the observation period, changes in the SD of 24-hour blood 
glucose values at the start of the observation period, and age as covariates, and calculate point 
estimation and 95% confidence interval (two sides) in difference of adjusted mean for each group. 
•Preliminary, “full analysis set ,” calculate point estimation and 95% confidence interval (two sides) 
in difference of adjusted mean in treatment groups (trelagliptin 100 mg group – alogliptin 25 mg 
group)  
[Secondary endpoints] 
• 
Changes in AUC over time when specific blood glucose levels ( 110, 140, 160, or 180 mg/dL) 
are observed during the 3 hour time period after breakfast, lunch and evening meal*1, 2 
• 
Change in AUC over time during periods when blood glucose 140, 160, or 180 mg/dL 
(hyperglycemia) is observed*1, 2 
• 
Changes in blood glucose 140, 160, or 180 mg/dL (hyperglycemia) over time*1, 2 
• 
Changes in AUC over time during periods when blood glucose < 70 mg/dL (hypoglycemia) is 
observed*1,2 
• 
Change in peak postprandial glucose levels over time 3 hours after breakfast, lunch, and evening 
meal*1, 2 
• 
Change in maximum variation of blood glucose levels over time between before and after 
breakfast, lunch, and evening meal *1, 2 
• 
Changes in MAGE*1, 2 
• 
Changes in mean 24-hour blood glucose levels *1, 2 
• 
Changes in mean daytime blood glucose levels*1, 2 
• 
Changes in mean nocturnal blood glucose levels*1, 2 
• 
Changes in AUC*1, 2 
• 
Changes in AUC over time during periods when blood glucose 110 mg/dL is observed*1,2  
• 
Changes in the SD of 24-hour blood glucose values*1,2 
• 
Changes in the SD of mean daytime blood glucose values*1,2 
• 
Changes in the SD of mean nocturnal blood glucose values*1,2 
*1: Measured value and percent changes for the each 7-day period between Week 3 and Week 4 
(between Day 22 and Day 28) of the treatment period calculated from the value at the start of 


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the observation period (however changes in the SD of 24-hour blood glucose values shall be 
measured value only)  
*2: Percent change from the value at the start of the observation period to the mean value during 
the 7-day period between Week 3 and Week 4 (between Day 22 and Day 28) of the treatment 
period 
 
(Analysis method) 
• 
Conduct the same analysis as the primary endpoints for *1 and *2 of the above endpoint section. 
However, for changes in mean/SD, only measured values of *1 and *2 shall be illustrated. 
[Other endpoints] 
• 
Glycoalbumin 
• 
1,5-AG 
• 
Fasting blood glucose 
• 
Fasting insulin 
• 
Fasting glucagon 
• 
Fasting proinsulin 
• 
FastingGLP-1 
• 
Fasting GIP 
• 
DPP-4 activity 
• 
Inhibitory rate of DPP-4 activity 
(Analysis method) 
• 
Calculate summary statistics and 95% confidence interval (two sides) of mean at each 
evaluation point (the start of the observation period by each treatment group, first day, 1 point 
during third to fifth day, and ninth day of CGM which is to be performed for 9 days from Day 
21) in measured values and changes from the start of the observation period, and illustrate 
changes in mean and SD  
13.1.4 Conversion method of data and handling of missing data 
Details shall be specified separately in the statistical analysis plan. 
13.1.5 Significance level and confidence coefficient 
 Confidence coefficient: 95% (two-sided estimation) 


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13.1.6 Safety analysis 
[Secondary endpoints] 
• 
Adverse event 
(Analysis method) 
• 
Adverse events shall be reported using MedDRA terminology and summarized using the 
Preferred Term (PT) and System Organ Class (SOC) of the MedDRA. For the “safety data 
analysis set”, frequency tabulation shall be conducted for adverse events after start of treatment 
with study drug by each treatment group. 
 
Frequency tabulation of all adverse events 
 
Frequency tabulation of adverse events that causal relationship is “related” to study drug. 
 
Frequency tabulation of the degree of all adverse events 
 
Frequency tabulation of degree of adverse events that causal relationship is “related” to 
study drug. 
 
Frequency tabulation of adverse events that were “discontinued” as a measurement 
concerning study drug. 
 
Frequency tabulation of serious adverse events 
13.2 
Criteria for interim analysis and premature discontinuation 
No interim analysis is planned. 
13.3 
Determination of the number of planned research subject 
Planned number of research subjects that are evaluable for primary endpoints in each group is as 
follows. 
Trelagliptin 100 mg group: 15 
Alogliptin 25 mg group: 15 
Set in consideration with the feasibility of the number of research subjects for exploring the effects 
of trelagliptin 100 mg and alogliptin 25 mg on glycemic variation. It is not based on statistical power 
calculation.  


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14.0 
QUALITY CONTROL AND QUALITY ASSURANCE 
14.1 
Monitoring of the research implementing entity 
The sponsor or its designee shall perform periodic monitoring of research implementing entities 
during the research to confirm that the research is conducted in accordance with all specifications in 
the research protocol. The data recorded on the CRF will be checked by comparing them with those 
in the source documents. Source documents are the original documents, data and records. The 
principal investigator and the chief executive of the research implementing entity shall ensure that 
the sponsor or its designee and the Ethics Review Committee, etc., have access to the source 
documents. 
The sponsor or its designee shall access the records, including the list of research subject ID 
numbers, medical records of the research subjects, and signed and dated original consent forms to 
confirm that the research is appropriately conducted in compliance with the research protocol. Also, 
confirm the consistency between CRF and the related source documents. The principal investigator, 
investigator, and other personnel involved in the research shall spare sufficient time to facilitate 
monitoring procedures during visits to the research implementing entity. 
Detailed procedures for monitoring shall be specified separately in a procedure manual. 
14.2 
Deviation from the Ethical Guidelines for Medical and Health Research 
Involving Human Subjects and the research protocol. 
The principal investigator or investigator shall record all deviations from Ethical Guidelines for 
Medical and Health Research Involving Human Subjects, and research protocol. 
If any deviation is found, the principal investigator shall promptly notify the chief executive of the 
research implementing entity for the clinical research and the sponsor. As necessary, the principal 
investigator will discuss protocol revisions with the sponsor to reach agreement. For protocol 
revisions, draft revisions should be submitted as early as possible to the chief executive of the 
research implementing entity for approval of the committee such as the IEC. 
14.3 
Quality assurance audits and regulatory agency inspections 
The research implementing entity may be subject to audits by the sponsor or its designee. In such a 
case, the auditor designated by the sponsor shall contact the research implementing entity in advance 
to determine the date of audit. The auditor may ask to visit the facilities where laboratory specimens 
are collected and any other facilities used during the clinical research. In addition, this research may 
be inspected by regulatory agencies, including those of foreign governments (e.g., the Food and 
Drug Administration [FDA], the United Kingdom Medicines and Healthcare products Regulatory 
Agency [MHRA]). If the research implementing entity is contacted for an inspection by a regulatory 


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body, the sponsor should be notified promptly. The principal investigator and the chief executive of 
the research implementing entity shall ensure that the auditor has access to all the research-related 
source documents. 


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15.0 
ETHICAL CONDUCT OF CLINICAL RESEARCH 
This research shall be conducted with the highest respect for the individual participants (i.e., 
research subjects) according to the research protocol, and the ethical principles that have their origin 
in the Declaration of Helsinki, Ethical Guidelines for Medical and Health Research Involving 
Human Subjects. Each principal investigator shall conduct the study according to regulatory 
requirements and in accordance with “Responsibilities of the Investigator” in Appendix B. 
15.1 
Approval of the Ethical Review Board, etc. 
The Ethical Review Board, etc., shall be constituted in accordance with the regulations. 
The sponsor or its designee should obtain the document listing the name and title of each committee 
member. When a committee member directly participates in this clinical research, the document 
describing that he/she is not participating in deliberation or voting for the study shall be obtained. 
The sponsor or its designee shall provide related documents for review and approval of the research 
protocol to the Ethical Review Board, etc. In addition to the research protocol, a copy of the 
informed consent form and information sheet, written materials related to research subject 
recruitment, advertisement, and other documents required by regulations, when necessary, shall be 
submitted to the central committee or a research implementing entity committee such as the Ethics 
Review Committee to obtain approval. The sponsor or its designee shall obtain records of approval 
by the Ethical Review Board, etc., for the research protocol and the informed consent form and 
information sheet before the start of the protocol therapy. The records of approval by the Ethical 
Review Board, etc., shall include the clinical research title, protocol number, preparation / revision 
date of the research protocol, and version number and approval date of other reviewed documents 
(example: informed consent and information sheet). The sponsor shall notify the research 
implementing entity, the principal investigator, and investigator after confirming the validity of the 
regulatory documents of the research implementing entity. Protocol procedures such as obtainment 
of consent shall not be started until the research implementing entity, the principal investigator, and 
investigator receive notification. 
The research implementing entity shall observe all requirements that the Ethical Review Board, etc. 
prescribe. The requirements may include notifications to committees such as the IEC, for example, 
revision of the protocol, revision of the informed consent form and information sheet, revision of 
materials related to research subject recruitment, reports on safety in accordance with the regulatory 
requirements, reports on status of implementation of the research at intervals determined by a 
research implementing entity committee such as the Ethics Review Committee, and submission of 
the study completion report. The sponsor or its designee shall obtain written approval from a 


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research implementing entity committee such as the Ethics Review Committee related to the above 
mentioned items and all related materials. 
15.2 
Conflict of interest 
This clinical research shall be conducted with the support of the sponsor. 
Prior to the conduction of this clinical research, the investigators involved in this clinical research 
shall ensure appropriate management of any conflicts (COI) in the conduct of the research in 
accordance with the rules of the research implementing entity 11-15). 
The research implementing entity shall comply with all requirements specified by a committee such 
as the Ethics Review Committee This includes the COI self-statement form, the research protocol, 
and the informed consent form and information sheet.  
15.3 
Informed consent and information sheet, and the agreement of the research 
subjects 
The informed consent and information sheet form shall contain specific requirements of the 
Declaration of Helsinki, Ethical Guidelines for Medical and Health Research Involving Human 
Subjects and all applicable laws and regulations. The informed consent form and information sheet 
shall specify the use of personal information and medical information of research subjects in this 
clinical research (both in and outside Japan: supply to a third party), and disclosure. The informed 
consent form and the information sheet will explain in detail the nature of the research, its objectives, 
and potential risks and benefits. Also, the informed consent form will detail the requirements for 
participation and the fact that research subject is free to withdraw at any time without giving a 
reason and without any negative effect on the further medical care. 
The principal investigator is responsible for the preparation, contents, and approval of the informed 
consent form and information sheet by the committee such as the IEC. The informed consent form 
and information sheet must be approved by the committee prior to use. 
The informed consent form and information sheet shall be written in language that can be easily 
understood by the potential research subjects. The principal investigator or investigator shall be 
responsible for providing detailed explanation of the informed consent form and information sheet to 
the potential subjects. Information should be given in both oral and written form whenever possible 
and in manner deemed appropriate by the committee such as the IEC. 
The principal investigator or investigator shall ensure that the potential research subjects have (1) an 
opportunity to inquire about the research and (2) sufficient time to decide on their participation. If a 
potential research subject decides he or she is willing to participate in the research, then the informed 
consent form must be signed and dated by the potential research subject prior to entering into the 


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research as a subject. The principal investigator or investigator shall instruct the potential research 
subject to sign using their legal names, not nicknames, using a blue or black ball point ink pen. Also 
the principal investigator or investigator shall sign and date the informed consent form prior to 
potential research subject entering into the research. 
Once signed, the original informed consent form shall be retained by the principal investigator or 
investigator. The principal investigator or investigator shall record the date that the potential research 
subject signed the informed consent form in the subject’s medical record. A copy of the signed 
informed consent form shall be given to the research subject. 
If the informed consent form and information sheet is revised, the principal investigator or 
investigator shall newly obtain re-consent from the concerned research subject by following the 
same procedure as for obtaining the initial consent. The date of obtaining new consent shall be 
recorded in the research subject’s medical record, and a copy of the revised consent form shall be 
provided to the research subject. 
15.4 
Personal information of the research subjects 
The sponsor or the designee shall affirm the principle of the protection of research subjects' 
private/personal information, etc. Throughout this study, research subject ID numbers shall be used 
to link the subject's source data to the sponsor's research database and research-related documents. 
Limited information on research subjects such as gender, age, and date of birth may be used within 
the scope of all applicable laws and regulations for identification of research subjects and 
confirmation of accuracy of research subject ID number. 
For verification of the conduct of the research in compliance with this protocol and the Ethical 
Guidelines for Medical and Health Research Involving Human Subjects, the sponsor shall require 
the principal investigator to provide the research sponsor’s designee, representatives of regulatory 
authorities, designated auditors, and committees such as the Ethical Review Board direct access to 
research subjects’ original medical records (source data or documents), including laboratory test 
results, ECG results, admission and discharge records during a subject’s research participation, and 
autopsy reports. The principal investigator or investigator shall obtain specific authorization from the 
research subject as part of the informed consent process for access to research subject's original 
medical records by research sponsor’s designee and representatives of regulatory authorities (see 
section 15.3). 
When providing a copy of source documents to the sponsor, the principal investigator or investigator 
shall delete information that may lead to identification of an individual (name and address of 
research subject, other personal information not recorded on the CRF of the research subject). 


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15.5 
Consultation windows for the research subjects or persons related to the 
research concerned 
The principal investigator shall establish a contact service to respond to inquiries concerning this 
clinical research from research subjects or concerned people. Details of the contacts for inquiries 
will be described in the informed consent form. 
15.6 
Financial burden or reward to the research subjects 
Of the expenses for this clinical research, the sponsor shall offer compensation for medical treatment 
not covered by health insurance as research expenses. The research subjects shall pay expenses for 
medical treatment covered by ordinary health insurance. 
In addition, the principal investigator shall pay expenses such as transportation expenses for 
participation in this clinical research to the research subjects at each visit from the research funds. 
Details of the financial burden on the research subjects and rewards shall be described in the 
informed consent form. 
15.7 
Benefits and inconveniences to the research subjects 
15.7.1 Benefits to research subjects 
By participating in this clinical research, the research subjects may understand one’s own condition 
of type 2 diabetes mellitus in detail. 
15.7.2 Inconveniences to research subjects 
By participating in this clinical research the burden of the research subject may increase as number 
of visits will increase compared to daily medical care. 
15.8 
Attribution of research results and access rights 
15.8.1 Attribution of research results 
The research results and data obtained from this research shall belong to the sponsor. In addition, 
secondary use (meta-analysis, etc.) of the data obtained in this clinical research may be possible if 
used in such a way that the data shall not be linked to personal identification information. 
15.8.2 Data access rights 
Access rights for all data and information generated from this study will be given to personnel 
approved by the sponsor. 


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15.9 
Reporting of results, publication, disclosure, and clinical research 
registration policy 
15.9.1 Reporting of results, publication and disclosure 
The principal investigator shall report a written summary of results of the research to the chief 
executive of the research implementing entity and provide the sponsor with all the results and data 
obtained from the research. Only the sponsor may disclose the research information to other 
principal investigators, investigators or regulatory authorities during the research period, except 
when required by laws and regulations. The sponsor shall be responsible for publication of the 
research protocol and research-related results (including the public web site) except for other cases 
permitted in the research contract. 
During research period and after the end of research, the sponsor or its designee should promptly 
summarize the results and present it to medical journals and academic conferences, etc. The sponsor 
may publish any data or information obtained from the research (including data and information 
provided by the principal investigator) without obtaining consent of the principal investigator. 
The principal investigator or the investigator should obtain the prior written approval from the 
sponsor when publishing the information obtained in this research at an academic conference, etc. 
15.9.2 Clinical research registration 
To ensure that information on clinical research is made accessible to the public in a timely manner 
and to comply with applicable laws, regulations, and guidelines, Takeda Pharmaceutical Company 
Limited shall register all clinical research being conducted in patients around the world at public trial 
registration sites, including at least the website(s) of ClinicalTrials.gov (and) Japan Pharmaceutical 
Information Center Clinical Trials Information (JAPIC). On such websites, the research location 
(city, country), subject recruitment status, and contact information for Takeda Pharmaceutical 
Company Limited are open to the public. 
15.9.3 Clinical trial results disclosure 
Takeda Pharmaceutical Company Limited shall post the research results, irrespective of the nature of 
the results, at the public trial registration site(s) of Clinical Trials.gov (and) JAPIC in accordance 
with applicable laws and regulations. 
15.10 Insurance and compensation for injury 
The research subjects participating in this research shall be compensated for any injury resulting 
from participation in the research according to local regulations applicable to the research 


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implementing entity. The sponsor or its designee shall buy an insurance policy to compensate for 
health injury in research subjects. 
Healthy injury in a research subject will be compensated as specified in the study contract. 
Compensation-related questions by the principal investigator or investigators should be made to the 
sponsor or its designee. 


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16.0 
REFERENCES 
1. 
Rimei Nishimura, Glucose variability and vascular disease risk. The Journal of the Japanese 
Society of Internal Medicine. 2013; 102: 922-930  
2. 
Gerstein HC. et al; The Action to Control Cardiovascular Risk in Diabetes Study Group. 
Effects of intensive glucose lowering in type 2 diabetes. The New England Journal of 
Medicine. 2008; 358: 2545-2559. 
3. 
Currie CJ, et al. Survival as a function of HbA（1c）in people with type 2 diabetes: a 
retrospective cohort study. Lancet. 2010; 375: 481- 489. 
4. 
Baggio LL, Drucker DJ. Biology of incretins: GLP-1 and GIP. Gastroenterology. 2007; 
132(6): 2131-2157. 
5. 
Monnier L, Mas E, et al; Activation of Oxidative Stress by Acute Glucose Fluctuations 
Compared With Sustained Chronic Hyperglycemia in Patients With Type 2 Diabetes. The 
Journal of the American Medical Association. 2006Apr 12; 295(14): 1681-1687.  
6. 
Klonoff DC, et al; Continuous Glucose Monitoring: roadmap for 21st century diabetes 
therapy. Diabetes Care. 2015 May; 28(5): 1231-1239. 
7. 
Drucker DJ. The biology of incretin hormones. Cell Metabolism. 2006; 3(3):153-165. 
8. 
Kaufman FR, Gibson LC, Halvorson M, et al. A pilot study of the continuous glucose 
monitoring system: clinical decisions and glycemic control after its use in pediatric type 1 
diabetic subjects. Diabetes Care. 2001; 24(12): 2030-2034. 
9. 
Su G, Mi S, et al; Association of glycemic variability and the presence and severity of 
coronary artery disease in patients with type 2 diabetes. Cardiovascular Diabetology. 2011; 
10:19. 
10. Inagaki N, Onouchi H, et al. Once-weekly trelagliptin versus daily alogliptin in Japanese 
patients with type 2 diabetes: a randomised, double-blind, phase 3, non-inferiority study.  
Lancet Diabetes Endocrinol. 2015 Mar; 3(3):191-197.. 
11. Report of the Working Group on Conflict of Interest (Ministry of Education, Culture, Sports, 
Science and Technology dated November 1, 2002) 
12. Guidelines for determining the conflict of interest polity for clinical research (Review group 
for ethical aspects of clinical research and conflict of interest, March 2006) 
13. Guidelines on the Management of Conflict of Interest (COI) in Health and Labour Sciences 
Research (March 31, 2008) 
14. Guidelines for management of COI in medical research (COI Committee of Japan 
Association of Medical Sciences, February 2011) 
15. Common guidelines for conflict of interest (COI) in clinical research (Japanese Society of 
Internal Medicine, Japan Society of Hematology, Japanese Circulation Society, Japan 
Endocrine Society, Japan Diabetes Society, Japanese Respiratory Society, Japanese Society 
of Hematology, Japanese Society of Allergology, Japanese Association for Infectious 
Diseases, Aug 2011) 


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Appendix A 
Schedule of Research Procedures 
 
 
Observation period 
Treatment period 
Time 
of 
Visit 
Week 
 
 
0 
 
 
4 
 
Disconti
nuation(g
) 
Day 
-14 
-2 
1(b) 
21(c) 
24(c) 
29(c) 
- 
Allowable range (Day) 
-28 to -2 
-4 to -2 
1 
19 to 35 24~39(f) 29 to 43 
- 
VISIT Number 
 
1 
2 
3 
4 
5 
- 
Informed 
consent 
procedure 
× 
 
 
 
 
 
 
Inclusion/Exclusion 
criteria 
× 
× 
 
 
 
 
 
Demographic 
information 
× 
 
 
 
 
 
 
Medical 
history, 
pre-treatment 
× 
× 
 
 
 
 
 
Physical examination 
× 
× 
(×) 
× 
× 
× 
× 
Body weight, BMI 
 
× 
 
× 
 
× 
× 
Height 
× 
 
 
 
 
 
 
Concomitant drugs 
× 
× 
(×) 
× 
× 
× 
× 
Concurrent disease 
× 
× 
 
 
 
 
 
Laboratory tests (a) 
 
× 
 
× 
× 
× 
× 
HbA1c 
 
× 
 
 
 
 
 
Drug -taking status 
 
 
 
× 
× 
× 
× 
Prescription of dietetic 
therapy and exercise 
therapy and assessment 
of compliance 
× 
× 
(×) 
× 
× 
× 
× 
CGM 
 
× (d) 
(Sensor 
insertion) 
×
(d) 
(Sensor 
remove) 
× (d) 
(Sensor  
insertion) 
× (d) 
(Exchange 
sensor) 
×
(d) 
(Sensor 
remove) 
 
Self-measurement of 
blood glucose 
 
× (e) 
× (e) 
× (e) 
× (e) 
× (e) 
 
Adverse event 
monitoring 
 
 
× 
(a) Measured on VISIT1 (Day-2), and the first and ninth days of the 9-day CGM starting on Day 21 
Blood tests: glycoalbumin, 1,5-AG, fasting insulin, fasting glucagon, fasting proinsulin, fasting GLP-1, fasting GIP*, DPP-4 activity 
Measured on 1 point during fourth and sixth day of the 9-day CGM starting on Day 21 
Blood tests: fasting GLP-1, fasting GIP, DPP-4 activity 
(b) The starting day of study treatment in the treatment period is designated as Day 1. The study drug shall be administered after required 
tests/observations, etc. The day before the start of study treatment in the treatment period is designated as Day -1. It is performed at the visit 
when principal investigator or investigator consider as needed. 
(c) Trelagliptin 100 mg/week group shall insert the sensor on a day between 3 day and a day before Trelagliptin administration day.  
Trelagliptin 100 mg/week shall be administered before breakfast on the day of the drug administration.  
Alogliptin 25 mg/day shall be administered after required tests/observations, etc at every VISIT without taking study drug. Research 
subjects shall take study drug prior to the every breakfast at home.  


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(d) To be performed by study site personnel 
(e) At least, blood glucose levels shall be measured at three time points on the first day of CGM ([1] at least 2 hours after the recorder is 
connected and [2] 2 hours after the first is measured. [3] at bedtime) and at four time points from the second day onward ([1] before 
breakfast, (2) before lunch, (3) before evening meal, and (4) at bedtime).  
(f) Research subjects should visit the study site on a day between fourth and sixth day of the 9-day CGM starting on Day 21. 
(g) To be performed to the extent possible 


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Appendix B 
Responsibilities of the sponsor 
1. 
To appropriately conduct the clinical research in compliance with this research protocol and the 
Ethical Guidelines for Medical and Health Research Involving Human Subjects and with the 
highest respect for human rights, safety, and welfare of research subjects. 
2. 
To prepare a list of any other investigators and/or research collaborators when certain important 
research-related activities are divided by investigators and/or research collaborators, and submit 
the list to the sponsor as required. 
3. 
To prepare the informed consent form and revise it as necessary. 
4. 
To check the contents of the study contract. 
5. 
To provide sufficient information on the protocol, drug and duties of each personnel to 
subinvestigators and study collaborators, and give guidance and supervision. 
6. 
To select research subjects who satisfy the inclusion criteria, give explanation using written 
information, and obtain consent in writing. 
7. 
To be responsible for all medical judgments related to the research. 
8. 
Corresponding to request from the chief executive of the research implementing entity, to report 
the latest progress status at least once a year to the chief executive of the research implementing 
entity. 
9. 
To ensure that the most update status is confirmed and comprehended regarding the COI of the 
investigators participating in the clinical research according to the research implementing 
entity. 
10. To ensure, together with the chief executive of the research implementing entity, that sufficient 
medical care is provided to research subjects for all research-related clinically problematic 
adverse events throughout the period of subjects’ research participation and thereafter. 
11. When a research subject is treated at another medical institution or department, to inform the 
acting physician at the medical institution or department in writing of the research subject’s 
study participation and research completion/discontinuation after obtaining the research subject’
s consent, and prepare a record. 
12. When emergency reporting of serious adverse events, is required, to immediately report it in 
writing to the chief executive of the research implementing entity and the sponsor. 
13. To ensure that the CRFs are accurate and complete, electronically sign and submit them to the 
sponsor. 
14. To verify any entries on the CRFs made by the investigator or transcribed by the collaborator 
from source documents, electronically sign and submit them to the sponsor. 
15. To discuss a revision of the protocol, etc., when proposed by the sponsor. 


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16. To report the research completion in writing to the chief executive of the research implementing 
entity. 
17. To receive continuing education and training for conducting the study properly including 
Ethical Guideline and GCP during the study period (at least once a year is recommended). 


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PROTOCOL 
 
 
An exploratory study to evaluate the effects of Trelagliptin and Alogliptin by CGM 
on glucose variability for one week with type 2 diabetes mellitus (TRACK) 
 
 
 
 
 
Sponsor 
Takeda Pharmaceutical Company Limited 
2-12-10 Nihonbashi, Chuo-ku, Tokyo 
Protocol number 
Trelagliptin-4001 
Version number 
2nd Version 
Study drug: 
Trelagliptin 
Alogliptin 
Creation date 
November 11, 2016 
 
 
CONFIDENTIAL PROPERTY 
This document is a confidential communication of Takeda. Acceptance of this document constitutes 
agreement by the potential recipient of the drug to be administered that no information contained herein 
will be published or disclosed without written authorization from Takeda except to the extent necessary to 
obtain informed consent from those research subjects to whom the drug may be administered. 
Furthermore, the information is only intended for review and compliance by the recipient, his or her staff, 
and applicable institutional review committee and regulatory agencies to enable conduction of the study. 


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1.0 
CLINICAL STUDY PRINCIPLES AND CLINICAL STUDY 
MANAGEMENT INFORMATION 
1.1 
Clinical Study Principals 
This study will be conducted with the highest respect for the individual participants in accordance 
with the requirements of this clinical study protocol and also in accordance with the following: 
• 
The ethical principles that have their origin in the Declaration of Helsinki. 
• 
Ethical Guideline for Clinical Research (the Ministry of Education, Culture, Sports, Science and 
Technology and the Ministry of Health, Labor and Welfare, December 22, 2014). 
• 
Good Clinical Practice: Consolidated Guideline (ICH. E6) 
• 
All applicable laws and regulations, including, without limitation, data privacy laws and conflict 
of interest guidelines. 
1.2 
CLINICAL STUDY ADMINISTRATIVE STRUCTURE 
This study will be conducted under the administrative structure described in the attached sheet 1 in 
accordance with the protocol prepared and planned by the sponsor.  
 


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Table of Contents 
1.0 
CLINICAL STUDY PRINCIPLES AND CLINICAL STUDY 
MANAGEMENT INFORMATION ....................................................................... 2 
1.1 
Clinical Study Principals ................................................................................... 2 
1.2 
CLINICAL STUDY ADMINISTRATIVE STRUCTURE ............................... 2 
2.0 
STUDY SUMMARY .............................................................................................. 8 
3.0 
ABBREVIATION ................................................................................................. 14 
4.0 
INTRODUCTION ................................................................................................. 15 
4.1 
Background ...................................................................................................... 15 
4.2 
Rationale for the proposed research ................................................................ 15 
5.0 
RESEARCH OBJECTIVES AND ENDPOINTS ................................................. 17 
5.1 
Objectives ........................................................................................................ 17 
5.2 
Definition of endpoints .................................................................................... 17 
5.2.1 Primary endpoints ...................................................................................... 17 
5.2.2 Secondary endpoints .................................................................................. 17 
5.2.3 Other endpoints ......................................................................................... 18 
6.0 
CLINICAL RESEARCH DESIGN ....................................................................... 19 
6.1 
Clinical research design ................................................................................... 19 
6.2 
Rationale for the clinical research design ........................................................ 20 
6.3 
Premature termination of entire clinical research or premature 
termination of clinical research at a research implementing entity ................. 21 
6.3.1 Premature termination criteria of entire clinical research ......................... 21 
6.3.2 Criteria for premature termination of research implementing entities ...... 22 
6.3.3 Procedures of clinical study suspension and premature termination of 
entire clinical study or study at a research implementing entity ............... 22 
6.4 
Procedures for protocol revision ..................................................................... 22 
7.0 
SELECTION AND WITHDRAWAL CRITERIA OF RESEARCH 
SUBJECTS ............................................................................................................ 23 
7.1 
Inclusion criteria .............................................................................................. 23 
7.2 
Exclusion criteria ............................................................................................. 24 
7.3 
Prohibited concomitant drugs and restricted concomitant drugs..................... 27 


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7.3.1 Prohibited concomitant drugs .................................................................... 27 
7.3.2 Restricted concomitant drugs .................................................................... 27 
7.4 
Research Subject Management ........................................................................ 27 
7.5 
Criteria for discontinuation or withdrawal of a research subject .................... 28 
7.6 
Procedures for discontinuation of individual research subjects ...................... 29 
8.0 
RESEARCH TREATMENT ................................................................................. 30 
8.1 
Treatment with the study drug ......................................................................... 30 
8.1.1 Study drug ................................................................................................. 30 
8.1.2 Dose and administration method ............................................................... 30 
8.1.3 Overdose .................................................................................................... 31 
8.2 
Medication other than the study drug .............................................................. 31 
8.3 
Allocation and prescription of the study drug and administration 
procedure ......................................................................................................... 31 
8.4 
Preparation and storage of allocation list ........................................................ 32 
9.0 
CLINICAL STUDY PROTOCOL ........................................................................ 33 
9.1 
Research procedures ........................................................................................ 33 
9.1.1 Informed consent procedure ...................................................................... 33 
9.1.2 Demographic data, medical history, and previous therapeutic drugs ........ 33 
9.1.3 Physical examination ................................................................................. 33 
9.1.4 Weight, height and BMI ............................................................................ 33 
9.1.5 Concomitant drugs ..................................................................................... 34 
9.1.6 Concurrent disease ..................................................................................... 34 
9.1.7 Laboratory tests ......................................................................................... 34 
9.1.8 HbA1c (NGSP value) ................................................................................ 35 
9.1.9 Continuous glucose monitoring (CGM) .................................................... 35 
9.1.10 Contraception ............................................................................................ 36 
9.1.11 Pregnancy .................................................................................................. 37 
9.1.12 Record of cases withdrawn before randomization .................................... 37 
9.1.13 Record of randomization ........................................................................... 37 
9.2 
Drug-taking status of the research subjects ..................................................... 38 
9.3 
Implementation time point of the test and observation items .......................... 38 


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9.3.1 Start of observation period (Visit 1: Day -2) ............................................. 38 
9.3.2 At start of treatment period (Visit 2: Day 1) ............................................. 39 
9.3.3 Treatment period (Visit 3: Day 21) ........................................................... 39 
9.3.4 Treatment period (Visit 4: Day 24) ........................................................... 40 
9.3.5 At end of treatment period (Visit 5: Day 29) or discontinuation 
during treatment period ............................................................................. 40 
10.0 
ADVERSE EVENT ............................................................................................... 42 
10.1 
Definitions ....................................................................................................... 42 
10.1.1 Adverse event ............................................................................................ 42 
10.1.2 Considerations for adverse events ............................................................. 42 
10.1.3 Serious adverse event ................................................................................ 44 
10.1.4 Adverse events of special interest (specific adverse events) ..................... 45 
10.1.5 Severity of adverse events ......................................................................... 46 
10.1.6 Causality of adverse events ....................................................................... 46 
10.1.7 Relationship to study procedures ............................................................... 47 
10.1.8 Date of onset .............................................................................................. 47 
10.1.9 Date of resolution ...................................................................................... 47 
10.1.10Actions taken for the study drug................................................................ 47 
10.1.11Outcome .................................................................................................... 48 
10.2 
Procedures ....................................................................................................... 49 
10.2.1 Collection and reporting of adverse events ............................................... 49 
10.2.2 Collection and reporting of serious adverse events ................................... 50 
10.2.3 Reporting of additional information concerning adverse events ............... 51 
10.3 
Follow-up of serious adverse events ............................................................... 51 
10.3.1 Reporting of serious adverse events to Ethics Review Committee, 
etc., and regulatory authorities .................................................................. 51 
11.0 
COMMITTEES ESTABLISHED FOR THIS STUDY ........................................ 53 
12.0 
DATA MANAGEMENT AND STORAGE OF RECORDS ............................... 54 
12.1 
Case report form .............................................................................................. 54 
12.2 
Timing of data entry into the electronic CRF system ...................................... 55 
12.3 
Storage of records ............................................................................................ 55 


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13.0 
STATISTICAL ANALYSIS METHODS ............................................................. 56 
13.1 
Statistical and analytical plans ......................................................................... 56 
13.1.1 Analysis set ................................................................................................ 56 
13.1.2 Analysis of demographic and other baseline characteristics ..................... 56 
13.1.3 Efficacy analysis ........................................................................................ 56 
13.1.4 Conversion method of data and handling of missing data ........................ 58 
13.1.5 Significance level and confidence coefficient ........................................... 58 
13.1.6 Safety analysis ........................................................................................... 59 
13.2 
Criteria for interim analysis and premature discontinuation ........................... 59 
13.3 
Determination of the number of planned research subject .............................. 59 
14.0 
QUALITY CONTROL AND QUALITY ASSURANCE .................................... 60 
14.1 
Monitoring of the research implementing entity ............................................. 60 
14.2 
Deviation from the Ethical Guidelines for Medical and Health Research 
Involving Human Subjects and the research protocol. .................................... 60 
14.3 
Quality assurance audits and regulatory agency inspections........................... 60 
15.0 
ETHICAL CONDUCT OF CLINICAL RESEARCH .......................................... 62 
15.1 
Approval of the Ethical Review Board, etc. .................................................... 62 
15.2 
Conflict of interest ........................................................................................... 63 
15.3 
Informed consent and information sheet, and the agreement of the 
research subjects .............................................................................................. 63 
15.4 
Personal information of the research subjects ................................................. 64 
15.5 
Consultation windows for the research subjects or persons related to the 
research concerned .......................................................................................... 65 
15.6 
Financial burden or reward to the research subjects........................................ 65 
15.7 
Benefits and inconveniences to the research subjects ..................................... 65 
15.7.1 Benefits to research subjects...................................................................... 65 
15.7.2 Inconveniences to research subjects .......................................................... 65 
15.8 
Attribution of research results and access rights ............................................. 65 
15.8.1 Attribution of research results ................................................................... 65 
15.8.2 Data access rights ...................................................................................... 65 
15.9 
Reporting of results, publication, disclosure, and clinical research 
registration policy ............................................................................................ 66 


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15.9.1 Reporting of results, publication and disclosure ....................................... 66 
15.9.2 Clinical research registration ..................................................................... 66 
15.9.3 Clinical trial results disclosure .................................................................. 66 
15.10 Insurance and compensation for injury ........................................................... 66 
16.0 
REFERENCES ...................................................................................................... 68 
LIST OF IN-TEXT TABLES 
Table8.a 
Administration group and administration method ..................................... 31 
Table 9.a 
Laboratory tests ......................................................................................... 35 
Table 10.a 
Takeda Medically Significant AE List ...................................................... 45 
LIST OF IN-TEXT FIGURES 
Figure6.a 
Outline of clinical research design ............................................................ 20 
LIST OF APPENDICES 
Appendix A 
Schedule of Research Procedures .............................................................. 69 
Appendix B 
Responsibilities of the sponsor .................................................................. 71 
 


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2.0 
STUDY SUMMARY 
Sponsor: 
Takeda Pharmaceutical Company Limited 
Study drug: 
Trelagliptin 
Alogliptin 
Study title: 
An exploratory study of the effects of trelagliptin and alogliptin on glycemic variation 
in patients with type 2 diabetes mellitus 
Protocol number: Trelagliptin-4001 (122/NRP-001) 
Clinical study design: 
This is a multi-center, randomized, open-label, parallel-group comparative, exploratory study to evaluate 
the effect of trelagliptin administered at a dose of 100 mg once weekly or alogliptin administered at a 
dose of 25 mg once daily for 4 weeks on glycemic variation in patients with type 2 diabetes mellitus using 
continuous glucose monitoring (CGM). 
After informed consent, patients determined to be eligible for this study based on the eligibility 
assessment will be randomized to either the trelagliptin 100 mg group or the alogliptin 25 mg group (at a 
ratio of 1:1), using "HbA1c at the start of the observation period (< 7.5% or ≥ 7.5%)" and age (< 65 or ≥ 
65) as a stratification factor for randomization. 
The total duration of evaluation will be 31 days, consisting of the observation period for 2 days and a 
treatment period for 29 days (4 weeks). CGM will be performed on research subjects on an outpatient 
basis (in 2 assessments) for 2 days from the start of the observation period (Day -2) and for 9 days from 
Day 21 of the treatment period. 
Objective:  
To evaluate the effect of trelagliptin administered orally at a dose of 100 mg once weekly or alogliptin 
administered orally at a dose of 25 mg once daily for 4 weeks on glycemic variation in an exploratory 
manner and as preliminary to examine the influence of the once-weekly administration and blood glucose 
fluctuations due to the difference in the daily administration in patients with type 2 diabetes mellitus 
Study population:  
Patients with type 2 diabetes mellitus 
Planned number of research subjects: 
The planned minimum number of research subjects evaluable 
for the primary endpoint in each group is as follows: 
Trelagliptin 100 mg group: 15 
Alogliptin 25 mg group: 15 
Number of study research 
implementing entities: 
3 medical institutions 


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Total: 30 
Dose and method of administration: 
Trelagliptin 100 mg once weekly or alogliptin 25 mg once 
daily, taken orally before breakfast 
Route of administration: 
Oral 
Duration of treatment: 
4 weeks 
Duration of evaluation: 
31 days (observation period for 2 days 
and treatment period for 4 weeks [29 
days]) 
Inclusion criteria 
1. 
Research subjects who, in the opinion of the principal investigator or the investigator, are capable of 
understanding the content of the clinical research and complying with the research protocol 
requirements. 
2. 
Patients who are able to sign and date the informed consent form and information sheet prior to the 
start of study procedures 
3. 
Patients diagnosed with type 2 diabetes mellitus 
4. 
Patients with an HbA1c (NGSP value) value ≥ 6.5% and < 8.5% at the start of the observation 
period (Day -2) 
5. 
Patients who experience a ≤ ±1.0% change in HbA1c (NGSP value) at the start of the observation 
period (Day -2) as compared with an HbA1c value obtained during the preceding 4 weeks 
6. 
Patients receiving stable dietetic therapy and exercise therapy (if performed) for ≥ 4 weeks before 
the start of the observation period 
7. 
Patients, who in the opinion of the principal investigator or the investigator, does not have to change 
(including discontinuation or interruption) HMG-CoA reductase inhibitors or add new HMG-CoA 
reductase inhibitors during treatment period. 
8. 
Men or women aged 20 years or older at the time of informed consent 
Exclusion criteria:  
1. 
Patients who received anti-diabetic medications within 4 weeks prior to the start of the observation 
period 
2. 
Patients who have changed (including discontinuation or interruption) HMG-CoA reductase 
inhibitors or received new HMG-CoA reductase inhibitors ≤ 4 weeks before the start of the 
observation period.  
3. 
Patients with clinically evident hepatic dysfunction (e.g., AST or ALT ≥ 2.5-fold the upper limit of 
normal at the start of the observation period [Day -2]) 


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4. 
Patients with moderate renal dysfunction, severe renal dysfunction or renal failure (e.g., creatinine 
clearance < 50 mL/min or serum creatinine > 1.4 mg/dL in men or > 1.2 mg/dL in women 
[equivalent to the creatinine clearance for persons aged 60 years with a body weight of 65 kg] at the 
start of the observation period [Day -2]) 
5. 
Patients with severe heart disease, cerebrovascular disorder, or severe pancreatic, hematologic or 
other diseases 
6. 
Patients with a history of gastric or small intestinal resection 
7. 
Patients with proliferative diabetic retinopathy 
8. 
Patients warranting insulin therapy for glycemic control (e.g., patients with severe ketosis, diabetic 
coma or precoma, type 1 diabetes mellitus, severe infection, perioperative patients, or serious 
trauma) 
9. 
Patients with a history of hypersensitivity or allergy to DPP-4 inhibitors 
10. Patients who experience an allergic reaction to metal during CGM at the start of the observation 
period (Day -2) 
11. Patients with any malignant tumors 
12. Habitual drinkers whose average daily alcohol consumption is > 100 mL 
13. Patients who have any contraindications for the study drug or are taking any contraindicated 
concomitant drugs listed in the package insert 
14. Patients anticipated to require any prohibited concomitant medications during the study period 
15. Patients who are day and night lifestyle reversal 
16. Patients participating in any other clinical studies at the time of informed consent for this study 
17. Pregnant women, nursing mothers, women who are possible pregnant, or women who plan to 
become pregnant 
18. Other patients who are considered inappropriate for participation in this study in the opinion of the 
principal investigator or investigator 
Endpoints: 
<Primary endpoints> 
• 
Changes in the standard deviation (SD) of 24-hour blood glucose values (mg/dL) for each 7-day 
period between Week 3 and Week 4 (between Day 22 and Day 28) of the treatment period, calculated 
from the value at the start of the observation period 
<Secondary endpoints> 
Efficacy endpoints: 
• 
Changes in AUC over time when specific blood glucose levels ( 110, 140, 160, or 180 mg/dL) are 
observed during the 3 hour time period after breakfast, lunch and evening meal*1, 2 
• 
Change in AUC over time during periods when blood glucose 140, 160, or 180 mg/dL 


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(hyperglycemia) is observed*1, 2 
• 
Changes in blood glucose 140, 160, or 180 mg/dL (hyperglycemia) over time*1, 2 
• 
Changes in AUC over time during periods when blood glucose < 70 mg/dL (hypoglycemia) is 
observed*1,2  
• 
Change in peak postprandial glucose levels over time 3 hours after breakfast, lunch, and evening 
meal*1,2 
• 
 Change in maximum variation of blood glucose levels over time between before and after breakfast, 
lunch, and evening meal*1,2  
• 
Changes in MAGE*1, 2 
• 
Changes in mean 24-hour blood glucose levels*1, 2 
• 
Changes in mean daytime blood glucose levels*1, 2 
• 
Changes in mean nocturnal  blood glucose levels*1, 2 
• 
Changes in AUC*1, 2 
• 
Changes in AUC over time during periods when blood glucose 110 mg/dL (hypoglycemia) is 
observed*1,2 
• 
Changes in the SD of 24-hour blood glucose values*1,2 
• 
Changes in the SD of daytime blood glucose values*1,2 
• 
Changes in the SD of nocturnal blood glucose values*1,2 
*1: Measured value and percent changes for each 7-day period between Week 3 and Week 4 (between 
Day 22 and Day 28) of the treatment period calculated from the value at the start of the observation 
period (however changes in the SD of 24-hour blood glucose values shall be measured value only)  
*2: Measured value and percent change from the value at the start of the observation period to the mean 
value during the 7-day period between Week 3 and Week 4 (between Day 22 and Day 28) of the 
treatment period 
[Safety endpoint] 
• 
Adverse events 
<Other endpoints> 
• 
Glycoalbumin 
• 
1,5-AG 
• 
Fasting blood glucose 
• 
Fasting insulin 
• 
Fasting glucagon 
• 
Fasting proinsulin 


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• 
Fasting GLP-1 
• 
Fasting GIP 
• 
DPP-4 activity 
• 
Inhibitory rate of DPP-4 activity 
Statistical method 
(1) Analysis set 
Two analysis sets, “full analysis set” and “safety data analysis set” are used in this study. "The Full 
Analysis Set" used as a primary analysis set in the efficacy analysis shall be defined as "the research 
subjects who were randomized and given at least one dose of the study drug." The safety data 
analysis set shall be defined as “the research subjects who were given at least one dose of the study 
drug”. 
(2) Efficacy analysis 
<Primary endpoints> 
• 
For the “full analysis set”, summary statistics (number of subjects, mean, SDs, maximum values, 
minimum values, quartiles [same apply hereafter]) and 95% confidence interval (two sides) of mean 
shall be calculated for each treatment group at each evaluation point (each day), and illustrating 
changes in mean and SD in order to evaluate changes in the SD of 24-hour blood glucose values 
(mg/dL) for each 7-day period between Week 3 and Week 4 (between Day 22 and Day 28) of the 
treatment period, calculated from the value at the start of the observation period for trelagliptin or 
alogliptin separately. Preliminary, for the “full analysis set”, calculate point estimation and 95% 
confidence interval (two sides) in difference of mean in treatment groups (trelagliptin 100 mg group 
– alogliptin 25 mg group) in order to examine the influence of the once-weekly administration and 
blood glucose fluctuations due to the difference in the daily administration exploratory. 
• 
As well, for the “full analysis set ,” conduct analysis of covariance at each evaluation point with 
changes in the SD of 24-hour blood glucose values between Week 3 and Week 4 from the value at 
the start of the observation period as dependent variable, treatment groups as independent variable, 
HbA1c (NGSP value) at the start of the observation period, changes in the SD of 24-hour blood 
glucose values at the start of the observation period, and age as covariates, and calculate point 
estimation and 95% confidence interval (two sides) in difference of adjusted mean for each group. 
• 
Preliminary, “full analysis set ,” calculate point estimation and 95% confidence interval (two sides) 
in difference of adjusted mean in treatment groups (trelagliptin 100 mg group – alogliptin 25 mg 
group) 
<Secondary endpoints> 
• 
Conduct the same analysis as the primary endpoints for *1 and *2 of the each endpoint section. 


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However, for changes in mean/SD, only measured values of *1 and *2 shall be illustrated. 
<Additional endpoints> 
• For the “full analysis set”, while calculating summary statistics and 95% confidence interval (two 
sides) of mean at each evaluation point (the start of the observation period by each treatment group, 
first day, 1 point during fourth to sixth day, and ninth day of CGM which is to be performed for 9 
days from Day 21) in measured values and changes from the start of the observation period, and 
illustrate changes in mean and SD. 
(3) Safety analysis 
• Adverse events shall be reported using MedDRA terminology and summarized using the Preferred 
Term (PT) and System Organ Class (SOC) of the MedDRA. For the “safety data analysis set”, 
frequency tabulation shall be conducted for adverse events after start of treatment with study drug by 
each treatment group: 
 
Frequency tabulation of all adverse events 
 
Frequency tabulation of adverse events that causal relationship is “related” to study drug. 
 
Frequency tabulation of the degree of all adverse events 
 
Frequency tabulation of degree of adverse events that causal relationship is “related” to study 
drug. 
 
Frequency tabulation of adverse events that were “discontinued” as a measurement concerning 
study drug. 
 
Frequency tabulation of serious adverse events 
Rationale for the number of planned research subjects: 
The planned minimum number of research subjects evaluable for the primary endpoint in each group is as 
follows: 
Trelagliptin 100 mg group: 15 
Alogliptin 25 mg group: 15 
Set in consideration with the feasibility of the number of research subjects for exploring the effects of 
trelagliptin 100 mg and alogliptin 25 mg on glycemic variation. It is not based on statistical power 
calculation. 


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3.0 
ABBREVIATION 
AE 
adverse event 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AUC 
Area under the curve 
1,5-AG 
1,5-anhydroglucitol 
BMI 
body mass index 
CGM 
continuous glucose monitoring 
COI 
conflict of interest 
CRO 
contract research organization 
DPP-4 
dipeptidyl-peptidase-4 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GIP 
glucose-dependent insulinotropic 
polypeptide 
GLP-1 
glucagon like peptide-1 
HbA1c 
hemoglobin A1c 
ICH 
International Conference on 
Harmonisation 
MAGE 
Mean Amplitude Glycemic Excursions 
MedDRA 
Medical Dictionary for Regulatory 
Activities 
PT 
preferred term  
SAE 
serious adverse event 
SD 
standard deviation 
SMBG 
Self Monitoring of Blood Glucose 
SOC 
system organ class 
WHO 
World Health Organization 
 


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4.0 
INTRODUCTION 
4.1 
Background 
Conventionally, although HbA1c has been used as an indicator for glycemic control for patients with 
diabetes mellitus, it has been indicated that it is insufficient for inhibiting cardiovascular events by 
only controlling HbA1c which reflects the long term glycemic variation 1-3) On the other hand, it has 
been reported that persistent hyperglycemia and the range of glycemic variation is related to 
oxidative stress and cardiovascular events, and it has been indicated that treatment is necessary in 
consideration of daily glycemic variation 4-6). Also, it is anticipated that the glycemic variation of 
patients with diabetes mellitus and the characteristics of each anti-diabetic medications may be 
revealed and to be able to make a choice for a more appropriate treatment. 
Self-measurement of blood glucose (SMBG) is used frequently for measuring glycemic variation 
and although one may understand the blood glucose level at the time of measurement, it is difficult 
to know if the blood glucose level has an upward trend or not changing or a downward trend at that 
time point, and it is reported that 80% hypoglycemia or hyperglycemia may be missed 7,8). That is 
why the continuous glucose monitor (CGM) was developed and it became possible to accurately 
evaluate variance of blood glucose which was difficult and planning of treatment course according to 
each patient’s condition is anticipated. Actually, in many researches that was conducted to collect 
various glycemic variation patterns to verify the optimization of treatment of diabetes mellitus, the 
benefits of various indicators of glycemic variation obtained from CGM has been reported 9). 
Dipeptidyl-peptidase-4 (DPP-4) inhibitors are used widely as oral treatment drug for type 2 diabetes 
mellitus and it has an effect to promote insulin secretion blood glucose dependently by raising blood 
concentration of glucagon like peptide-1 (GLP-1). Conventionally, although DPP-4 inhibitors are 
taken once to twice daily commonly, once weekly trelagliptin was developed for a new treatment 
option as good glycemic control from improvement of drug compliance rate and flexibility of timing 
of taking drug according to lifestyle and further improvement of Quality Of Life(QOL) from less 
number of doses was in need. The phase III clinical study conducted at the development stage has 
shown that trelagliptin, when administered for 24 weeks, was not inferior to alogliptin, a DPP-4 
inhibitor used as control, in terms of the change in HbA1c at the end of the treatment period 10). 
However, effect on glycemic variation of trelagliptin and alogliptin has not been clarified efficiently, 
and it is anticipated that understanding the characteristics of once weekly DPP-4 inhibitors and once 
daily DPP-4 inhibitors may be an efficient rational for therapeutic use. 
 
4.2 
Rationale for the proposed research 
 


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Because there is no enough evidence assayed for glycemic variation of not only once weekly DPP-4 
inhibitors but also once daily DPP-4 inhibitor, Trelagliptin, once weekly DPP-4 inhibitor, and 
Alogliptin, once daily DPP -4 inhibitor, were set as study drugs to collect the consecutive data of 
glycemic variation obtained from CGM and to evaluate difference of DPP-4 inhibitors.  
Although trelagliptin was non-inferior to alogliptin, once daily DPP-4 inhibitor, in terms of the 
change from baseline in HbA1c at the phase III clinical study conducted during the development 
period, the effect on glycemic variation of alogliptin have to be clarified when the effect of different 
dose and method of administration of DPP-4 inhibitors on glycemic variation would like to be 
evaluated. 
In this present study, therefore, the effect of once weekly trelagliptin or once daily alogliptin on 
glycemic variation will be evaluated in patients with type 2 diabetes mellitus in an exploratory 
manner as a primary objective, and the effect by difference of dose and method of administration on 
glycemic variation will be evaluated as secondary as far as possible. 


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5.0 
RESEARCH OBJECTIVES AND ENDPOINTS 
5.1 
Objectives 
 
To evaluate the effect of trelagliptin administered orally at a dose of 100 mg once weekly or 
alogliptin orally administered at a dose of 25 mg once daily for 4 weeks on glycemic variation in an 
exploratory manner as a primary objective and to evaluate, as far as possible, the effect of difference 
method of administration of DPP-4 on glycemic variation as secondary objective. 
 
5.2 
Definition of endpoints 
5.2.1 Primary endpoints 
Changes in the standard deviation (SD) of 24-hour blood glucose values (mg/dL) for each 7-day 
period between Week 3 and Week 4 (between Day 22 and Day 28) of the treatment period, 
calculated from the value at the start of the observation period 
5.2.2 Secondary endpoints 
(1) Efficacy: 
 
Changes in AUC over time when specific blood glucose levels ( 110, 140, 160, or 180 
mg/dL) are observed during the 3 hour time period after breakfast, lunch and evening meal 
 
Change in AUC over time during periods when blood glucose 140, 160, or 180 mg/dL 
(hyperglycemia) is observed 
 
Changes in blood glucose 140, 160, or 180 mg/dL (hyperglycemia) over time 
 
Changes in AUC over time during periods when blood glucose < 70 mg/dL 
(hypoglycemia) is observed 
 
Change in peak postprandial glucose levels over time 3 hours after breakfast, lunch, and 
evening meal 
 
Change in maximum variation of blood glucose levels over time between before and after 
breakfast, lunch, and evening meal 
 
Changes in MAGE  
 
Changes in mean 24-hour blood glucose levels  
 
Changes in mean daytime blood glucose levels 
 
Changes in mean nocturnal blood glucose levels 


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 
Changes in AUC 
 
Changes in AUC over time during periods when blood glucose 110 mg/dL is observed 
 
Changes in the SD of 24-hour blood glucose values 
 
Changes in the SD of daytime blood glucose values 
 
Changes in the SD of nocturnal blood glucose values 
(2) Safety: Adverse events 
5.2.3 Other endpoints 
(1) Efficacy: 
 
Glycoalbumin 
 
1,5-AG 
 
Fasting blood glucose 
 
Fasting insulin 
 
Fasting glucagon 
 
Fasting proinsulin 
 
Fasting GLP-1 
 
Fasting GIP 
 
DPP-4 activity 
 
Inhibitory rate of DPP-4 activity 


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6.0 
CLINICAL RESEARCH DESIGN 
6.1 
Clinical research design 
<Clinical study design> 
This is a multi-center, randomized, open-label, parallel-group comparative, exploratory study to 
evaluate the effect of trelagliptin administered at a dose of 100 mg once weekly or alogliptin at a 
dose of 25 mg once daily for 4 weeks on glycemic variation in patients with type 2 diabetes mellitus 
using continuous glucose monitoring (CGM). 
 
<Research TREATMENT> 
After informed consent, patients determined to be eligible for this study based on the eligibility 
assessment will be randomized to either the trelagliptin 100 mg group or the alogliptin 25 mg group 
(at a ratio of 1:1), using "HbA1c at the start of the observation period (< 7.5% or ≥ 7.5%)" and age 
(< 65 or ≥ 65) as a stratification factor for randomization. 
The principal investigator or investigator shall prescribe trelagliptin 100 mg/week or alogliptin 25 
mg/day according to the allocation results notified from the enrollment center. 
Trelagliptin 100 mg once weekly or alogliptin 25 mg once daily, taken orally before breakfast 
Planned number of research subjects: 
The planned minimum number of research subjects evaluable for the primary endpoint in each group 
is as follows: 
Trelagliptin 100 mg group: 15 
Alogliptin 25 mg group: 15 
Number of study research implementing entities: 
3 medical institutions 
<Duration of evaluation and number of visits of research subjects> 
Duration of evaluation: 31 days, consisting of the observation period for 2 days and a treatment 
period for 29 days (4 weeks). 
Number of visits: a total of 5 visits. Research subjects shall visit the study site at the start of the 
observation period (VISIT 1: Day-2), at the start of the treatment period (VISIT 2: Day 1), during 
the treatment period for CGM insertion (VISIT 3: Day 21) and for CGM sensor exchange (VISIT 4: 
Day 24), and at the end of the treatment period (VISIT 5: Day 29). 
Figure 6 (a) shows a schematic of the clinical research design. Refer to Appendix A for schedule of 
examinations, observations, and assessments. 


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Figure 6.a Outline of clinical research design 
< Outline of clinical research > 
 
 
 
Week 0 
 
 
 
 
 
Week 3 
 
Week 4 
 
 
 
(Randomizati
on) 
 
 
 
 
 
 
 
 
 
 
Day -2 
（Day 1） 
 
 
 
 
Day 21 
Day 22 
Day 24 
Day 29 
 
 
VISIT 1 
（VISIT 2） 
 
 
 
 
VISIT 3 
 
VISIT 4 
VISIT 5 
 
 
Insert CGM 
sensor 
Laborator
y tests 
Remove CGM 
sensor 
Start study 
medication 
 
 
 
 
Insert CGM sensor 
Laboratory 
tests 
 
 
Exchange 
CGM sensor 
 
Remove CGM 
sensor 
Laboratory 
tests 
Informed 
consent 
procedure 
Assess eligibility 
 
 
 
 
 
 
 
     ←Observation period→ 
←      Treatment period     → 
 
Trelagliptin 100 mg 
 
Alogliptin 25 mg 
Stable dietetic therapy and exercise therapy 
*: In the trelagliptin 100 mg group, a sensor shall be inserted on the day before dosing. 
6.2 
Rationale for the clinical research design 
(1) Rationale for the clinical research design 
  
Because there is no enough evidence assayed for glycemic variation of not only once weekly 
DPP-4 inhibitors but also once daily DPP-4 inhibitor, Trelagliptin, once weekly DPP-4 inhibitor, 
and Alogliptin, once daily DPP -4 inhibitor, were set as study drugs to collect the consecutive 
data of glycemic variation obtained from CGM and to evaluate difference of DPP-4 inhibitors.  
Although trelagliptin was non-inferior to alogliptin, once daily DPP-4 inhibitor, in terms of the 
change from baseline in HbA1c at the phase III clinical study conducted during the development 
period, the effect on glycemic variation of alogliptin have to be clarified when the effect of 
different dose and method of administration of DPP-4 inhibitors on glycemic variation would like 
to be evaluated.  
In this present study, therefore, the effect of once weekly trelagliptin or once daily alogliptin on 
glycemic variation will be evaluated in patients with type 2 diabetes mellitus in an exploratory 
manner as a primary objective, and the effect by difference of dose and method of administration 
on glycemic variation will be evaluated as secondary as far as possible. 


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Therefore this unblind study was designed to objectively evaluate the effect on glycemic variation of 
trelagliptin 100 mg and alogliptin 25 mg administered in patients with type 2 diabetes mellitus. And 
also to evaluate the effect of different method of administration on glycemic variation, stratified 
randomization comparison method between 2 groups was adopted with “HbA1c at the start of the 
observation period (< 7.5% or ≥ 7.5%) and age (< 65 or ≥ 65)” as a stratification factor for 
randomization. 
Also, to exclude effect on glycemic variation from other anti-diabetic medications, research 
subjects who were taking anti-diabetic medications ≤ 4 weeks before start of observation period 
were excluded. 
(2) Rationale for dosage 
The dosages of trelagliptin and alogliptin were set at 100 mg/week and 25 mg/day, respectively, 
to evaluate glycemic variation at the usual dosage in clinical settings.  
(3) Rationale for dosage 
Study drugs show the glucose lowering effect by increasing incretin which are secreted by food 
intake. Thus, in order to eliminate the influence on the blood glucose by food intake. To further 
unify the administration timing of the research subjects prior to breakfast in terms of evaluating 
their glycemic variation. 
(4) Rationale for duration of treatment 
From the results of trelagliptin and alogliptin in phase II and III trials, duration was set at 4 
weeks taking into account that the effect on blood glucose levels stabilize after 2 to 4 weeks 
with either drugs. 
(5) Rationale for the number of planned research subjects: 
Refer section 13.3 
6.3 
Premature termination of entire clinical research or premature termination 
of clinical research at a research implementing entity 
6.3.1 Premature termination criteria of entire clinical research 
The sponsor should immediately discontinue the study when at least one of the following criteria is 
applicable: 
 
When new information or other evaluation on the safety or efficacy of the study drug becomes 
available that shows a change in the known risk/benefit profile of the concerned compound, and 
risks/benefits are no longer tolerable for research subject participation in the study. 


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 
When there is serious deviation from ethical guidelines or ICH-GCP that may threaten safety of 
the research subjects. 
6.3.2 Criteria for premature termination of research implementing entities 
A study site may be notified by the sponsor to discontinue clinical study if the site (including the 
principal investigator) is found in significant violation of Ethical Guideline for Clinical Research, 
protocol, or contractual agreement, is unable to ensure adequate performance of the study, or as 
otherwise permitted by the contractual agreement. 
6.3.3 Procedures of clinical study suspension and premature termination of 
entire clinical study or study at a research implementing entity 
In the event that the sponsor or a research implementing entity committee such as an ethics review 
committee decides to prematurely suspend or terminate the entire clinical study or clinical study at a 
research implementing entity, a study-specific procedure shall be provided by the sponsor. The 
procedure shall be followed by applicable research implementing entities during the course of 
clinical study suspension or premature termination. 
6.4 
Procedures for protocol revision 
If the protocol needs to be revised, the sponsor shall consider and decide whether to revise the 
protocol. 
The principal investigator of each research implementing entity shall be informed of the details of 
each protocol revision. Also, principal investigators shall confirm the content of the revision of the 
protocol and submit a letter of agreement to the sponsor as evidence of agreement with the protocol 
revision. 
Upon notification, the principal investigator at each research implementing entity shall submit the 
revised contents to committees such as the IEC, as necessary according to institutional regulations 
for review, and obtain approval from the director of the entity. 


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7.0 
SELECTION AND WITHDRAWAL CRITERIA OF RESEARCH 
SUBJECTS 
7.1 
Inclusion criteria 
Research subjects shall fulfill all of the following criteria to be included in this clinical study: 
1. Research subjects who, in the opinion of the principal investigator or the investigator, are 
capable of understanding the content of the clinical research and complying with the 
research protocol requirements. 
2. Patients who are able to sign and date the informed consent form and information sheet 
prior to the start of study procedures 
3. Patients diagnosed with type 2 diabetes mellitus 
4. Patients with an HbA1c (NGSP value) value ≥ 6.5% and < 8.5% at the start of the 
observation period (Day -2) 
5. Patients who experience a ≤ ±1.0% change in HbA1c (NGSP value) at the start of the 
observation period (Day -2) as compared with an HbA1c value obtained during the 
preceding 4 weeks 
6. Patients receiving stable dietetic therapy and exercise therapy (if performed) for ≥ 4 weeks 
before the start of the observation period 
7. Patients who in the opinion of the principal investigator or the investigator, does not have to 
change (including discontinuation or interruption) HMG-CoA reductase inhibitors or 
addition of new HMG-CoA reductase inhibitors during treatment period.  
8. Men or women aged 20 years or older at the time of informed consent 
[Rational for the inclusion criteria] 
1.2. These were set as essential conditions for the clinical research. 
3. 
Set as target disease for this study. 
4. 
To evaluate the glycemic variation caused by the study drug accurately, the upper limit 
value was set at 8.5% (NGSP value) to exclude research subject with insufficient glycemic 
control. 
5. 
To evaluate the glycemic variation accurately, the change variation of HbA1c was set to 
exclude research subject with unstable glycemic control 
6. 
Set in consideration of the possibility of change in dietetic/exercise therapy may affect 
evaluation of glycemic variation. 


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7. This was set in consideration of the possibility that HMG-CoA reductase inhibitors may 
affect glycemic variation. 
8. 
This was set to allow for separate assessment of men/women. The lower age limit was set 
to 20 years to allow patients to make a voluntary decision regarding their participation in 
this clinical research. 
 
7.2 
Exclusion criteria 
Research subjects meeting any of the criteria below shall not be included in this research. 
1. Patients who received anti-diabetic medications within 4 weeks prior to the start of the 
observation period. 
2. Patients who have changed (including discontinuation or interruption) HMG-CoA reductase 
inhibitors or received new HMG-CoA reductase inhibitors ≤ 4 weeks before the start of the 
observation period. 
3. Patients with clinically evident hepatic dysfunction (e.g., AST or ALT ≥ 2.5-fold the upper 
limit of normal at the start of the observation period [Day -2]) 
4. Patients with moderate renal dysfunction, severe renal dysfunction or renal failure (e.g., 
creatinine clearance < 50 mL/min or serum creatinine > 1.4 mg/dL in men or > 1.2 mg/dL in 
women [equivalent to the creatinine clearance for persons aged 60 years with a body weight 
of 65 kg] at the start of the observation period [Day -2]) 
5. Patients with severe heart disease, cerebrovascular disorder, or severe pancreatic, 
hematologic or other diseases 
6. Patients with a history of gastric or small intestinal resection 
7. Patients with proliferative diabetic retinopathy 
8. Patients warranting insulin therapy for glycemic control (e.g., patients with severe ketosis, 
diabetic coma or precoma, type 1 diabetes mellitus, severe infection, perioperative patients, 
or serious trauma) 
9. Patients with a history of hypersensitivity or allergy to DPP-4 inhibitors 
10. Patients who experience an allergic reaction to metal during CGM at the start of the 
observation period (Day -2) 
11. Patients with any malignant tumors 
12. Habitual drinkers whose average daily alcohol consumption is > 100 mLNote 1) 


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13. Patients who have any contraindications for the study drug or are taking any contraindicated 
concomitant drugs listed in the package insert 
14. Patients anticipated to require any prohibited concomitant medications during the study 
period 
15. Patients who are day and night lifestyle reversal 
16. Patients participating in any other clinical studies at the time of informed consent for this 
study 
17. Pregnant women, nursing mothers, women who are possible pregnant, or women who plan 
to become pregnant 
18. Other patients who are considered inappropriate for participation in this study in the opinion 
of the principal investigator or investigator 


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Note 1: Alcohol conversion table (for reference) 
Alcohol type 
Variation 
Alcohol strength (%) 
Amount equivalent to alcohol 100 mL 
Brewed alcohol 
Sake 
15% 
670 mL (about 3 gos, 1 go=180 mL) 
Beer 
5% 
2,000 mL (about 3 large bottles) 
Happoshu 
(low-malt beer –
like beverage) 
5% 
2,000 mL 
Wine 
12% 
830 mL 
Shaoxing rice 
wine 
18% 
560 mL 
Spirits 
Shochu  
(group ko) 
35% 
290 mL 
Shochu  
(group otsu) 
25% 
400 mL 
Whisky 
40% 
250 mL (about 3 double glasses) 
Brandy 
40% 
250 mL (about 3 double glasses) 
Vodka 
40% 
250 mL (about 3 double glasses) 
Combined alcohol 
Plum wine 
13% 
770 mL 
Combined sake 
16% 
630 mL 
[Rationale for the exclusion criteria] 
1, 2. Set in order to evaluate drug efficacy accurately. 
3, 5, 7, 10, 11, 13. These were set in consideration of safety of research subjects. 
4. Severe renal dysfunction and renal failure shall be excluded because trelagliptin is 
contraindicated for these conditions. Moderate renal dysfunction shall be excluded in 
consideration of safety of research subjects. 
6, 12, 14. Set in order to take in consideration of safety of research subjects and to evaluate drug 
efficacy accurately. 
8, 9. Set as contraindication for trelagliptin and alogliptin treatment. 
15..,16 Set in order to establish rational for evaluation of this study. 
17. Set as safety of trelagliptin and alogliptin in pregnant women has not been established. Also, 
set as excretion of trelagliptin and alogliptin in breast milk was confirmed in non-clinical 
trials. 
18. These were set as fundamental items for the research. 


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7.3 
Prohibited concomitant drugs and restricted concomitant drugs 
7.3.1 Prohibited concomitant drugs 
The following drugs are prohibited from the start of observation period to end of treatment period. 
1. Anti-diabetic medications other than the allocated oral hypoglycemic drug 
2. Glucocorticoids (medications for local effect such as external preparations are excluded) 
3. Estrogen preparations 
4. HMG-CoA reductase inhibitors* other than those used at the time of informed consent 
*Dosage of HMG-CoA reductase inhibitors those used at the time of informed consent may 
not be changed.  
5. Acetaminophen 
 [Rational for prohibited concomitant drugs] 
1 to 5. Set as it may affect evaluation of drug efficacy. 
7.3.2 Restricted concomitant drugs 
The following drugs those used at the time of informed consent are permitted from the start of 
observation period to end of treatment period. However, change of dosage, addition of or change to a 
new drug for those drugs is prohibited unless the principal investigator and investigator consider 
necessary due to adverse events. 
1. Lipid lowering agents other than HMG-CoA reductase inhibitors 
2. Anti-hypertensive drug 
7.4 
Research Subject Management 
The principal investigator and investigator shall instruct the research subject the items below. 
(1) Give instructions to take allocated oral hypoglycemic drug as directed. If poor compliance with 
study treatment (e.g., < 75% of the prescribed dose) after the previous visit has been found and 
does not improve, the research subject may be withdrawn from the research if appropriate for 
the circumstances. 
(2) If hypoglycemia symptom (hunger abnormal, feeling of weakness, trembling of hands and 
fingers, cold sweat, palpitations, etc.) is observed, take glucose or sucrose (sugar), and if it does 
not improve give instructions to visit promptly. 
(3) For dietetic therapy and exercise therapy (if performed), the principal investigator and 
investigator shall make sure prescriptions (instructions for calories, etc.) are consistent 
throughout the research period, and instruct the research subject to adhere to the dietetic therapy 
and exercise therapy (if performed). 


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(4) When CGM is being conducted, the principal investigator and investigator shall instruct 
exercise therapy (if performed) that may be performed under the same conditions every day, 
and instruct the research subject to adhere to it. 
(5) When CGM is being conducted, give instruction to photograph every meal contents. 
(6) Instruct the research subject not to eat high-sugar, high-calorie food or beverage between meals 
during CGM. 
(7) When CGM is being conducted, give instructions to note necessary items into the research 
subject diary. 
(8) On visit days for planned laboratory tests, give instructions not to take oral hypoglycemic drug 
scheduled to be taken on that day. Further, at each visit, have the research subject report if drug 
has been taken or not the day before, and on the day of visit. 
(9) On visit days for planned laboratory tests, give instructions for fasting ≥ 10 hours before visit. 
(10) For research subjects of childbearing potential, give instructions to use adequate contraception. 
If pregnancy is discovered, have the research subject report promptly, and discontinue the 
research immediately. 
(11) The principal investigator and investigator shall instruct the research subject to adhere to 
instructed prohibited concomitant drugs. When drugs are taken other than the drugs prescribed 
by the principal investigator and investigator, have the research subject report its content. 
(12) Regarding subjective symptoms/objective findings, have the research subject report at visit the 
necessary items from its contents, onset date, degree, outcome and date of outcome. 
7.5 
Criteria for discontinuation or withdrawal of a research subject 
The principal investigator or investigator shall record the main reason for discontinuation of protocol 
treatment on the case report form according to the classification described below. Refer section 
9.1.12 for discontinuation case before randomization. 
1. Adverse event 
When the research subject had an adverse event that requires withdrawal of the research subject 
from the study because continued participation in the study would impose an unacceptable risk 
to the research subject’s health, or when the research subject is unwilling to continue study 
participation because of the pretreatment event or adverse event. 
2. Major protocol deviation 
When it is discovered after randomization that a research subject does not meet the eligibility 
criteria or is not adhering to the protocol, and continued participation in the research would 
impose an unacceptable risk to the research subject’s health.  
3. Lost to follow-up 
When the research subject failed to make visits and could not be contacted. The attempts that 
were made to contact the research subject shall be recorded in the source documents. 


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4. Voluntary termination 
When the research subject wishes to withdraw from the research. The reason for discontinuation 
shall be recorded on the CRF when it is clarified. 
5. Research termination 
When the sponsor or a committee such as the IEC or regulatory authority has decided to 
terminate the study. Refer to Section 6.3.1 for details. 
6. Pregnancy 
When a female research subject is found to be pregnant. 
Note: Research participation shall be immediately discontinued when pregnancy is known. 
Refer to Section 9.1.11 for procedure. 
7. Others 
Note: The specific reasons should be recorded on the CRF. 
7.6 
Procedures for discontinuation of individual research subjects 
The principal investigator or investigator shall terminate a research subject’s research participation 
when the research subject meets the criteria described in Section 7.5. Individual research subjects 
may discontinue their research participation without giving a reason at any time during the research. 
Should a research subject’s participation be discontinued, the primary reason for termination shall be 
recorded on the CRF by the principal investigator or investigator. In addition, efforts shall be made 
to perform all tests/observations/evaluations scheduled at the time of discontinuation. 


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8.0 
RESEARCH TREATMENT 
This section indicates the treatment regimen of this clinical research. See the latest package insert for 
details and handling of each drug. 
8.1 
Treatment with the study drug 
8.1.1 Study drug 
(1) Study drug: 
Generic name: Trelagliptin Succinate 
Chemical name: 2- ({6- [（3R）-3-Aminopiperidin-1-yl] -3-methyl-2, 4-dioxo-3, 4- 
dihydropyrimidin -1 (2H)-yl} )methyl-4-fluorobenzonitrile monosuccinate 
Generic name: Alogliptin benzonate 
Chemical name:2- ({6- [(3R) -3-Aminopiperidin-1-yl] 
-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1 (2H) –yl} methyl) benzonitrile 
monobenzoate 
8.1.2 Dose and administration method 
Trelagliptin 100 mg (once weekly) or alogliptin 25 mg (once daily) shall be administered orally 
before breakfast. However, the drug shall be administered as described below at the start of the 
treatment period (VISIT 2: Day 1) or during the treatment period (VISIT 3: Day 21). 
At the start of the treatment period (VISIT 2: Day 1): The drug shall be administered after required 
tests/observations, etc. 
During the treatment period (from VISIT 3 to VISIT 5):  
Trelagliptin 100 mg/week group shall insert the sensor on the day before Trelagliptin 
administration day.  Trelagliptin 100 mg/week shall be administered before breakfast on 
the next day of the sensor insertion day. The next administration of Trelagliptin 100 mg is 
after the sensor removal.  
Alogliptin 25 mg/day shall be administered after required tests/observations, etc at every 
VISIT without taking study drug. Research subjects shall take study drug prior to the every 
breakfast at home.  
Duration of treatment shall be start of treatment period (Day 1) to end of treatment period (Day 29). 
Dose and administration method for each administration group are shown in table 8.a. 
 


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Table8.a Administration group and administration method 
Administration group 
Dose 
Route of 
administration: 
Administration method 
Trelagliptin group 
Trelagliptin 100 mg 
Oral 
administration 
Once weekly, before 
breakfast  
Alogliptin group 
Alogliptin 25 mg  
Oral 
administration 
Once daily, before 
breakfast 
8.1.3 Overdose 
Overdose is defined as intentional or accidental administration of the study drug at a higher dose 
than that specified in the protocol, either by a health professional or by the research subject. 
To consistently collect important safety information about overdose, the principal investigator or 
investigator(s) shall record all cases of overdose on the “Overdose” page of the CRF, 
irrespective of the presence or absence of accompanying adverse event. Adverse events associated 
with overdose shall be recorded on the “Adverse events” page of the CRF, in accordance with the 
procedures described in Section 10.0, “ADVERSE EVENTS.” 
In addition, serious adverse events associated with overdose shall be recorded in accordance with the 
procedures described in Section 10.2.2, “Collection and reporting of SAEs.” 
In the event of overdose, the principal investigator or investigator shall treat the subject as required 
based on symptoms. 
8.2 
Medication other than the study drug 
Prohibited concomitant drugs (refer to Section 7.3.1) may not be used. Also, restricted drugs (refer 
to Section 7.3.2) may be used if used at the time of informed consent. However, dose change for 
those restricted drugs or addition of or change to a new drug shall be prohibited unless the principal 
investigator and investigator consider necessary due to adverse events. Other treatments shall be 
conducted under normal medical practice 
8.3 
Allocation and prescription of the study drug and administration procedure 
The principal investigator or its designee shall access the web case enrollment system to allocate 
research subjects. In addition the principal investigator or its designee shall notify information 
necessary for allocation such as the research subject ID number. Thereafter, the drug to be 
administered to the research subjects shall be notified by the web case enrollment system. The 
principal investigator and investigator shall prescribe the study drug according to the notification and 
record the drug information into the CRF of each research subject. 


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8.4 
Preparation and storage of allocation list 
The person responsible for allocation (designated by the sponsor) shall create an allocation list. 
Allocation shall be conducted at the enrollment center using web case enrollment system at start of 
treatment period (Day 1) with "HbA1c at the start of the observation period (< 7.5% or ≥ 7.5%)" and 
age (< 65 or ≥ 65) as a stratification factor for randomization. The enrollment center shall use the 
allocation list for stratified randomization created by the allocation responsible person. 
Information on the allocation shall be kept in a safe place and shall not be available to anyone other 
than authorized persons, to secure independency from the clinical research. 


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9.0 
CLINICAL STUDY PROTOCOL 
9.1 
Research procedures 
The principal investigator or investigator shall collect data in accordance with the procedure below. 
The same principal investigator or investigator shall perform tests/observations/evaluation of 
research subjects, in principle. The study schedule is provided in Appendix A. 
9.1.1 Informed consent procedure 
The procedures for obtaining informed consent are described in Section 15.3. 
Consent shall be obtained from the research subject before initiation of research procedures. 
Research subject ID code is given to each research subject from whom informed consent was 
acquired and who was randomized. The research subject ID code shall be used throughout the 
research period and shall not be changed. 
9.1.2 Demographic data, medical history, and previous therapeutic drugs 
(1) Demographic information 
Demographic data shall be collected regarding birth, gender, smoking history, drinking history, 
time (year/month) of onset (or diagnosis of diabetes). 
(2) Medical history 
Medical history data shall be collected regarding clinically problematic diseases or symptoms 
that disappeared within 1 year or were terminated from the start of observation period. When 
the symptoms or disease continues, it shall be considered as a concurrent disease (Refer to 
Section 9.1.6). 
(3) Pre-treatment 
Regarding pre-treatment, name of drug, route of administration and date of final administration 
shall be collected for all anti-diabetic medication (including injections) that ended use ≤ 12 
weeks before start of observation period. 
9.1.3 Physical examination 
All subsequent physical examinations after the start of the treatment period shall be assessed for 
clinically significant changes from the baseline examination. 
9.1.4 Weight, height and BMI 
Body weight shall be measured to one decimal place in kilograms.  


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Height shall be measured or asked to the nearest whole number in centimeters.  
BMI shall be calculated by the sponsor using the following formula and shown to one decimal place:  
Body Mass Index:  BMI = weight (kg) / (height (m))2 
Example: 
Height = 176 cm, weight = 79.2 kg, BMI = 79.2/1.762 = 25.6 kg/m2  
9.1.5 Concomitant drugs 
Concomitant drugs are all drugs to be given in addition to the study drug. Drugs prescribed by 
doctors or the over-the-counter medicines purchased by the research subjects shall be included. At 
every hospital visit of the research subject, the status of use of drugs (name of drug, route of 
administration) other than the allocated oral hypoglycemic drug, from start of observation period to 
the completion of the clinical research shall be monitored. 
9.1.6 Concurrent disease 
A concurrent disease is defined as a disease or symptom that is present at the start of the observation 
period or that develops between the start of the observation period and the start of study treatment. 
Clinically significant abnormalities, including laboratory test data and physical examination findings, 
observed in tests and physical examinations at the start of study treatment shall be considered as a 
concurrent disease at the discretion of the principal investigator or investigator. The content of 
concurrent disease (diagnosis) shall be investigated. 
9.1.7 Laboratory tests 
Laboratory tests in table 9.a shall be measured at clinical laboratory institutions according to the 
observation schedule (Appendix A). Regarding tests at fasting, blood sampling shall be conducted 
after ≥ 10 hours of fasting. The principal investigator and investigator shall evaluate and keep the 
reported laboratory test results. 
Inhibitory rate of DPP-4 activity will be calculated by the sponsor using formula below: 
Inhibitory rate of DPP-4 activity (%) = (DPP-4 activity at start of observation period – DPP-4 
activity at each visit of treatment period) / DPP-4 activity at start of observation period x 100 


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Table 9.a 
Laboratory tests 
Serum chemistry 
 
Fasting blood glucose 
Fasting insulin 
Fasting glucagon 
Fasting proinsulin 
FastingGLP-1 
Fasting GIP 
DPP-4 activity 
Glycoalbumin 
1,5-AG 
 
The principal investigator shall keep laboratory test reference values, including the historical data. 
9.1.8 HbA1c (NGSP value) 
Measured at research implementing entities to confirm eligibility of research subject at start of 
observation period. The principal investigator and investigator shall evaluate and keep the reported 
laboratory test results. 
9.1.9 Continuous glucose monitoring (CGM)  
Conducted according to Schedule of Research Procedures (Appendix A) Details shall be specified 
separately in the operation procedures manual. 
(1) Device used in this study 
, leased from the sponsor. 
(2) Self-measurement of blood glucose (SMBG)  
Use device leased from sponsor 
Research subjects shall measure blood glucose levels every day during CGM in the observation 
and treatment periods. At least, blood glucose levels shall be measured at three time points on 
the first day of CGM ([1] at least 2 hours after the recorder is connected and [2] 2 hours after 
the first is measured. [3] at bedtime) and at four time points from the second day onward ([1] 
before breakfast, (2) before lunch, (3) before evening meal, and (4) at bedtime).  
The glucose levels from SMBG shall be used for correction of glucose levels obtained from 
CGM. 
(3) Observation period 


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A sensor shall be inserted at the start of the observation period (Day -2) and removed at the start 
of treatment (Day 1) 
(4) Treatment period 
A sensor shall be inserted (VISIT 3: Day 21), exchanged (VISIT 4: Days 24 to 26), and 
removed (VISIT 5: Day 29) during the treatment period. 
(5) Dietetic therapy and exercise therapy 
Research subjects shall present photographs of all meals to the principal investigator or 
investigator during CGM. Also, the meal provided by the sponsor shall be taken according to 
the calories prescribed by the sponsor for each research subject at the meal times shown below. 
Time point of provision of meals: evening meal at start of observation period (Day-2), evening 
meal on first and seventh of CGM to be performed from Day 21 for 9 days.  
Research subjects shall only conduct exercise therapy feasible (if performed) under the same 
conditions every day during CGM. 
The principal investigator or investigator shall prescribe consistent dietetic therapy and exercise 
therapy (if performed) throughout the research period. Compliance with dietetic therapy and 
exercise therapy(if performed) shall be investigated and rated on a four-point scale as follows: 
1. 
Compliant (compliance rate ≥ 90%)  
2. 
Almost compliant (compliance rate ≥ 70%)  
3. 
Generally compliant (compliance rate ≥ 50%)  
4. 
Minimally compliant (compliance rate < 50%) 
(6) Research subject diary 
Research subjects shall complete the subject diary every day during CGM and submit the diary 
to the principal investigator or investigator. 
The following information shall be recorded in the subject diary: date and time of dosing, time 
of SMBG and blood glucose levels, meal time and contents, exercise time, wake-up time, 
bedtime, etc.  
9.1.10 Contraception 
Women of childbearing potential (e.g., women who have not undergone surgical sterilization, 
women who have not reached menopause) shall use appropriate contraception during participation in 
this clinical research from the time of informed consent. During the informed consent process, 
appropriate contraceptive methods and the necessity of avoiding pregnancy during participation in 


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the clinical research shall be fully explained to women of childbearing potential with the use of the 
informed consent form and information sheet, and the research subjects shall fully understand these 
explanations before providing consent. 
9.1.11 Pregnancy 
When a study subject or a partner of study subject was found to be pregnant during the study period, 
the principal investigator or investigator notify the monitoring staff of the sponsor. The principal 
investigator or investigator provide detailed information using the Follow-up Form for Pregnancy 
separately wherever possible. 
9.1.12 Record of cases withdrawn before randomization 
The consent form shall be signed, and a CRF shall be created for all research subjects who are 
withdrawn before randomization. 
The following items are to be described on the CRF. 
• 
Informed consent procedure 
• 
<MMM/DD/YYYY> 
• 
Sex 
• 
Eligibility 
• 
Reason for discontinuation 
The primary reason for withdrawal before randomization shall be recorded on the CRF according to 
the following classification: 
• 
Not meeting inclusion criteria or meeting exclusion criteria 
• 
Serious deviation from protocol 
• 
Lost to follow-up 
• 
Voluntary discontinuation (specify the reason) 
• 
Premature termination criteria of entire clinical research 
• 
Others (specify the reason) 
Research subject ID numbers assigned to research subjects withdrawn from the research before 
randomization shall not be reused. 
9.1.13 Record of randomization 
Research subjects to be randomized shall meet all of the inclusion criteria and shall not meet any of 
the exclusion criteria according to Section 8.2. The principal investigator or investigator shall 
specify the reason why the subject cannot be randomized to the treatment period. 


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9.2 
Drug-taking status of the research subjects 
The principal investigator or investigator shall confirm the treatment compliance and the date and 
time of dosing during CGM with the research subject at every visit. At the end of study drug 
administration, Treatment compliance shall be rated on a two-point scale as follows: 
1. Compliant (compliance rate ≥ 75%) 
2. Not compliant (compliance rate < 75%) 
Medication instruction shall be given to research subjects throughout the clinical research period. If 
poor compliance with study treatment (e.g., < 75% of the prescribed dose) after the previous visit 
has been found and does not improve, the research subject may be withdrawn from the research if 
appropriate for the circumstances. 
9.3 
Implementation time point of the test and observation items 
The schedule for all tests, observations, and evaluations is shown in Appendix A. The principal 
investigator or investigator shall perform the tests, observations, and evaluations at the time points 
shown below. 
9.3.1 Start of observation period (Visit 1: Day -2)  
After consent is obtained, physical examination/tests are to be conducted for research enrollment. 
Eligibility of research subjects shall be determined in accordance with the inclusion and exclusion 
criteria as described in section 7.0. Refer to section 9.1.12 for the recording of research subjects who 
are withdrawn before randomization. 
Tests and observations to be performed and endpoints to be assessed during the observation period 
(VISIT 1: Day -2) are shown below. 
• 
Informed consent procedure 
• 
Demographic information 
• 
Medical history, pre-treatment 
• 
Physical examination 
• 
Height 
• 
Concomitant drugs 
• 
Concurrent disease 
• 
Prescription of and compliance with dietetic therapy and exercise therapy 


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Tests and observations to be performed and endpoints to be assessed during the observation period 
VISIT 1(Day -2) are shown below. 
• 
Physical examination 
• 
Body weight 
• 
Laboratory tests 
• 
HbA1c 
• 
CGM  (remove sensor) 
• 
Self-measurement of blood glucose (self-measured by research subject) 
9.3.2 At start of treatment period (Visit 2: Day 1) 
Research subjects whose eligibility has been confirmed shall be randomized according to section 8.3 
following the results of test, observation and endpoints implemented before start of treatment period. 
Randomization is performed at the visit when the principal investigator or investigator is considered 
as necessity. 
The test, observation, and endpoints to be implemented at the start of treatment period (Visit 2: Day 
1) are shown below. 
• 
Physical examination 
• 
Concomitant drugs 
• 
Compliance with dietetic therapy and exercise therapy 
• 
CGM (remove sensor) 
• 
SMBG (research subject perform by own) 
• 
Adverse Event 
9.3.3 Treatment period (Visit 3: Day 21) 
The test, observation, and endpoints to be implemented during the treatment period (Visit 3: Day 21) 
are shown below. 
• 
Physical examination 
• 
Body weight 
• 
Concomitant drugs 
• 
Laboratory tests 


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• 
Treatment status 
• 
Compliance with dietetic therapy and exercise therapy 
• 
CGM (remove) 
• 
Self-measurement of blood glucose (self-measured by research subject) 
• 
Adverse event 
9.3.4 Treatment period (Visit 4: Day 24) 
The test, observation, and endpoints to be implemented during the treatment period (Visit 4: Day 24) 
are shown below. 
• 
Physical examination 
• 
Concomitant drugs 
• 
Laboratory tests 
• 
Drug-taking status 
• 
Compliance with dietetic therapy and exercise therapy 
• 
CGM (exchange sensor) 
• 
Self-measurement of blood glucose (self-measured by research subject) 
• 
Adverse event 
9.3.5 At end of treatment period (Visit 5: Day 29) or discontinuation during 
treatment period 
The test, observation, and evaluation items to be implemented during at the end of treatment period 
(Visit 5: Day 29) are shown below. 
• 
Physical examination 
• 
Body weight 
• 
Concomitant drugs 
• 
Laboratory tests 
• 
Drug-taking status 
• 
Compliance with dietetic therapy and exercise therapy 
• 
CGM (remove sensor) 


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• 
Self-measurement of blood glucose (self-measured by research subject until removal of 
CGM sensor) 
• 
Adverse event 
The test, observation, and endpoints to be implemented at discontinuation of treatment period are 
shown below. 
• 
Physical examination 
• 
Body weight 
• 
Concomitant drugs 
• 
Laboratory tests 
• 
Drug-taking status 
• 
Compliance with dietetic therapy and exercise therapy 
• 
Adverse event 
• 
Reason of discontinuation  
The status of all randomized research subjects at the end of the clinical research shall be recorded on 
the CRF. 


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10.0 
ADVERSE EVENT 
10.1 
Definitions 
10.1.1 Adverse event 
An adverse event is defined as any untoward medical occurrence in a patient or a research subject 
receiving a pharmaceutical product (including the study drug). It does not necessarily have an 
apparent causal relationship with this pharmaceutical product (including study drug). 
An adverse event can therefore be any unfavorable or unintended sign (e.g., clinically significant 
laboratory abnormality), symptom, or disease temporally associated with the use of a pharmaceutical 
product (including the study drug), regardless of whether it is considered related to the 
pharmaceutical product (including the study drug) or not. 
10.1.2 Considerations for adverse events 
Generally unfavorable findings are described below: 
• 
Newly diagnosed disease or unexpected aggravation of existing symptom (intermittent 
event of an existing symptom is not considered an adverse event) 
• 
Requiring action or medical practice 
• 
Requiring invasive diagnostic treatment 
• 
Requiring discontinuation or a change in the dose of the study drug or a concomitant 
medication 
• 
Considered unfavorable by the principal investigator or the investigator 
Diagnosis name and signs/symptoms: 
Adverse events shall be recorded by diagnosis name. Accompanying signs (including abnormal 
laboratory values, abnormal ECG findings) and symptoms shall not be recorded as adverse events. If 
an adverse event could not be expressed by a diagnosis name, the signs or symptoms shall be 
recorded as the adverse event. 
Laboratory test values and ECG findings: 
Abnormal laboratory values and ECG findings shall be recorded as adverse events when the 
principal investigator or investigator judges the results are clinically problematic (in other words, 
when certain action or medical practice is required, or when the principal investigator or the 
investigator judges the change has exceeded the normal physiological variation range of the research 
subject). Retest and/or continued monitoring of an abnormality are not considered medical practice. 


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Also, repeated or additional conduction of non-invasive tests for verification, evaluation, and 
monitoring of an abnormality are not considered medical practice. 
However, when abnormal laboratory values and ECG findings are the accompanying symptoms of a 
disease diagnosed as an adverse event (e.g., increased creatinine due to renal dysfunction, etc.), the 
adverse event shall be handled by its diagnosis name. 
Pre-existing conditions (disease or symptom that has been present since before the start of study 
treatment): Pre-existing disease or symptom that has been present since before the start of study 
treatment shall be regarded as a concurrent disease and not an adverse event. When a concurrent 
medical condition is aggravated, the aggravation shall be determined as an adverse event and the 
principal investigator or the investigator shall record on the CRF that the adverse event is an 
aggravation of the concurrent disease (e.g., “aggravation of hypertension,” etc.). 
If a research subject has a pre-existing episodic condition (e.g., asthma, epilepsy), each episode shall 
be recorded as an adverse event if the episodes become more frequent, serious, or severe in nature. If 
a research subject has a chronic concurrent condition (e.g., cataracts, rheumatoid arthritis), 
worsening of the condition shall be recorded as adverse event if the degree of the worsening exceeds 
that which would be expected. The principal investigator or investigator shall ensure that the adverse 
event term to be recorded represents the change in the condition from baseline (e.g. “worsening 
of…”). 
Worsening of adverse events :  
If a research subject experiences a worsening of the adverse event after a change to the study drug, 
or secondary signs and symptoms are caused by the adverse event, the worsening or the secondary 
signs and symptoms shall be recorded as a new adverse event on the CRF. The principal investigator 
or investigator shall use an adverse event term that explicitly means a change of the condition (e.g., 
“worsening of…”). 
Change of severity of adverse events:  
If the research subject experiences changes in the severity of an adverse event, the event shall be 
recorded once, at its peak severity. 
Previously planned surgery or treatment:  
Preplanned surgeries or interventions that were scheduled before study treatment shall not be 
considered adverse events. However, when the existing symptom is aggravated to a degree requiring 
emergency surgery or treatment, the condition or the event shall be considered an adverse event. A 
concurrent disease that resulted from previously planned surgery shall be reported as an adverse 
event. 


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Non-urgent surgery or treatment:  
Non-urgent surgery or treatment that does not induce a change in the condition of a research subject 
(cosmetic surgery, etc.) shall not be considered an adverse event; However, it shall be recorded in 
the source documents. Concurrent diseases due to a non-urgent surgery shall be reported as an 
adverse event. 
The insufficient clinical response (lack of efficacy): insufficient clinical response, efficacy, or 
pharmacological action shall not be recorded as an adverse event. The principal investigator or 
investigator shall make the distinction between worsening of a pre-existing condition and lack of 
therapeutic efficacy. 
Overdose of the study drug:  
Overdose of any medication without onset of event shall not be recorded as an adverse event, but the 
overdose shall be recorded on the “Overdose” page of the CRF. Any onset of event shall be recorded 
as adverse events on the “Adverse events” of the CRF. 
10.1.3 Serious adverse event 
Of all unfavorable medical events that develop after administration of a pharmaceutical product 
(including the study drug) (irrespective of dose), a serious adverse event is an event that: 
1. results in death, 
2. is life threatening*, 
3. requires inpatient hospitalization or prolongation of existing hospitalization, 
4. results in persistent or significant disability/incapacity, 
5. leads to a congenital anomaly/birth defect, or 
6. Medically important event that causes a risk to the research subject even if it is not 
immediately life-threatening and does not result in death or hospitalization, or requires an 
action or treatment to prevent the results described in 1 to 5 above. Points described in the 
Takeda Medically Significant Adverse Event List (Table 10.a) are included in this section. 
* The term “life threatening” refers to an event in which the research subject was at risk of death at 
the time of the event; it does not refer to an event that hypothetically might have caused death if it 
were more severe. 


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Table 10.a 
Takeda Medically Significant AE List 
Acute respiratory failure/acute respiratory 
distress syndrome (ARDS) 
Torsades de pointes/ ventricular 
fibrillation/ventricular tachycardia 
Malignant hypertension 
Convulsive seizure (including convulsion 
and epilepsy) 
Agranulocytosis 
Aplastic anemia 
Toxic epidermal necrolysis/ 
Oculomucocutaneous syndrome 
(Stevens-Johnson syndrome) 
Hepatic necrosis 
Acute hepatic failure 
Anaphylactic shock 
Acute renal failure  
Pulmonary hypertension 
Pulmonary fibrosis (including interstitial 
pneumonia) 
Neuroleptic malignant syndrome/ malignant 
hyperpyrexia 
Spontaneous abortion/ stillbirth and fetal death 
Confirmed or suspected transmission of 
infection by a medicinal product 
Confirmed or suspected endotoxin shock 
10.1.4 Adverse events of special interest (specific adverse events) 
An AE of Special Interest (AESI) (serious or non-serious) is one of scientific and medical concern 
specific to the study drug, for which ongoing monitoring and rapid communication by the principal 
investigator or investigator to Takeda may be appropriate. Such events may require further 
investigation in order to establish assessment, and instructions provided to investigators on how and 
when they should be reported to the sponsor are described in Section 10.2.1.3. 
AESIs: Hypoglycemia-related AEs, intestinal obstruction-related AEs and acute pancreatitis-related 
AEs (for both Trelagliptin and Alogliptin), QT/QTc interval prolongation-related AEs (for 
Trelagliptin), and Liver dysfunction or jaundice-related AEs (for Alogliptin). 
<For both Trelagliptin and Alogliptin> 
[Hypoglycemia-related AEs] 
Hypoglycemia-related AEs are designated as AESIs because, in general, attention should be paid to 
the events in the treatment of diabetes mellitus. 
[Intestinal obstruction-related AEs] 
Intestinal obstruction-related AEs are designated as AESIs because there are accumulated reports of 
intestinal obstruction as an adverse reaction to similar incretin-related drugs (GLP-1 receptor 
agonists and other DPP-4 inhibitors). 
[Acute pancreatitis-related AEs] 


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Acute pancreatitis-related AEs are designated as AESIs because there are accumulated reports of 
acute pancreatitis as an adverse reaction to similar incretin-related drugs. 
<For Trelagliptin> 
[QT/QTc interval prolongation-related AEs] 
QT/QTc interval prolongation-related AEs are designated as AESIs because, in the QT/QTc 
assessment study conducted during the development, QT/QTc interval prolongation was reported in 
the trelagliptin 800 mg group although it did not occur in the trelagliptin 200 mg group. 
<For Alogliptin> 
【Liver dysfunction or jaundice-related AEs】 
Liver dysfunction or jaundice-related AEs are designated as AESIs because there are accumulated 
reports as serious adverse reaction. 
10.1.5 Severity of adverse events 
The severity of adverse events shall be classified and defined as shown below. 
Mild 
The event is transient and easily 
tolerated by the subject. 
Moderate 
The event interrupts the subject’s usual 
activities. 
Severe 
The 
event 
causes 
considerable 
interference with the subject’s usual 
activities. 
10.1.6 Causality of adverse events 
The causal relationship of each adverse event to the study drug shall be classified and defined as 
shown below. 
Related 
An adverse event that follows an apparent temporal sequence (including clinical course 
after discontinuation). An adverse event the causal relationship could not be denied and 
there is reasonable possibility due to the study drug, although other factors such as 
underlying disease, concurrent diseases, or concomitant drugs/treatment are also 
suspected. 
Not 
related 
An adverse event that does not follow an apparent temporal sequence from 
administration of the study drug. Very likely due to other factors such as underlying 


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disease, concurrent diseases, or concomitant drugs/treatment. 
10.1.7 Relationship to study procedures 
The relationship shall be recorded as “Yes” if the principal investigator or investigator considers that 
there is reasonable possibility that an adverse event is due to a study procedure. Otherwise, the 
relationship shall be recorded as “No.” 
10.1.8 Date of onset 
The date of onset of adverse events shall be determined according to the following rules: 
Adverse event 
Date of onset 
Signs, symptoms, diseases 
(diagnoses) 
The date on which the first signs/symptoms were noted by the 
research subject and/or the principal investigator or investigator. 
Asymptomatic diseases 
The date on which a diagnosis was confirmed through a test(s). 
The date on which a diagnosis was confirmed, even when the test 
results indicate an old sign(s) of the disease or an approximate time 
of its onset. 
Exacerbation of concurrent 
diseases 
The date on which the first worsening of diseases/symptoms was 
noted by the research subject and/or the principal investigator or 
investigator. 
Onset of a test abnormality after 
the start of the study drug 
administration 
The date on which a clinically significant laboratory abnormality 
was detected. 
Worsening of a baseline test 
abnormality after initiation of 
study treatment 
The date on which a clear increase/decrease in a laboratory 
parameter was clinically confirmed based on the time profile of the 
parameter. 
10.1.9 Date of resolution 
The date of resolution of an adverse event is the date on which the research subject recovered 
(including resolution with sequelae). If a research subject died due to the adverse event concerned, it 
shall be the date of death. The adverse event shall be recorded as “ongoing” if the research subject 
has not yet recovered by the end of the study. 
10.1.10 Actions taken for the study drug 
Actions taken for the study drug shall be classified or defined as shown below. 
Drug withdrawn 
The study drug is discontinued because of an adverse event (including withdrawal 
by the research subject at his/her own discretion). 
When the treatment with the study drug is continued after withdrawal from the 
study, it shall be defined as “Dose not changed.” 


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Dose not changed 
If the dose was unchanged after the onset of the adverse event it shall be defined 
as “Dose not changed.” 
If the study drug was discontinued, reduced, or increased because of another 
adverse event it shall be defined as “Dose not changed.” 
If the study drug was discontinued or reduced for a reason other than for the 
adverse event, e.g., inadvertence of the research subject, it shall be defined as 
“Dose not changed”. 
Unknown 
It has not been possible to determine what action has been taken because the 
research subject is lost to follow-up. 
Not Applicable 
The study treatment had already been completed or discontinued before the onset 
of the adverse event. 
Dose reduced 
The dose of the study drug was reduced because of the adverse event (including 
dose reduction by the research subject at his/her own discretion). 
Dose increased 
The dose of the study drug was increased because of the adverse event (including 
dose increase by the research subject at his/her discretion). 
Washout 
If the study treatment is suspended (i.e., interrupted) (including 
suspension/interruption by the research subject at his/her discretion) because of 
the adverse event but resumed thereafter, shall be defined as “washout”. 
10.1.11 Outcome 
Outcome of adverse events is classified as follows: 
Category 
Criteria 
Recovered 
Disappearance or recovery of symptoms and findings 
Laboratory values returned to normal or baseline 
Improved 
The intensity is lowered by one or more stages 
Symptoms or findings mostly disappeared 
Laboratory values improved, but have not returned to normal or baseline 
The research subject died from a cause other than the concerned adverse event while 
the condition was resolving (recording of the date of death unnecessary) 
Not recovered 
No change in symptoms, findings, or laboratory data 
The symptoms, findings, or laboratory data on the final day of observable period 
were aggravated compared with the date of onset 
Irreversible congenital anomaly 
The research subject died from another cause before resolution of the concerned 
adverse event (recording of the date of death unnecessary) 
Recovered 
with sequelae 
Disability that disturbs daily life 


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Death 
Direct relationship between death and the concerned adverse event 
“Direct relationship” means that the concerned adverse event was the cause of 
death, or the concerned adverse event was clearly responsible for death. 
Outcome of an adverse event which was not determined (judged, presumed) a direct 
cause of death observed in the same research subject is not considered as death. 
If outcome is death, the date of death shall be recorded. 
Unknown 
Follow-up specified in the protocol after the date of onset was not possible due to 
change of hospitals or relocation, etc. 
10.2 
Procedures 
10.2.1 Collection and reporting of adverse events 
10.2.1.1 Adverse event collection period 
Collection of the adverse events shall commence at the start of administration of the study drug (Day 
1) and shall continue until end of treatment (Day 29). 
10.2.1.2 Reporting of adverse events 
At each study visit, the principal investigator or investigator shall check for the presence of any 
onset of subjective symptoms. A neutral question, such as “How have you been feeling since your 
last visit?” may be asked to collect any adverse events that occurred between the previous and 
present visits. 
The principal investigator or investigator shall follow up all research subjects experiencing an 
adverse event irrespective of the causal relationship with the study drug, until the symptom resolves, 
or any clinically significant abnormal laboratory values have returned to baseline or there is a 
satisfactory explanation for the change (permanent or irreversible adverse events). All adverse 
events shall be entered on the CRF. Adverse event term, onset date, resolution date, severity, causal 
relationship with the study drug (i.e. "Unrelated" or "Related"), action taken for the study drug, 
outcome, causal relationship with any study procedure (with specific procedure if assessed to be 
causally related), and seriousness shall be entered. 
Follow-up period of adverse events shall be until recovery of the adverse events, or the time when 
the principal investigator or investigator judges that further follow-up would be unnecessary. 
10.2.1.3 Reporting of adverse events of special interest (specific adverse events) 
If AESI occurring during the AE collection period is considered to be clinically significant based on 
the criteria below, it should be reported to the sponsor (refer to the attachment  for contact 
information) within 1 business day of first onset, or subject’s notification of the event by the 


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principal investigator or investigator. AESI Form should be completed and signed (or signed and 
sealed) by the principal investigator and reported to the sponsor within 10 business days. 
The criteria for AESIs (hypoglycemia-related AEs, intestinal obstruction-related AEs, acute 
pancreatitis-related AEs, and QT/QTc interval prolongation-related AEs) are as shown below. If any 
other AEs potentially related to the study drug occur, it will be considered whether to include them 
in the AESIs. 
[Hypoglycemia-related AEs] 
AEs related to hypoglycemia 
[Intestinal obstruction-related AEs] 
Intestinal obstruction, ileus, subileus, obstruction of the digestive tract, gastrointestinal motility 
disorder, impaired gastric emptying, and AEs related to these conditions 
[Acute pancreatitis-related AEs] 
AEs related to pancreatitis or acute pancreatitis 
[QT/QTc interval prolongation-related AEs] 
Torsade de pointes, sudden death, ventricular tachycardia, ventricular fibrillation, ventricular flutter, 
consciousness disturbed, convulsion, ECG QT prolonged, and AEs related to these conditions 
【Liver dysfunction or jaundice-related AEs】 
Adverse events corresponding to ' Liver dysfunction related to drug - comprehensive search' in 
MedDRA standard search formula.  
The AESIs have to be recorded as AEs in the CRF. A report along with all other required 
documentation must be submitted to the sponsor. 
10.2.2 Collection and reporting of serious adverse events 
When a serious adverse event develops during the period of collecting adverse events, it shall be 
reported according to the following procedures. At the time of onset of a serious adverse event or 
notification of the onset by the research subject, the principal investigator shall report the serious 
adverse event to the chief executive of the research implementing entity immediately, and the 
sponsor or CRO to whom the sponsor has entrusted responsibility shall notify the principal 
investigator of the research implementing entity. 
The principal investigator shall then report the serious adverse event to the sponsor (for the contact 
information, refer to the attachment) within 1 day of notification of the event onset. Further, the 
principal investigator shall submit a formal report within 10 calendar days to the sponsor. 


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Furthermore, it shall be mandatory to include the contents below in the report to be submitted to the 
sponsor within 1 working day, and other items shall be reported as far as possible. 
• 
Brief description of adverse event and the reason for why it was determined as serious 
• 
Research subject ID number 
• 
Name of principal investigator or the investigator 
• 
Name of the study drug 
• 
Determined causal relationship 
The principal investigator or investigator shall report spontaneously reported serious adverse events 
that are collected even after the adverse event collection period to the sponsor. 
10.2.3 Reporting of additional information concerning adverse events 
If the sponsor requests provision of additional information concerning adverse events for reporting 
to regulatory authorities, the principal investigator or the investigator shall confirm the necessary 
additional information and enter in the EDC system or submit a report within the period specified by 
the sponsor. 
10.3 
Follow-up of serious adverse events 
When information that was not included in the detailed report was obtained later, the principal 
investigator or investigator shall state it in the copy of the report on serious adverse events, or create 
another document and submit it to the contact address shown on the attached sheet within 1 working 
day. Relevant data collected at the research implementing entity (e.g., ECG charts, laboratory test 
values, discharge summary, postmortem results) shall be sent to the sponsor or the committee such 
as the IEC upon request. 
The principal investigator or the investigator shall follow-up all serious adverse events, etc., until 
recovery is confirmed, or the final outcome is determined. 
10.3.1 Reporting of serious adverse events to Ethics Review Committee, etc., and 
regulatory authorities 
When the chief executive of the research implementing entity receives a report of a serious adverse 
event from the principal investigator, the chief shall consult the Ethics Review Committee, etc., and 
notify the research implementing entities that are conducting the clinical research through the 
sponsor or the CRO consigned by the sponsor. 
If the serious adverse event reported by the principal investigator in which direct causal relationship 
cannot be denied with this study (the study drug) and is unexpected, the chief executive of the 


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research implementing entity shall prepare a written report of the unexpected serious adverse event 
containing the information reported by the principal investigator plus the information below, and 
submit the report to the Minister of Health, Labour and Welfare, and notify other clinical research 
implementing entities. (Reporting to the Minister of Health, Labour and Welfare via the sponsor, or 
notification to other clinical research implementing entities via the sponsor may also be possible) 
• 
Actions taken for serious adverse events (discontinuation of new enrollment, revision of 
informed consent form, re-consents to other research subjects, etc.) 
• 
Date of review, summery of review, result, necessary action, etc., related to Ethics Review 
Committee, etc. 
• 
Notification to other research implementing entities 
The sponsor shall report, in accordance with regulations, unexpected serious adverse drug reactions 
and other serious adverse events that are subject to emergency reporting to regulatory authorities, the 
principal investigators, and chief executives of the research implementing entities. 
From the time point of first acknowledging the event or receiving additional information, the 
sponsor or the CRO consigned by the sponsor shall comply with regulatory required time frames for 
reporting, and make emergency reports concerning unexpected serious adverse drug reactions and 
expected serious adverse drug reactions to regulatory authorities. Also, the sponsor shall, in the same 
way, make an emergency report of other critical safety information that may have a major effect on 
the study drug risk-benefit, continuation of study drug administration, or continuation of clinical 
research. The research implementing entity shall submit copies of emergency report documents to 
the Ethics Review Committee, etc. 


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11.0 
COMMITTEES ESTABLISHED FOR THIS STUDY 
In this clinical research, none of Clinical Research Steering Committee, Data and Safety Monitoring 
Committee, or Central Assessment Committee shall be established. 


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12.0 
DATA MANAGEMENT AND STORAGE OF RECORDS 
Data management operations shall be performed according to the standard operating procedure by 
the data management department of the sponsor independent from the medical affairs department. 
Adverse events, medical history, and concurrent conditions shall be coded using MedDRA. Drugs 
shall be translated using the WHO Drug Dictionary. 
12.1 
Case report form 
The principal investigator or investigator shall complete a CRF for each research subject who has 
signed the informed consent form. 
The sponsor or its designee shall provide research implementing entities with access authorization to 
the electronic CRF. Before use of the electric CRF system, the sponsor shall provide training to the 
principal investigator, investigators, and study collaborators. The CRF shall be used to report the 
information collected during the study period to the sponsor. The CRF shall be made in Japanese. 
Data shall be directly entered in preparing the CRF. 
A change or correction of the CRF shall be recorded as an audit trail that records the information 
before and after the change or correction, the person who made the change or correction, date of 
change or correction, and its reason. 
The principal investigator shall ensure the accuracy and completeness of the CRF, and provide an 
electronic signature on the relevant page of the case report form. The principal investigator shall bear 
full responsibility for the accuracy and reliability of all data entered on the CRF. 
The following data shall be recorded on the CRF directly. (Except if there is a description in the 
source material) 
• 
Eligibility, end state, reason of termination, severity, degree, the causal relationship with the 
study drug or the study procedures, outcome of the adverse event. 
The following data shall not be recorded on the CRF directly. 
• 
Measurement results of CGM 
• 
Laboratory result tested at central. 
When the principal investigator or the investigator makes a change or correction in the data entered 
on the CRF after fixation of clinical data base, a record (Data Clarification Form) of change or 
correction on the CRF provided by the sponsor shall be used. The principal investigator shall 
confirm that the record of change or correction on the CRF is accurate and complete, and sign or 
write name/ affix a seal, and date it. 


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The sponsor or its designee shall confirm that CRFs have been made appropriately according to the 
procedures defined for each study. The sponsor or its designee shall have access to the medical 
records of the research subjects and in-house records to ensure the accuracy of the CRF as necessary. 
The completed CRF is the property of the sponsor, and the principal investigator or investigator shall 
not disclose the information to a third party without a written permission from the sponsor. 
12.2 
Timing of data entry into the electronic CRF system 
The sponsor or its designee shall request the principal investigator and investigator to promptly enter 
data into the EDC at enrollment of the research subject, each visit during study treatment, 
completion/discontinuation of study treatment, and follow-up period. Details of deadlines for data 
entry shall be specified separately in a procedure manual. 
12.3 
Storage of records 
The principal investigator or the chief executive of research implementing entity shall store the 
following materials, including those specified in section 12.1, and study-specific documents to be 
used by the regulatory authority and the sponsor or its designee for investigation and audit. The 
documents include research subject ID code, medical records, clinical study worksheets (if used), 
original signed and dated informed consent forms, the change and fix record of CRF (copy) and 
electric copies of electronic CRF including audit trail. The principal investigator and the chief 
executive of the research implementing entity shall appropriately retain the material/information 
related to this study for at least 5 years from the date of reporting the end of the research by the 
principal investigator, or for 3 years from the date of reporting final publication of the study result, 
whichever date is later. However, when the sponsor requires a longer storage period, the chief 
executive of the research implementing entity shall discuss the period and methods of storage with 
the sponsor. 
 


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13.0 
STATISTICAL ANALYSIS METHODS 
The person responsible for statistical analysis and the designee (a person employed by a CRO 
independent of the sponsor; the person in charge of analysis) shall conduct analyses. The sponsor will 
not be involved in statistical analyses. 
13.1 
Statistical and analytical plans 
The person in charge of analysis shall prepare a statistical analysis plan (hereinafter referred to as 
SAP) before the acquisition of the informed consent of the earliest research subject, and issue the 
first edition. Detailed definition of endpoints and analysis methods should be specified in the SAP to 
deal with all the purposes of the research. 
13.1.1 Analysis set 
Two analysis sets, “full analysis set” and “Safety data analysis set” are used in this study. The “full 
analysis set" used as a primary analysis set in the efficacy analysis shall be defined as "the research 
subjects who were randomized and given at least one dose of the study drug." The “Safety data 
analysis set” shall be defined as "the research subjects who are given at least one dose of the study 
drug." 
13.1.2 Analysis of demographic and other baseline characteristics 
From the “full analysis set” primary research subject background items will be tabulated by each 
treatment group and by merging the treatment groups. 
13.1.3 Efficacy analysis 
[Primary endpoints] 
• 
Changes in the SD of 24-hour blood glucose values (mg/dL) for each 7-day period between 
Week 3 and Week 4 (between Day 22 and Day 28) of the treatment period, calculated from the 
value at the start of the observation period  
(Analysis method) 
•For the “full analysis set”, summary statistics (number of subjects, mean, SDs, maximum values, 
minimum values, quartiles [same apply hereafter]) and 95% confidence interval (two sides) of mean 
shall be calculated for each treatment group at each evaluation point (each day), and illustrating 
changes in mean and SD in order to evaluate changes in the SD of 24-hour blood glucose values 
(mg/dL) for each 7-day period between Week 3 and Week 4 (between Day 22 and Day 28) of the 
treatment period, calculated from the value at the start of the observation period for treagliptin or 
alogliptin separately. 
•Preliminary, for the “full analysis set”, calculate point estimation and 95% confidence interval (two 


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sides) in difference of mean in treatment groups (trelagliptin 100 mg group – alogliptin 25 mg 
group) in order to examine the influence of the once-weekly administration and blood glucose 
fluctuations due to the difference in the daily administration exploratory. 
•As well, for the “full analysis set ,” conduct analysis of covariance at each evaluation point with 
changes in the SD of 24-hour blood glucose values between Week 3 and Week 4 from the value at 
the start of the observation period as dependent variable, treatment groups as independent variable, 
HbA1c (NGSP value) at the start of the observation period, changes in the SD of 24-hour blood 
glucose values at the start of the observation period, and age as covariates, and calculate point 
estimation and 95% confidence interval (two sides) in difference of adjusted mean for each group. 
•Preliminary, “full analysis set ,” calculate point estimation and 95% confidence interval (two sides) 
in difference of adjusted mean in treatment groups (trelagliptin 100 mg group – alogliptin 25 mg 
group)  
[Secondary endpoints] 
• 
Changes in AUC over time when specific blood glucose levels ( 110, 140, 160, or 180 mg/dL) 
are observed during the 3 hour time period after breakfast, lunch and evening meal*1, 2 
• 
Change in AUC over time during periods when blood glucose 140, 160, or 180 mg/dL 
(hyperglycemia) is observed*1, 2 
• 
Changes in blood glucose 140, 160, or 180 mg/dL (hyperglycemia) over time*1, 2 
• 
Changes in AUC over time during periods when blood glucose < 70 mg/dL (hypoglycemia) is 
observed*1,2 
• 
Change in peak postprandial glucose levels over time 3 hours after breakfast, lunch, and evening 
meal*1, 2 
• 
Change in maximum variation of blood glucose levels over time between before and after 
breakfast, lunch, and evening meal *1, 2 
• 
Changes in MAGE*1, 2 
• 
Changes in mean 24-hour blood glucose levels *1, 2 
• 
Changes in mean daytime blood glucose levels*1, 2 
• 
Changes in mean nocturnal blood glucose levels*1, 2 
• 
Changes in AUC*1, 2 
• 
Changes in AUC over time during periods when blood glucose 110 mg/dL is observed*1,2  
• 
Changes in the SD of 24-hour blood glucose values*1,2 
• 
Changes in the SD of mean daytime blood glucose values*1,2 
• 
Changes in the SD of mean nocturnal blood glucose values*1,2 
*1: Measured value and percent changes for the each 7-day period between Week 3 and Week 4 
(between Day 22 and Day 28) of the treatment period calculated from the value at the start of 


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the observation period (however changes in the SD of 24-hour blood glucose values shall be 
measured value only)  
*2: Percent change from the value at the start of the observation period to the mean value during 
the 7-day period between Week 3 and Week 4 (between Day 22 and Day 28) of the treatment 
period 
 
(Analysis method) 
• 
Conduct the same analysis as the primary endpoints for *1 and *2 of the above endpoint section. 
However, for changes in mean/SD, only measured values of *1 and *2 shall be illustrated. 
[Other endpoints] 
• 
Glycoalbumin 
• 
1,5-AG 
• 
Fasting blood glucose 
• 
Fasting insulin 
• 
Fasting glucagon 
• 
Fasting proinsulin 
• 
FastingGLP-1 
• 
Fasting GIP 
• 
DPP-4 activity 
• 
Inhibitory rate of DPP-4 activity 
(Analysis method) 
• 
Calculate summary statistics and 95% confidence interval (two sides) of mean at each 
evaluation point (the start of the observation period by each treatment group, first day, 1 point 
during fourth to sixth day, and ninth day of CGM which is to be performed for 9 days from Day 
21) in measured values and changes from the start of the observation period, and illustrate 
changes in mean and SD  
13.1.4 Conversion method of data and handling of missing data 
Details shall be specified separately in the statistical analysis plan. 
13.1.5 Significance level and confidence coefficient 
 Confidence coefficient: 95% (two-sided estimation) 


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13.1.6 Safety analysis 
[Secondary endpoints] 
• 
Adverse event 
(Analysis method) 
• 
Adverse events shall be reported using MedDRA terminology and summarized using the 
Preferred Term (PT) and System Organ Class (SOC) of the MedDRA. For the “safety data 
analysis set”, frequency tabulation shall be conducted for adverse events after start of treatment 
with study drug by each treatment group. 
 
Frequency tabulation of all adverse events 
 
Frequency tabulation of adverse events that causal relationship is “related” to study drug. 
 
Frequency tabulation of the degree of all adverse events 
 
Frequency tabulation of degree of adverse events that causal relationship is “related” to 
study drug. 
 
Frequency tabulation of adverse events that were “discontinued” as a measurement 
concerning study drug. 
 
Frequency tabulation of serious adverse events 
13.2 
Criteria for interim analysis and premature discontinuation 
No interim analysis is planned. 
13.3 
Determination of the number of planned research subject 
Planned number of research subjects that are evaluable for primary endpoints in each group is as 
follows. 
Trelagliptin 100 mg group: 15 
Alogliptin 25 mg group: 15 
Set in consideration with the feasibility of the number of research subjects for exploring the effects 
of trelagliptin 100 mg and alogliptin 25 mg on glycemic variation. It is not based on statistical power 
calculation.  


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14.0 
QUALITY CONTROL AND QUALITY ASSURANCE 
14.1 
Monitoring of the research implementing entity 
The sponsor or its designee shall perform periodic monitoring of research implementing entities 
during the research to confirm that the research is conducted in accordance with all specifications in 
the research protocol. The data recorded on the CRF will be checked by comparing them with those 
in the source documents. Source documents are the original documents, data and records. The 
principal investigator and the chief executive of the research implementing entity shall ensure that 
the sponsor or its designee and the Ethics Review Committee, etc., have access to the source 
documents. 
The sponsor or its designee shall access the records, including the list of research subject ID 
numbers, medical records of the research subjects, and signed and dated original consent forms to 
confirm that the research is appropriately conducted in compliance with the research protocol. Also, 
confirm the consistency between CRF and the related source documents. The principal investigator, 
investigator, and other personnel involved in the research shall spare sufficient time to facilitate 
monitoring procedures during visits to the research implementing entity. 
Detailed procedures for monitoring shall be specified separately in a procedure manual. 
14.2 
Deviation from the Ethical Guidelines for Medical and Health Research 
Involving Human Subjects and the research protocol. 
The principal investigator or investigator shall record all deviations from Ethical Guidelines for 
Medical and Health Research Involving Human Subjects, and research protocol. 
If any deviation is found, the principal investigator shall promptly notify the chief executive of the 
research implementing entity for the clinical research and the sponsor. As necessary, the principal 
investigator will discuss protocol revisions with the sponsor to reach agreement. For protocol 
revisions, draft revisions should be submitted as early as possible to the chief executive of the 
research implementing entity for approval of the committee such as the IEC. 
14.3 
Quality assurance audits and regulatory agency inspections 
The research implementing entity may be subject to audits by the sponsor or its designee. In such a 
case, the auditor designated by the sponsor shall contact the research implementing entity in advance 
to determine the date of audit. The auditor may ask to visit the facilities where laboratory specimens 
are collected and any other facilities used during the clinical research. In addition, this research may 
be inspected by regulatory agencies, including those of foreign governments (e.g., the Food and 
Drug Administration [FDA], the United Kingdom Medicines and Healthcare products Regulatory 
Agency [MHRA]). If the research implementing entity is contacted for an inspection by a regulatory 


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body, the sponsor should be notified promptly. The principal investigator and the chief executive of 
the research implementing entity shall ensure that the auditor has access to all the research-related 
source documents. 


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15.0 
ETHICAL CONDUCT OF CLINICAL RESEARCH 
This research shall be conducted with the highest respect for the individual participants (i.e., 
research subjects) according to the research protocol, and the ethical principles that have their origin 
in the Declaration of Helsinki, Ethical Guidelines for Medical and Health Research Involving 
Human Subjects. Each principal investigator shall conduct the study according to regulatory 
requirements and in accordance with “Responsibilities of the Investigator” in Appendix B. 
15.1 
Approval of the Ethical Review Board, etc. 
The Ethical Review Board, etc., shall be constituted in accordance with the regulations. 
The sponsor or its designee should obtain the document listing the name and title of each committee 
member. When a committee member directly participates in this clinical research, the document 
describing that he/she is not participating in deliberation or voting for the study shall be obtained. 
The sponsor or its designee shall provide related documents for review and approval of the research 
protocol to the Ethical Review Board, etc. In addition to the research protocol, a copy of the 
informed consent form and information sheet, written materials related to research subject 
recruitment, advertisement, and other documents required by regulations, when necessary, shall be 
submitted to the central committee or a research implementing entity committee such as the Ethics 
Review Committee to obtain approval. The sponsor or its designee shall obtain records of approval 
by the Ethical Review Board, etc., for the research protocol and the informed consent form and 
information sheet before the start of the protocol therapy. The records of approval by the Ethical 
Review Board, etc., shall include the clinical research title, protocol number, preparation / revision 
date of the research protocol, and version number and approval date of other reviewed documents 
(example: informed consent and information sheet). The sponsor shall notify the research 
implementing entity, the principal investigator, and investigator after confirming the validity of the 
regulatory documents of the research implementing entity. Protocol procedures such as obtainment 
of consent shall not be started until the research implementing entity, the principal investigator, and 
investigator receive notification. 
The research implementing entity shall observe all requirements that the Ethical Review Board, etc. 
prescribe. The requirements may include notifications to committees such as the IEC, for example, 
revision of the protocol, revision of the informed consent form and information sheet, revision of 
materials related to research subject recruitment, reports on safety in accordance with the regulatory 
requirements, reports on status of implementation of the research at intervals determined by a 
research implementing entity committee such as the Ethics Review Committee, and submission of 
the study completion report. The sponsor or its designee shall obtain written approval from a 


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research implementing entity committee such as the Ethics Review Committee related to the above 
mentioned items and all related materials. 
15.2 
Conflict of interest 
This clinical research shall be conducted with the support of the sponsor. 
Prior to the conduction of this clinical research, the investigators involved in this clinical research 
shall ensure appropriate management of any conflicts (COI) in the conduct of the research in 
accordance with the rules of the research implementing entity 11-15). 
The research implementing entity shall comply with all requirements specified by a committee such 
as the Ethics Review Committee This includes the COI self-statement form, the research protocol, 
and the informed consent form and information sheet.  
15.3 
Informed consent and information sheet, and the agreement of the research 
subjects 
The informed consent and information sheet form shall contain specific requirements of the 
Declaration of Helsinki, Ethical Guidelines for Medical and Health Research Involving Human 
Subjects and all applicable laws and regulations. The informed consent form and information sheet 
shall specify the use of personal information and medical information of research subjects in this 
clinical research (both in and outside Japan: supply to a third party), and disclosure. The informed 
consent form and the information sheet will explain in detail the nature of the research, its objectives, 
and potential risks and benefits. Also, the informed consent form will detail the requirements for 
participation and the fact that research subject is free to withdraw at any time without giving a 
reason and without any negative effect on the further medical care. 
The principal investigator is responsible for the preparation, contents, and approval of the informed 
consent form and information sheet by the committee such as the IEC. The informed consent form 
and information sheet must be approved by the committee prior to use. 
The informed consent form and information sheet shall be written in language that can be easily 
understood by the potential research subjects. The principal investigator or investigator shall be 
responsible for providing detailed explanation of the informed consent form and information sheet to 
the potential subjects. Information should be given in both oral and written form whenever possible 
and in manner deemed appropriate by the committee such as the IEC. 
The principal investigator or investigator shall ensure that the potential research subjects have (1) an 
opportunity to inquire about the research and (2) sufficient time to decide on their participation. If a 
potential research subject decides he or she is willing to participate in the research, then the informed 
consent form must be signed and dated by the potential research subject prior to entering into the 


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research as a subject. The principal investigator or investigator shall instruct the potential research 
subject to sign using their legal names, not nicknames, using a blue or black ball point ink pen. Also 
the principal investigator or investigator shall sign and date the informed consent form prior to 
potential research subject entering into the research. 
Once signed, the original informed consent form shall be retained by the principal investigator or 
investigator. The principal investigator or investigator shall record the date that the potential research 
subject signed the informed consent form in the subject’s medical record. A copy of the signed 
informed consent form shall be given to the research subject. 
If the informed consent form and information sheet is revised, the principal investigator or 
investigator shall newly obtain re-consent from the concerned research subject by following the 
same procedure as for obtaining the initial consent. The date of obtaining new consent shall be 
recorded in the research subject’s medical record, and a copy of the revised consent form shall be 
provided to the research subject. 
15.4 
Personal information of the research subjects 
The sponsor or the designee shall affirm the principle of the protection of research subjects' 
private/personal information, etc. Throughout this study, research subject ID numbers shall be used 
to link the subject's source data to the sponsor's research database and research-related documents. 
Limited information on research subjects such as gender, age, and date of birth may be used within 
the scope of all applicable laws and regulations for identification of research subjects and 
confirmation of accuracy of research subject ID number. 
For verification of the conduct of the research in compliance with this protocol and the Ethical 
Guidelines for Medical and Health Research Involving Human Subjects, the sponsor shall require 
the principal investigator to provide the research sponsor’s designee, representatives of regulatory 
authorities, designated auditors, and committees such as the Ethical Review Board direct access to 
research subjects’ original medical records (source data or documents), including laboratory test 
results, ECG results, admission and discharge records during a subject’s research participation, and 
autopsy reports. The principal investigator or investigator shall obtain specific authorization from the 
research subject as part of the informed consent process for access to research subject's original 
medical records by research sponsor’s designee and representatives of regulatory authorities (see 
section 15.3). 
When providing a copy of source documents to the sponsor, the principal investigator or investigator 
shall delete information that may lead to identification of an individual (name and address of 
research subject, other personal information not recorded on the CRF of the research subject). 


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15.5 
Consultation windows for the research subjects or persons related to the 
research concerned 
The principal investigator shall establish a contact service to respond to inquiries concerning this 
clinical research from research subjects or concerned people. Details of the contacts for inquiries 
will be described in the informed consent form. 
15.6 
Financial burden or reward to the research subjects 
Of the expenses for this clinical research, the sponsor shall offer compensation for medical treatment 
not covered by health insurance as research expenses. The research subjects shall pay expenses for 
medical treatment covered by ordinary health insurance. 
In addition, the principal investigator shall pay expenses such as transportation expenses for 
participation in this clinical research to the research subjects at each visit from the research funds. 
Details of the financial burden on the research subjects and rewards shall be described in the 
informed consent form. 
15.7 
Benefits and inconveniences to the research subjects 
15.7.1 Benefits to research subjects 
By participating in this clinical research, the research subjects may understand one’s own condition 
of type 2 diabetes mellitus in detail. 
15.7.2 Inconveniences to research subjects 
By participating in this clinical research the burden of the research subject may increase as number 
of visits will increase compared to daily medical care. 
15.8 
Attribution of research results and access rights 
15.8.1 Attribution of research results 
The research results and data obtained from this research shall belong to the sponsor. In addition, 
secondary use (meta-analysis, etc.) of the data obtained in this clinical research may be possible if 
used in such a way that the data shall not be linked to personal identification information. 
15.8.2 Data access rights 
Access rights for all data and information generated from this study will be given to personnel 
approved by the sponsor. 


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15.9 
Reporting of results, publication, disclosure, and clinical research 
registration policy 
15.9.1 Reporting of results, publication and disclosure 
The principal investigator shall report a written summary of results of the research to the chief 
executive of the research implementing entity and provide the sponsor with all the results and data 
obtained from the research. Only the sponsor may disclose the research information to other 
principal investigators, investigators or regulatory authorities during the research period, except 
when required by laws and regulations. The sponsor shall be responsible for publication of the 
research protocol and research-related results (including the public web site) except for other cases 
permitted in the research contract. 
During research period and after the end of research, the sponsor or its designee should promptly 
summarize the results and present it to medical journals and academic conferences, etc. The sponsor 
may publish any data or information obtained from the research (including data and information 
provided by the principal investigator) without obtaining consent of the principal investigator. 
The principal investigator or the investigator should obtain the prior written approval from the 
sponsor when publishing the information obtained in this research at an academic conference, etc. 
15.9.2 Clinical research registration 
To ensure that information on clinical research is made accessible to the public in a timely manner 
and to comply with applicable laws, regulations, and guidelines, Takeda Pharmaceutical Company 
Limited shall register all clinical research being conducted in patients around the world at public trial 
registration sites, including at least the website(s) of ClinicalTrials.gov (and) Japan Pharmaceutical 
Information Center Clinical Trials Information (JAPIC). On such websites, the research location 
(city, country), subject recruitment status, and contact information for Takeda Pharmaceutical 
Company Limited are open to the public. 
15.9.3 Clinical trial results disclosure 
Takeda Pharmaceutical Company Limited shall post the research results, irrespective of the nature of 
the results, at the public trial registration site(s) of Clinical Trials.gov (and) JAPIC in accordance 
with applicable laws and regulations. 
15.10 Insurance and compensation for injury 
The research subjects participating in this research shall be compensated for any injury resulting 
from participation in the research according to local regulations applicable to the research 


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implementing entity. The sponsor or its designee shall buy an insurance policy to compensate for 
health injury in research subjects. 
Healthy injury in a research subject will be compensated as specified in the study contract. 
Compensation-related questions by the principal investigator or investigators should be made to the 
sponsor or its designee. 


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16.0 
REFERENCES 
1. 
Rimei Nishimura, Glucose variability and vascular disease risk. The Journal of the Japanese 
Society of Internal Medicine. 2013; 102: 922-930  
2. 
Gerstein HC. et al; The Action to Control Cardiovascular Risk in Diabetes Study Group. 
Effects of intensive glucose lowering in type 2 diabetes. The New England Journal of 
Medicine. 2008; 358: 2545-2559. 
3. 
Currie CJ, et al. Survival as a function of HbA（1c）in people with type 2 diabetes: a 
retrospective cohort study. Lancet. 2010; 375: 481- 489. 
4. 
Baggio LL, Drucker DJ. Biology of incretins: GLP-1 and GIP. Gastroenterology. 2007; 
132(6): 2131-2157. 
5. 
Monnier L, Mas E, et al; Activation of Oxidative Stress by Acute Glucose Fluctuations 
Compared With Sustained Chronic Hyperglycemia in Patients With Type 2 Diabetes. The 
Journal of the American Medical Association. 2006Apr 12; 295(14): 1681-1687.  
6. 
Klonoff DC, et al; Continuous Glucose Monitoring: roadmap for 21st century diabetes 
therapy. Diabetes Care. 2015 May; 28(5): 1231-1239. 
7. 
Drucker DJ. The biology of incretin hormones. Cell Metabolism. 2006; 3(3):153-165. 
8. 
Kaufman FR, Gibson LC, Halvorson M, et al. A pilot study of the continuous glucose 
monitoring system: clinical decisions and glycemic control after its use in pediatric type 1 
diabetic subjects. Diabetes Care. 2001; 24(12): 2030-2034. 
9. 
Su G, Mi S, et al; Association of glycemic variability and the presence and severity of 
coronary artery disease in patients with type 2 diabetes. Cardiovascular Diabetology. 2011; 
10:19. 
10. Inagaki N, Onouchi H, et al. Once-weekly trelagliptin versus daily alogliptin in Japanese 
patients with type 2 diabetes: a randomised, double-blind, phase 3, non-inferiority study.  
Lancet Diabetes Endocrinol. 2015 Mar; 3(3):191-197.. 
11. Report of the Working Group on Conflict of Interest (Ministry of Education, Culture, Sports, 
Science and Technology dated November 1, 2002) 
12. Guidelines for determining the conflict of interest polity for clinical research (Review group 
for ethical aspects of clinical research and conflict of interest, March 2006) 
13. Guidelines on the Management of Conflict of Interest (COI) in Health and Labour Sciences 
Research (March 31, 2008) 
14. Guidelines for management of COI in medical research (COI Committee of Japan 
Association of Medical Sciences, February 2011) 
15. Common guidelines for conflict of interest (COI) in clinical research (Japanese Society of 
Internal Medicine, Japan Society of Hematology, Japanese Circulation Society, Japan 
Endocrine Society, Japan Diabetes Society, Japanese Respiratory Society, Japanese Society 
of Hematology, Japanese Society of Allergology, Japanese Association for Infectious 
Diseases, Aug 2011) 


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Appendix A 
Schedule of Research Procedures 
 
 
Observation period 
Treatment period 
Time 
of 
Visit 
Week 
 
 
0 
 
 
4 
 
Disconti
nuation(g
) 
Day 
-14 
-2 
1(b) 
21(c) 
24(c) 
29(c) 
- 
Allowable range (Day) 
-28 to -2 
-2 
1 
21 to 35 24~39(f) 29 to 43 
- 
VISIT Number 
 
1 
2 
3 
4 
5 
- 
Informed 
consent 
procedure 
× 
 
 
 
 
 
 
Inclusion/Exclusion 
criteria 
× 
× 
 
 
 
 
 
Demographic 
information 
× 
 
 
 
 
 
 
Medical 
history, 
pre-treatment 
× 
× 
 
 
 
 
 
Physical examination 
× 
× 
(×) 
× 
× 
× 
× 
Body weight, BMI 
 
× 
 
× 
 
× 
× 
Height 
× 
 
 
 
 
 
 
Concomitant drugs 
× 
× 
(×) 
× 
× 
× 
× 
Concurrent disease 
× 
× 
 
 
 
 
 
Laboratory tests (a) 
 
× 
 
× 
× 
× 
× 
HbA1c 
 
× 
 
 
 
 
 
Drug -taking status 
 
 
 
× 
× 
× 
× 
Prescription of dietetic 
therapy and exercise 
therapy and assessment 
of compliance 
× 
× 
(×) 
× 
× 
× 
× 
CGM 
 
× (d) 
(Sensor 
insertion) 
×
(d) 
(Sensor 
remove) 
× (d) 
(Sensor  
insertion) 
× (d) 
(Exchange 
sensor) 
×
(d) 
(Sensor 
remove) 
 
Self-measurement of 
blood glucose 
 
× (e) 
× (e) 
× (e) 
× (e) 
× (e) 
 
Adverse event 
monitoring 
 
 
× 
(a) Measured on VISIT1 (Day-2), and the first and ninth days of the 9-day CGM starting on Day 21 
Blood tests: glycoalbumin, 1,5-AG, fasting insulin, fasting glucagon, fasting proinsulin, fasting GLP-1, fasting GIP*, DPP-4 activity 
Measured on 1 point during fourth and sixth day of the 9-day CGM starting on Day 21 
Blood tests: fasting GLP-1, fasting GIP, DPP-4 activity 
(b) The starting day of study treatment in the treatment period is designated as Day 1. The study drug shall be administered after required 
tests/observations, etc. The day before the start of study treatment in the treatment period is designated as Day -1. It is performed at the visit 
when principal investigator or investigator consider as needed. 
(c) Trelagliptin 100 mg/week group shall insert the sensor on the day before Trelagliptin administration day.  Trelagliptin 100 mg/week shall 
be administered before breakfast on the day after the sensor insertion day.  
Alogliptin 25 mg/day shall be administered after required tests/observations, etc at every VISIT without taking study drug. Research 
subjects shall take study drug prior to the every breakfast at home.  


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(d) To be performed by study site personnel 
(e) At least, blood glucose levels shall be measured at three time points on the first day of CGM ([1] at least 2 hours after the recorder is 
connected and [2] 2 hours after the first is measured. [3] at bedtime) and at four time points from the second day onward ([1] before 
breakfast, (2) before lunch, (3) before evening meal, and (4) at bedtime).  
(f) After taking trelagliptin 100 mg/week or alogliptin 25 mg/day on the nest day from sensor insertion on Visit3 (Day 21), research subjects 
should visit the study site between the third day and the fifth day. 
(g) To be performed to the extent possible 


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Appendix B 
Responsibilities of the sponsor 
1. 
To appropriately conduct the clinical research in compliance with this research protocol and the 
Ethical Guidelines for Medical and Health Research Involving Human Subjects and with the 
highest respect for human rights, safety, and welfare of research subjects. 
2. 
To prepare a list of any other investigators and/or research collaborators when certain important 
research-related activities are divided by investigators and/or research collaborators, and submit 
the list to the sponsor as required. 
3. 
To prepare the informed consent form and revise it as necessary. 
4. 
To check the contents of the study contract. 
5. 
To provide sufficient information on the protocol, drug and duties of each personnel to 
subinvestigators and study collaborators, and give guidance and supervision. 
6. 
To select research subjects who satisfy the inclusion criteria, give explanation using written 
information, and obtain consent in writing. 
7. 
To be responsible for all medical judgments related to the research. 
8. 
Corresponding to request from the chief executive of the research implementing entity, to report 
the latest progress status at least once a year to the chief executive of the research implementing 
entity. 
9. 
To ensure that the most update status is confirmed and comprehended regarding the COI of the 
investigators participating in the clinical research according to the research implementing 
entity. 
10. To ensure, together with the chief executive of the research implementing entity, that sufficient 
medical care is provided to research subjects for all research-related clinically problematic 
adverse events throughout the period of subjects’ research participation and thereafter. 
11. When a research subject is treated at another medical institution or department, to inform the 
acting physician at the medical institution or department in writing of the research subject’s 
study participation and research completion/discontinuation after obtaining the research subject’
s consent, and prepare a record. 
12. When emergency reporting of serious adverse events, is required, to immediately report it in 
writing to the chief executive of the research implementing entity and the sponsor. 
13. To ensure that the CRFs are accurate and complete, electronically sign and submit them to the 
sponsor. 
14. To verify any entries on the CRFs made by the investigator or transcribed by the collaborator 
from source documents, electronically sign and submit them to the sponsor. 
15. To discuss a revision of the protocol, etc., when proposed by the sponsor. 


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16. To report the research completion in writing to the chief executive of the research implementing 
entity. 
17. To receive continuing education and training for conducting the study properly including 
Ethical Guideline and GCP during the study period (at least once a year is recommended). 


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PROTOCOL 
 
 
An exploratory study to evaluate the effects of Trelagliptin and Alogliptin by CGM 
on glucose variability for one week with type 2 diabetes mellitus (TRACK) 
 
 
 
 
 
Sponsor 
Takeda Pharmaceutical Company Limited 
2-12-10 Nihonbashi, Chuo-ku, Tokyo 
Protocol number 
Trelagliptin-4001 
Version number 
Initial Version 
Study drug: 
Trelagliptin 
Alogliptin 
Creation date 
Mar 29, 2016 
 
 
CONFIDENTIAL PROPERTY 
This document is a confidential communication of Takeda. Acceptance of this document constitutes 
agreement by the potential recipient of the drug to be administered that no information contained herein 
will be published or disclosed without written authorization from Takeda except to the extent necessary to 
obtain informed consent from those research subjects to whom the drug may be administered. 
Furthermore, the information is only intended for review and compliance by the recipient, his or her staff, 
and applicable institutional review committee and regulatory agencies to enable conduction of the study. 


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1.0 
CLINICAL STUDY PRINCIPLES AND CLINICAL STUDY 
MANAGEMENT INFORMATION 
1.1 
Clinical Study Principals 
This study will be conducted with the highest respect for the individual participants in accordance 
with the requirements of this clinical study protocol and also in accordance with the following: 
• 
The ethical principles that have their origin in the Declaration of Helsinki. 
• 
Ethical Guideline for Clinical Research (the Ministry of Education, Culture, Sports, Science and 
Technology and the Ministry of Health, Labor and Welfare, December 22, 2014). 
• 
Good Clinical Practice: Consolidated Guideline (ICH. E6) 
• 
All applicable laws and regulations, including, without limitation, data privacy laws and conflict 
of interest guidelines. 
1.2 
CLINICAL STUDY ADMINISTRATIVE STRUCTURE 
This study will be conducted under the administrative structure described in the attached sheet 1 in 
accordance with the protocol prepared and planned by the sponsor.  
 


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Table of Contents 
1.0 
CLINICAL STUDY PRINCIPLES AND CLINICAL STUDY 
MANAGEMENT INFORMATION ....................................................................... 2 
1.1 
Clinical Study Principals ................................................................................... 2 
1.2 
CLINICAL STUDY ADMINISTRATIVE STRUCTURE ............................... 2 
2.0 
STUDY SUMMARY .............................................................................................. 8 
3.0 
ABBREVIATION ................................................................................................. 14 
4.0 
INTRODUCTION ................................................................................................. 15 
4.1 
Background ...................................................................................................... 15 
4.2 
Rationale for the proposed research ................................................................ 15 
5.0 
RESEARCH OBJECTIVES AND ENDPOINTS ................................................. 17 
5.1 
Objectives ........................................................................................................ 17 
5.2 
Definition of endpoints .................................................................................... 17 
5.2.1 Primary endpoints ...................................................................................... 17 
5.2.2 Secondary endpoints .................................................................................. 17 
5.2.3 Other endpoints ......................................................................................... 18 
6.0 
CLINICAL RESEARCH DESIGN ....................................................................... 19 
6.1 
Clinical research design ................................................................................... 19 
6.2 
Rationale for the clinical research design ........................................................ 20 
6.3 
Premature termination of entire clinical research or premature 
termination of clinical research at a research implementing entity ................. 21 
6.3.1 Premature termination criteria of entire clinical research ......................... 21 
6.3.2 Criteria for premature termination of research implementing entities ...... 22 
6.3.3 Procedures of clinical study suspension and premature termination of 
entire clinical study or study at a research implementing entity ............... 22 
6.4 
Procedures for protocol revision ..................................................................... 22 
7.0 
SELECTION AND WITHDRAWAL CRITERIA OF RESEARCH 
SUBJECTS ............................................................................................................ 23 
7.1 
Inclusion criteria .............................................................................................. 23 
7.2 
Exclusion criteria ............................................................................................. 24 
7.3 
Prohibited concomitant drugs and restricted concomitant drugs..................... 27 


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7.3.1 Prohibited concomitant drugs .................................................................... 27 
7.3.2 Restricted concomitant drugs .................................................................... 27 
7.4 
Research Subject Management ........................................................................ 27 
7.5 
Criteria for discontinuation or withdrawal of a research subject .................... 28 
7.6 
Procedures for discontinuation of individual research subjects ...................... 29 
8.0 
RESEARCH TREATMENT ................................................................................. 30 
8.1 
Treatment with the study drug ......................................................................... 30 
8.1.1 Study drug ................................................................................................. 30 
8.1.2 Dose and administration method ............................................................... 30 
8.1.3 Overdose .................................................................................................... 31 
8.2 
Medication other than the study drug .............................................................. 31 
8.3 
Allocation and prescription of the study drug and administration 
procedure ......................................................................................................... 31 
8.4 
Preparation and storage of allocation list ........................................................ 31 
9.0 
CLINICAL STUDY PROTOCOL ........................................................................ 33 
9.1 
Research procedures ........................................................................................ 33 
9.1.1 Informed consent procedure ...................................................................... 33 
9.1.2 Demographic data, medical history, and previous therapeutic drugs ........ 33 
9.1.3 Physical examination ................................................................................. 33 
9.1.4 Weight, height and BMI ............................................................................ 33 
9.1.5 Concomitant drugs ..................................................................................... 34 
9.1.6 Concurrent disease ..................................................................................... 34 
9.1.7 Laboratory tests ......................................................................................... 34 
9.1.8 HbA1c (NGSP value) ................................................................................ 35 
9.1.9 Continuous glucose monitoring (CGM) .................................................... 35 
9.1.10 Contraception ............................................................................................ 36 
9.1.11 Pregnancy .................................................................................................. 37 
9.1.12 Record of cases withdrawn before randomization .................................... 37 
9.1.13 Record of randomization ........................................................................... 37 
9.2 
Drug-taking status of the research subjects ..................................................... 38 
9.3 
Implementation time point of the test and observation items .......................... 38 


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9.3.1 Start of observation period (Visit 1: Day -2) ............................................. 38 
9.3.2 At start of treatment period (Visit 2: Day 1) ............................................. 39 
9.3.3 Treatment period (Visit 3: Day 21) ........................................................... 39 
9.3.4 Treatment period (Visit 4: Day 24) ........................................................... 40 
9.3.5 At end of treatment period (Visit 5: Day 29) or discontinuation 
during treatment period ............................................................................. 40 
10.0 
ADVERSE EVENT ............................................................................................... 42 
10.1 
Definitions ....................................................................................................... 42 
10.1.1 Adverse event ............................................................................................ 42 
10.1.2 Considerations for adverse events ............................................................. 42 
10.1.3 Serious adverse event ................................................................................ 44 
10.1.4 Adverse events of special interest (specific adverse events) ..................... 45 
10.1.5 Severity of adverse events ......................................................................... 46 
10.1.6 Causality of adverse events ....................................................................... 46 
10.1.7 Relationship to study procedures ............................................................... 47 
10.1.8 Date of onset .............................................................................................. 47 
10.1.9 Date of resolution ...................................................................................... 47 
10.1.10Actions taken for the study drug................................................................ 47 
10.1.11Outcome .................................................................................................... 48 
10.2 
Procedures ....................................................................................................... 49 
10.2.1 Collection and reporting of adverse events ............................................... 49 
10.2.2 Collection and reporting of serious adverse events ................................... 50 
10.2.3 Reporting of additional information concerning adverse events ............... 51 
10.3 
Follow-up of serious adverse events ............................................................... 51 
10.3.1 Reporting of serious adverse events to Ethics Review Committee, 
etc., and regulatory authorities .................................................................. 51 
11.0 
COMMITTEES ESTABLISHED FOR THIS STUDY ........................................ 53 
12.0 
DATA MANAGEMENT AND STORAGE OF RECORDS ............................... 54 
12.1 
Case report form .............................................................................................. 54 
12.2 
Timing of data entry into the electronic CRF system ...................................... 55 
12.3 
Storage of records ............................................................................................ 55 


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13.0 
STATISTICAL ANALYSIS METHODS ............................................................. 56 
13.1 
Statistical and analytical plans ......................................................................... 56 
13.1.1 Analysis set ................................................................................................ 56 
13.1.2 Analysis of demographic and other baseline characteristics ..................... 56 
13.1.3 Efficacy analysis ........................................................................................ 56 
13.1.4 Conversion method of data and handling of missing data ........................ 58 
13.1.5 Significance level and confidence coefficient ........................................... 58 
13.1.6 Safety analysis ........................................................................................... 58 
13.2 
Criteria for interim analysis and premature discontinuation ........................... 59 
13.3 
Determination of the number of planned research subject .............................. 59 
14.0 
QUALITY CONTROL AND QUALITY ASSURANCE .................................... 60 
14.1 
Monitoring of the research implementing entity ............................................. 60 
14.2 
Deviation from the Ethical Guidelines for Medical and Health Research 
Involving Human Subjects and the research protocol. .................................... 60 
14.3 
Quality assurance audits and regulatory agency inspections........................... 60 
15.0 
ETHICAL CONDUCT OF CLINICAL RESEARCH .......................................... 62 
15.1 
Approval of the Ethical Review Board, etc. .................................................... 62 
15.2 
Conflict of interest ........................................................................................... 63 
15.3 
Informed consent and information sheet, and the agreement of the 
research subjects .............................................................................................. 63 
15.4 
Personal information of the research subjects ................................................. 64 
15.5 
Consultation windows for the research subjects or persons related to the 
research concerned .......................................................................................... 65 
15.6 
Financial burden or reward to the research subjects........................................ 65 
15.7 
Benefits and inconveniences to the research subjects ..................................... 65 
15.7.1 Benefits to research subjects...................................................................... 65 
15.7.2 Inconveniences to research subjects .......................................................... 65 
15.8 
Attribution of research results and access rights ............................................. 65 
15.8.1 Attribution of research results ................................................................... 65 
15.8.2 Data access rights ...................................................................................... 65 
15.9 
Reporting of results, publication, disclosure, and clinical research 
registration policy ............................................................................................ 66 


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15.9.1 Reporting of results, publication and disclosure ....................................... 66 
15.9.2 Clinical research registration ..................................................................... 66 
15.9.3 Clinical trial results disclosure .................................................................. 66 
15.10 Insurance and compensation for injury ........................................................... 66 
16.0 
REFERENCES ...................................................................................................... 68 
LIST OF IN-TEXT TABLES 
Table8.a 
Administration group and administration method ..................................... 30 
Table 9.a 
Laboratory tests ......................................................................................... 35 
Table 10.a 
Takeda Medically Significant AE List ...................................................... 45 
LIST OF IN-TEXT FIGURES 
Figure6.a 
Outline of clinical research design ............................................................ 20 
LIST OF APPENDICES 
Appendix A 
Schedule of Research Procedures .............................................................. 69 
Appendix B 
Responsibilities of the sponsor .................................................................. 71 
 


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2.0 
STUDY SUMMARY 
Sponsor: 
Takeda Pharmaceutical Company Limited 
Study drug: 
Trelagliptin 
Alogliptin 
Study title: 
An exploratory study of the effects of trelagliptin and alogliptin on glycemic variation 
in patients with type 2 diabetes mellitus 
Protocol number: Trelagliptin-4001 (122/NRP-001) 
Clinical study design: 
This is a multi-center, randomized, open-label, parallel-group comparative, exploratory study to evaluate 
the effect of trelagliptin administered at a dose of 100 mg once weekly or alogliptin administered at a 
dose of 25 mg once daily for 4 weeks on glycemic variation in patients with type 2 diabetes mellitus using 
continuous glucose monitoring (CGM). 
After informed consent, patients determined to be eligible for this study based on the eligibility 
assessment will be randomized to either the trelagliptin 100 mg group or the alogliptin 25 mg group (at a 
ratio of 1:1), using "HbA1c at the start of the observation period (< 7.5% or ≥ 7.5%)" and age (< 65 or ≥ 
65) as a stratification factor for randomization. 
The total duration of evaluation will be 31 days, consisting of the observation period for 2 days and a 
treatment period for 29 days (4 weeks). CGM will be performed on research subjects on an outpatient 
basis (in 2 assessments) for 2 days from the start of the observation period (Day -2) and for 9 days from 
Day 21 of the treatment period. 
Objective:  
To evaluate the effect of trelagliptin administered orally at a dose of 100 mg once weekly or alogliptin 
administered orally at a dose of 25 mg once daily for 4 weeks on glycemic variation in an exploratory 
manner and as preliminary to examine the influence of the once-weekly administration and blood glucose 
fluctuations due to the difference in the daily administration in patients with type 2 diabetes mellitus 
Study population:  
Patients with type 2 diabetes mellitus 
Planned number of research subjects: 
The planned minimum number of research subjects evaluable 
for the primary endpoint in each group is as follows: 
Trelagliptin 100 mg group: 15 
Alogliptin 25 mg group: 15 
Number of study research 
implementing entities: 
3 medical institutions 


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Total: 30 
Dose and method of administration: 
Trelagliptin 100 mg once weekly or alogliptin 25 mg once 
daily, taken orally before breakfast 
Route of administration: 
Oral 
Duration of treatment: 
4 weeks 
Duration of evaluation: 
31 days (observation period for 2 days 
and treatment period for 4 weeks [29 
days]) 
Inclusion criteria 
1. 
Research subjects who, in the opinion of the principal investigator or the investigator, are capable of 
understanding the content of the clinical research and complying with the research protocol 
requirements. 
2. 
Patients who are able to sign and date the informed consent form and information sheet prior to the 
start of study procedures 
3. 
Patients diagnosed with type 2 diabetes mellitus 
4. 
Patients with an HbA1c (NGSP value) value ≥ 6.5% and < 8.5% at the start of the observation 
period (Day -2) 
5. 
Patients who experience a ≤ ±1.0% change in HbA1c (NGSP value) at the start of the observation 
period (Day -2) as compared with an HbA1c value obtained during the preceding 4 weeks 
6. 
Patients receiving stable dietetic therapy and exercise therapy (if performed) for ≥ 4 weeks before 
the start of the observation period 
7. 
Patients, who in the opinion of the principal investigator or the investigator, does not have to change 
(including discontinuation or interruption) HMG-CoA reductase inhibitors or add new HMG-CoA 
reductase inhibitors during treatment period. 
8. 
Men or women aged 20 years or older at the time of informed consent 
Exclusion criteria:  
1. 
Patients who received anti-diabetic medications within 4 weeks prior to the start of the observation 
period 
2. 
Patients who have changed (including discontinuation or interruption) HMG-CoA reductase 
inhibitors or received new HMG-CoA reductase inhibitors ≤ 4 weeks before the start of the 
observation period.  
3. 
Patients with clinically evident hepatic dysfunction (e.g., AST or ALT ≥ 2.5-fold the upper limit of 
normal at the start of the observation period [Day -2]) 


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4. 
Patients with moderate renal dysfunction, severe renal dysfunction or renal failure (e.g., creatinine 
clearance < 50 mL/min or serum creatinine > 1.4 mg/dL in men or > 1.2 mg/dL in women 
[equivalent to the creatinine clearance for persons aged 60 years with a body weight of 65 kg] at the 
start of the observation period [Day -2]) 
5. 
Patients with severe heart disease, cerebrovascular disorder, or severe pancreatic, hematologic or 
other diseases 
6. 
Patients with a history of gastric or small intestinal resection 
7. 
Patients with proliferative diabetic retinopathy 
8. 
Patients warranting insulin therapy for glycemic control (e.g., patients with severe ketosis, diabetic 
coma or precoma, type 1 diabetes mellitus, severe infection, perioperative patients, or serious 
trauma) 
9. 
Patients with a history of hypersensitivity or allergy to DPP-4 inhibitors 
10. Patients who experience an allergic reaction to metal during CGM at the start of the observation 
period (Day -2) 
11. Patients with any malignant tumors 
12. Habitual drinkers whose average daily alcohol consumption is > 100 mL 
13. Patients who have any contraindications for the study drug or are taking any contraindicated 
concomitant drugs listed in the package insert 
14. Patients anticipated to require any prohibited concomitant medications during the study period 
15. Patients who are day and night lifestyle reversal 
16. Patients participating in any other clinical studies at the time of informed consent for this study 
17. Pregnant women, nursing mothers, women who are possible pregnant, or women who plan to 
become pregnant 
18. Other patients who are considered inappropriate for participation in this study in the opinion of the 
principal investigator or investigator 
Endpoints: 
<Primary endpoints> 
• 
Changes in the standard deviation (SD) of 24-hour blood glucose values (mg/dL) for each 7-day 
period between Week 3 and Week 4 (between Day 22 and Day 28) of the treatment period, calculated 
from the value at the start of the observation period 
Secondary endpoints 
Efficacy endpoints: 
• 
Changes in AUC over time when specific blood glucose levels ( 110, 140, 160, or 180 mg/dL) are 
observed during the 3 hour time period after breakfast, lunch and evening meal*1, 2 
• 
Change in AUC over time during periods when blood glucose 140, 160, or 180 mg/dL 


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(hyperglycemia) is observed*1, 2 
• 
Changes in blood glucose 140, 160, or 180 mg/dL (hyperglycemia) over time*1, 2 
• 
Changes in AUC over time during periods when blood glucose < 70 mg/dL (hypoglycemia) is 
observed*1,2  
• 
Change in peak postprandial glucose levels over time 3 hours after breakfast, lunch, and evening 
meal*1,2 
• 
 Change in maximum variation of blood glucose levels over time between before and after breakfast, 
lunch, and evening meal*1,2  
• 
Changes in MAGE*1, 2 
• 
Changes in mean 24-hour blood glucose levels*1, 2 
• 
Changes in mean daytimeblood glucose levels*1, 2 
• 
Changes in mean nocturnal  blood glucose levels*1, 2 
• 
Changes in AUC*1, 2 
• 
Changes in AUC over time during periods when blood glucose 110 mg/dL (hypoglycemia) is 
observed*1,2 
• 
Changes in the SD of 24-hour blood glucose values*1,2 
• 
Changes in the SD of daytime blood glucose values*1,2 
• 
Changes in the SD of nocturnal blood glucose values*1,2 
*1: Measured value and percent changes for each 7-day period between Week 3 and Week 4 (between 
Day 22 and Day 28) of the treatment period calculated from the value at the start of the observation 
period (however changes in the SD of 24-hour blood glucose values shall be measured value only)  
*2: Measured value and percent change from the value at the start of the observation period to the mean 
value during the 7-day period between Week 3 and Week 4 (between Day 22 and Day 28) of the 
treatment period 
[Safety endpoint] 
• 
Adverse events 
<Other endpoints> 
• 
Glycoalbumin 
• 
1,5-AG 
• 
Fasting blood glucose 
• 
Fasting insulin 
• 
Fasting glucagon 
• 
Fasting proinsulin 


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• 
Fasting GLP-1 
• 
Fasting GIP 
Statistical method 
(1) Analysis set 
Two analysis sets, “full analysis set” and “safety data analysis set” are used in this study. "The Full 
Analysis Set" used as a primary analysis set in the efficacy analysis shall be defined as "the research 
subjects who were randomized and given at least one dose of the study drug." The safety data 
analysis set shall be defined as “the research subjects who were given at least one dose of the study 
drug”. 
(2) Efficacy analysis 
<Primary endpoints> 
• 
For the “full analysis set”, summary statistics (number of subjects, mean, SDs, maximum values, 
minimum values, quartiles [same apply hereafter]) and 95% confidence interval (two sides) of mean 
shall be calculated for each treatment group at each evaluation point (each day), and illustrating 
changes in mean and SD in order to evaluate changes in the SD of 24-hour blood glucose values 
(mg/dL) for each 7-day period between Week 3 and Week 4 (between Day 22 and Day 28) of the 
treatment period, calculated from the value at the start of the observation period for treagliptin or 
alogliptin separately.Preliminary, for the “full analysis set”, calculate point estimation and 95% 
confidence interval (two sides) in difference of mean in treatment groups (trelagliptin 100 mg group 
– alogliptin 25 mg group) in order to examine the influence of the once-weekly administration and 
blood glucose fluctuations due to the difference in the daily administration exploratory. 
• 
As well, for the “full analysis set ,” conduct analysis of covariance at each evaluation point with 
changes in the SD of 24-hour blood glucose values between Week 3 and Week 4 from the value at 
the start of the observation period as dependent variable, treatment groups as independent variable, 
HbA1c (NGSP value) at the start of the observation period, changes in the SD of 24-hour blood 
glucose values at the start of the observation period, and age as covariates, and calculate point 
estimation and 95% confidence interval (two sides) in difference of adjusted mean for each group. 
• 
Preliminary, “full analysis set ,” calculate point estimation and 95% confidence interval (two sides) 
in difference of adjusted mean in treatment groups (trelagliptin 100 mg group – alogliptin 25 mg 
group) 
Secondary endpoints 
• 
Conduct the same analysis as the primary endpoints for *1 and *2 of the each endpoint section. 
However, for changes in mean/SD, only measured values of *1 and *2 shall be illustrated. 
Additional endpoints: 


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• For the “full analysis set”, while calculating summary statistics and 95% confidence interval (two 
sides) of mean at each evaluation point (the start of the observation period by each treatment group, 
first and ninth of CGM which is to be performed for 9 days from Day 21) in measured values and 
changes from the start of the observation period, and illustrate changes in mean and SD. 
(3) Safety analysis 
• Adverse events shall be reported using MedDRA terminology and summarized using the Preferred 
Term (PT) and System Organ Class (SOC) of the MedDRA. For the “safety data analysis set”, 
frequency tabulation shall be conducted for adverse events after start of treatment with study drug by 
each treatment group: 
 
Frequency tabulation of all adverse events 
 
Frequency tabulation of adverse events that causal relationship is “related” to study drug. 
 
Frequency tabulation of the degree of all adverse events 
 
Frequency tabulation of degree of adverse events that causal relationship is “related” to study 
drug. 
 
Frequency tabulation of adverse events that were “discontinued” as a measurement concerning 
study drug. 
 
Frequency tabulation of serious adverse events 
Rationale for the number of planned research subjects: 
The planned minimum number of research subjects evaluable for the primary endpoint in each group is as 
follows: 
Trelagliptin 100 mg group: 15 
Alogliptin 25 mg group: 15 
Set in consideration with the feasibility of the number of research subjects for exploring the effects of 
trelagliptin 100 mg and alogliptin 25 mg on glycemic variation. It is not based on statistical power 
calculation. 


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3.0 
ABBREVIATION 
AE 
adverse event 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AUC 
Area under the curve 
1,5-AG 
1,5-anhydroglucitol 
BMI 
body mass index 
CGM 
continuous glucose monitoring 
COI 
conflict of interest 
CRO 
contract research organization 
DPP-4 
dipeptidyl-peptidase-4 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GIP 
glucose-dependent insulinotropic 
polypeptide 
GLP-1 
glucagon like peptide-1 
HbA1c 
hemoglobin A1c 
ICH 
International Conference on 
Harmonisation 
MAGE 
Mean Amplitude Glycemic Excursions 
MedDRA 
Medical Dictionary for Regulatory 
Activities 
PT 
prefferd term  
SAE 
serious adverse event 
SD 
standard deviation 
SMBG 
Self Monitoring of Blood Glucose 
SOC 
system organ class 
WHO 
World Health Organaization 
 


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4.0 
INTRODUCTION 
4.1 
Background 
Conventionally, although HbA1c has been used as an indicator for glycemic control for patients with 
diabetes mellitus, it has been indicated that it is insufficient for inhibiting cardiovascular events by 
only controlling HbA1c which reflects the long term glycemic variation1-3) On the other hand, it has 
been reported that persistent hyperglycemia and the range of glycemic variation is related to 
oxidative stress and cardiovascular events, and it has been indicated that treatment is necessary in 
consideration of daily glycemic variation4-6). Also, it is anticipated that the glycemic variation of 
patients with diabetes mellitus and the characteristics of each anti-diabetic medications may be 
revealed and to be able to make a choice for a more appropriate treatment. 
Self-measurement of blood glucose (SMBG) is used frequently for measuring glycemic variation 
and although one may understand the blood glucose level at the time of measurement, it is difficult 
to know if the blood glucose level has an upward trend or not changing or a downward trend at that 
time point, and it is reported that 80% hypoglycemia or hyperglycemia may be missed7,8). That is 
why the continuous glucose monitor (CGM) was developed and it became possible to accurately 
evaluate variance of blood glucose which was difficult and planning of treatment course according to 
each patient’s condition is anticipated. Actually, in many researches that was conducted to collect 
various glycemic variation patterns to verify the optimization of treatment of diabetes mellitus, the 
benefits of various indicators of glycemic variation obtained from CGM has been reported9). 
Dipeptidyl-peptidase-4 (DPP-4) inhibitors are used widely as oral treatment drug for type 2 diabetes 
mellitus and it has an effect to promote insulin secretion blood glucose dependently by raising blood 
concentration of glucagon like peptide-1 (GLP-1). Conventionally, although DPP-4 inhibitors are 
taken once to twice daily commonly, once weekly trelagliptin was developed for a new treatment 
option as good glycemic control from improvement of drug compliance rate and flexibility of timing 
of taking drug according to lifestyle and further improvement of Quality Of Life(QOL) from less 
number of doses was in need. The phase III clinical study conducted at the development stage has 
shown that trelagliptin, when administered for 24 weeks, was not inferior to alogliptin, a DPP-4 
inhibitor used as control, in terms of the change in HbA1c at the end of the treatment period 10). 
However, effect on glycemic variation of trelagliptin and alogliptin has not been clarified efficiently, 
and it is anticipated that understanding the characteristics of once weekly DPP-4 inhibitors and once 
daily DPP-4 inhibitors may be an efficient rational for therapeutical use. 
 
4.2 
Rationale for the proposed research 
 


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Because there is no enough evidence assayed for glycemic variation of not only once weekly DPP-4 
inhibitors but also once daily DPP-4 inhibitor, Trelagliptin, once weekly DPP-4 inhibitor, and 
Alogliptin, once daily DPP -4 inhibitor, were set as study drugs to collect the consecutive data of 
glycemic variation obtained from CGM and to evaluate difference of DPP-4 inhibitors.  
Although trelagliptin was non-inferior to alogliptin, once daily DPP-4 inhinitor, in terms of the 
change from baseline in HbA1c at the phase III clinical study conducted during the development 
period, the effect on glycemic variation of alogliptin have to be clarified when the effect of different 
dose and method of administraion of DPP-4 inhibitors on glycemic variation would like to be 
evaluated. 
In this present study, therefore, the effect of once weekly trelagliptin or once daily alogliptin on 
glycemic variation will be evaluated in patients with type 2 diabetes mellitus in an exploratory 
manner as a primary objective, and the effect by difference of dose and method of administraion on 
glycemic variation will be evaluated as secondary as far as possible. 


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5.0 
RESEARCH OBJECTIVES AND ENDPOINTS 
5.1 
Objectives 
 
To evaluate the effect of trelagliptin administered orally at a dose of 100 mg once weekly or 
alogliptin orally administered at a dose of 25 mg once daily for 4 weeks on glycemic variation in an 
exploratory manner as a primary objective and to evaluate, as far as possible, the effect of difference 
method of administration of DPP-4 on glycemic variation as secondary objective. 
 
5.2 
Definition of endpoints 
5.2.1 Primary endpoints 
Changes in the standard deviation (SD) of 24-hour blood glucose values (mg/dL) for each 7-day 
period between Week 3 and Week 4 (between Day 22 and Day 28) of the treatment period, 
calculated from the value at the start of the observation period 
5.2.2 Secondary endpoints 
(1) Efficacy: 
 
Changes in AUC over time when specific blood glucose levels ( 110, 140, 160, or 180 
mg/dL) are observed during the 3 hour time period after breakfast, lunch and evening meal 
 
Change in AUC over time during periods when blood glucose 140, 160, or 180 mg/dL 
(hyperglycemia) is observed 
 
Changes in blood glucose 140, 160, or 180 mg/dL (hyperglycemia) over time 
 
Changes in AUC over time during periods when blood glucose < 70 mg/dL 
(hypoglycemia) is observed 
 
Change in peak postprandial glucose levels over time 3 hours after breakfast, lunch, and 
evening meal 
 
Change in maximum variation of blood glucose levels over time between before and after 
breakfast, lunch, and evening meal 
 
Changes in MAGE  
 
Changes in mean 24-hour blood glucose levels  
 
Changes in mean daytimeblood glucose levels 
 
Changes in mean nocturnalblood glucose levels 


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 
Changes in AUC 
 
Changes in AUC over time during periods when blood glucose 110 mg/dL is observed 
 
Changes in the SD of 24-hour blood glucose values 
 
Changes in the SD of daytime blood glucose values 
 
Changes in the SD of nocturnal blood glucose values 
(2) Safety: Adverse events 
5.2.3 Other endpoints 
(1) Efficacy: 
 
Glycoalbumin 
 
1,5-AG 
 
Fasting blood glucose 
 
Fasting insulin 
 
Fasting glucagon 
 
Fasting proinsulin 
 
FastingGLP-1 
 
Fasting GIP 


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6.0 
CLINICAL RESEARCH DESIGN 
6.1 
Clinical research design 
<Clinical study design> 
This is a multi-center, randomized, open-label, parallel-group comparative, exploratory study to 
evaluate the effect of trelagliptin administered at a dose of 100 mg once weekly or alogliptin at a 
dose of 25 mg once daily for 4 weeks on glycemic variation in patients with type 2 diabetes mellitus 
using continuous glucose monitoring (CGM). 
 
<Research TREATMENT> 
After informed consent, patients determined to be eligible for this study based on the eligibility 
assessment will be randomized to either the trelagliptin 100 mg group or the alogliptin 25 mg group 
(at a ratio of 1:1), using "HbA1c at the start of the observation period (< 7.5% or ≥ 7.5%)" and age 
(< 65 or ≥ 65) as a stratification factor for randomization. 
The principal investigator or investigator shall prescribe trelagliptin 100 mg/week or alogliptin 25 
mg/day according to the allocation results notified from the enrollment center. 
Trelagliptin 100 mg once weekly or alogliptin 25 mg once daily, taken orally before breakfast 
Planned number of research subjects: 
The planned minimum number of research subjects evaluable for the primary endpoint in each group 
is as follows: 
Trelagliptin 100 mg group: 15 
Alogliptin 25 mg group: 15 
Number of study research implementing entities: 
3 medical institutions 
<Duration of evaluation and number of visits of research subjects> 
Duration of evaluation: 31 days, consisting of the observation period for 2 days and a treatment 
period for 29 days (4 weeks). 
Number of visits: a total of 5 visits. Research subjects shall visit the study site at the start of the 
observation period (VISIT 1: Day-2), at the start of the treatment period (VISIT 2: Day 1), during 
the treatment period for CGM insertion (VISIT 3: Day 21) and for CGM sensor exchange (VISIT 4: 
Day 24), and at the end of the treatment period (VISIT 5: Day 29). 
Figure 6 (a) shows a schematic of the clinical research design. Refer to Appendix A for schedule of 
examinations, observations, and assessments. 


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Figure6.a Outline of clinical research design 
< Outline of clinical research > 
 
 
 
Week 0 
 
 
 
 
 
Week 3 
 
Week 4 
 
 
 
(Randomizati
on) 
 
 
 
 
 
 
 
 
 
 
Day -2 
（Day 1） 
 
 
 
 
Day 21 
Day 22 
Day 24 
Day 29 
 
 
VISIT 1 
（VISIT 2） 
 
 
 
 
VISIT 3 
 
VISIT 4 
VISIT 5 
 
 
Insert CGM 
sensor 
Laborator
y tests 
Remove CGM 
sensor 
Start study 
medication 
 
 
 
 
Insert CGM sensor 
Laboratory 
tests 
 
 
Exchange 
CGM sensor 
 
Remove CGM 
sensor 
Laboratory 
tests 
Informed 
consent 
procedure 
Assess eligibility 
 
 
 
 
 
 
 
     ←Observation period→ 
←      Treatment period     → 
 
Trelagliptin 100 mg 
 
Alogliptin 25 mg 
Stable dietetic therapy and exercise therapy 
*: In the trelagliptin 100 mg group, a sensor shall be inserted on the day before dosing. 
6.2 
Rationale for the clinical research design 
(1) Rationale for the clinical research design 
  
Because there is no enough evidence assayed for glycemic variation of not only once weekly 
DPP-4 inhibitors but also once daily DPP-4 inhibitor, Trelagliptin, once weekly DPP-4 inhibitor, 
and Alogliptin, once daily DPP -4 inhibitor, were set as study drugs to collect the consecutive 
data of glycemic variation obtained from CGM and to evaluate difference of DPP-4 inhibitors.  
Although trelagliptin was non-inferior to alogliptin, once daily DPP-4 inhinitor, in terms of the 
change from baseline in HbA1c at the phase III clinical study conducted during the development 
period,  the effect on glycemic variation of alogliptin have to be clarified when the effect of 
different dose and method of administraion of DPP-4 inhibitors on glycemic variation would like 
to be evaluated.  
In this present study, therefore, the effect of once weekly trelagliptin or once daily alogliptin on 
glycemic variation will be evaluated in patients with type 2 diabetes mellitus in an exploratory 
manner as a primary objective, and the effect by difference of dose and method of administraion 
on glycemic variation will be evaluated as secondary as far as possible. 


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Therefore this unblind study was designed to objectively evaluate the effect on glycemic variation of 
trelagliptin 100 mg and alogliptin 25 mg administered in patients with type 2 diabetes mellitus. And 
also to evaluate the effect of different method of administraion on glycemic variation, stratified 
randomization comparison method between 2 groups was adopted with “HbA1c at the start of the 
observation period (< 7.5% or ≥ 7.5%) and age (< 65 or ≥ 65)” as a stratification factor for 
randomization. 
Also, to exclude effect on glycemic variation from other anti-diabetic medications, research 
subjects who were taking anti-diabetic medications ≤ 4 weeks before start of observation period 
were excluded. 
(2) Rationale for dosage 
The dosages of trelagliptin and alogliptin were set at 100 mg/week and 25 mg/day, respectively, 
to evaluate glycemic variation at the usual dosage in clinical settings.  
(3) Rationale for dosage 
Study drugs show the glucose lowering effect by increasing incretin which are secreted by food 
intake. Thus, in order to eliminate the influence on the blood glucose by food intake. To further 
unify the administration timing of the research subjects prior to breakfast in terms of evaluating 
their glycemic variation. 
(4) Rationale for duration of treatment 
From the results of trelagliptin and alogliptin in phase II and III trials, duration was set at 4 
weeks taking into account that the effect on blood glucose levels stabilize after 2 to 4 weeks 
with either drugs. 
(5) Rationale for the number of planned research subjects: 
Refer section 13.3 
6.3 
Premature termination of entire clinical research or premature termination 
of clinical research at a research implementing entity 
6.3.1 Premature termination criteria of entire clinical research 
The sponsor should immediately discontinue the study when at least one of the following criteria is 
applicable: 
 
When new information or other evaluation on the safety or efficacy of the study drug becomes 
available that shows a change in the known risk/benefit profile of the concerned compound, and 
risks/benefits are no longer tolerable for research subject participation in the study. 


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 
When there is serious deviation from ethical guidelines or ICH-GCP that may threaten safety of 
the research subjects. 
6.3.2 Criteria for premature termination of research implementing entities 
A study site may be notified by the sponsor to discontinue clinical study if the site (including the 
principal investigator) is found in significant violation of Ethical Guideline for Clinical Research, 
protocol, or contractual agreement, is unable to ensure adequate performance of the study, or as 
otherwise permitted by the contractual agreement. 
6.3.3 Procedures of clinical study suspension and premature termination of 
entire clinical study or study at a research implementing entity 
In the event that the sponsor or a research implementing entity committee such as an ethics review 
committee decides to prematurely suspend or terminate the entire clinical study or clinical study at a 
research implementing entity, a study-specific procedure shall be provided by the sponsor. The 
procedure shall be followed by applicable research implementing entities during the course of 
clinical study suspension or premature termination. 
6.4 
Procedures for protocol revision 
If the protocol needs to be revised, the sponsor shall consider and decide whether to revise the 
protocol. 
The principal investigator of each research implementing entity shall be informed of the details of 
each protocol revision. Also, principal investigators shall confirm the content of the revision of the 
protocol and submit a letter of agreement to the sponsor as evidence of agreement with the protocol 
revision. 
Upon notification, the principal investigator at each research implementing entity shall submit the 
revised contents to committees such as the IEC, as necessary according to institutional regulations 
for review, and obtain approval from the director of the entity. 


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7.0 
SELECTION AND WITHDRAWAL CRITERIA OF RESEARCH 
SUBJECTS 
7.1 
Inclusion criteria 
Research subjects shall fulfill all of the following criteria to be included in this clinical study: 
1. Research subjects who, in the opinion of the principal investigator or the investigator, are 
capable of understanding the content of the clinical research and complying with the 
research protocol requirements. 
2. Patients who are able to sign and date the informed consent form and information sheet 
prior to the start of study procedures 
3. Patients diagnosed with type 2 diabetes mellitus 
4. Patients with an HbA1c (NGSP value) value ≥ 6.5% and < 8.5% at the start of the 
observation period (Day -2) 
5. Patients who experience a ≤ ±1.0% change in HbA1c (NGSP value) at the start of the 
observation period (Day -2) as compared with an HbA1c value obtained during the 
preceding 4 weeks 
6. Patients receiving stable dietetic therapy and exercise therapy (if performed) for ≥ 4 weeks 
before the start of the observation period 
7. Patients who in the opinion of the principal investigator or the investigator, does not have to 
change (including discontinuation or interruption) HMG-CoA reductase inhibitors or 
addition of new HMG-CoA reductase inhibitors during treatment period.  
8. Men or women aged 20 years or older at the time of informed consent 
[Rational for the inclusion criteria] 
1.2. These were set as essential conditions for the clinical research. 
3. 
Set as target disease for this study. 
4. 
To evaluate the glycemic variation caused by the study drug accurately, the upper limit 
value was set at 8.5% (NGSP value) to exclude research subject with insufficient glycemic 
control. 
5. 
To evaluate the glycemic variation accurately, the change variation of HbA1c was set to 
exclude research subject with unstable glycemic control 
6. 
Set in consideration of the possibility of change in dietetic/exercise therapy may affect 
evaluation of glycemic variation. 


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7. This was set in consideration of the possibility that HMG-CoA reductase inhibitors may 
affect glycemic variation. 
8. 
This was set to allow for separate assessment of men/women. The lower age limit was set 
to 20 years to allow patients to make a voluntary decision regarding their participation in 
this clinical research. 
 
7.2 
Exclusion criteria 
Research subjects meeting any of the criteria below shall not be included in this research. 
1. Patients who received anti-diabetic medications within 4 weeks prior to the start of the 
observation period. 
2. Patients who have changed (including discontinuation or interruption) HMG-CoA reductase 
inhibitors or received new HMG-CoA reductase inhibitors ≤ 4 weeks before the start of the 
observation period. 
3. Patients with clinically evident hepatic dysfunction (e.g., AST or ALT ≥ 2.5-fold the upper 
limit of normal at the start of the observation period [Day -2]) 
4. Patients with moderate renal dysfunction, severe renal dysfunction or renal failure (e.g., 
creatinine clearance < 50 mL/min or serum creatinine > 1.4 mg/dL in men or > 1.2 mg/dL in 
women [equivalent to the creatinine clearance for persons aged 60 years with a body weight 
of 65 kg] at the start of the observation period [Day -2]) 
5. Patients with severe heart disease, cerebrovascular disorder, or severe pancreatic, 
hematologic or other diseases 
6. Patients with a history of gastric or small intestinal resection 
7. Patients with proliferative diabetic retinopathy 
8. Patients warranting insulin therapy for glycemic control (e.g., patients with severe ketosis, 
diabetic coma or precoma, type 1 diabetes mellitus, severe infection, perioperative patients, 
or serious trauma) 
9. Patients with a history of hypersensitivity or allergy to DPP-4 inhibitors 
10. Patients who experience an allergic reaction to metal during CGM at the start of the 
observation period (Day -2) 
11. Patients with any malignant tumors 
12. Habitual drinkers whose average daily alcohol consumption is > 100 mLNote 1) 


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13. Patients who have any contraindications for the study drug or are taking any contraindicated 
concomitant drugs listed in the package insert 
14. Patients anticipated to require any prohibited concomitant medications during the study 
period 
15. Patients who are day and night lifestyle reversal 
16. Patients participating in any other clinical studies at the time of informed consent for this 
study 
17. Pregnant women, nursing mothers, women who are possible pregnant, or women who plan 
to become pregnant 
18. Other patients who are considered inappropriate for participation in this study in the opinion 
of the principal investigator or investigator 


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Note 1: Alcohol conversion table (for reference) 
Alcohol type 
Variation 
Alcohol strength (%) 
Amount equivalent to alcohol 100 mL 
Brewed alcohol 
Sake 
15% 
670 mL (about 3 gos, 1 go=180 mL) 
Beer 
5% 
2,000 mL (about 3 large bottles) 
Happoshu 
(low-malt beer –
like beverage) 
5% 
2,000 mL 
Wine 
12% 
830 mL 
Shaoxing rice 
wine 
18% 
560 mL 
Spirits 
Shochu  
(group ko) 
35% 
290 mL 
Shochu  
(group otsu) 
25% 
400 mL 
Whisky 
40% 
250 mL (about 3 double glasses) 
Brandy 
40% 
250 mL (about 3 double glasses) 
Vodka 
40% 
250 mL (about 3 double glasses) 
Combined alcohol 
Plum wine 
13% 
770 mL 
Combined sake 
16% 
630 mL 
[Rationale for the exclusion criteria] 
1, 2. Set in order to evaluate drug efficacy accurately. 
3, 5, 7, 10, 11, 13. These were set in consideration of safety of research subjects. 
4. Severe renal dysfunction and renal failure shall be excluded because trelagliptin is 
contraindicated for these conditions. Moderate renal dysfunction shall be excluded in 
consideration of safety of research subjects. 
6, 12, 14. Set in order to take in consideration of safety of research subjects and to evaluate drug 
efficacy accurately. 
8, 9. Set as contraindication for trelagliptin and alogliptin treatment. 
15..,16 Set in order to establish rational for evaluation of this study. 
17. Set as safety of trelagliptin and alogliptin in pregnant women has not been established. Also, 
set as excretion of trelagliptin and alogliptin in breast milk was confirmed in non-clinical 
trials. 
18. These were set as fundamental items for the research. 


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7.3 
Prohibited concomitant drugs and restricted concomitant drugs 
7.3.1 Prohibited concomitant drugs 
The following drugs are prohibited from the start of observation period to end of treatment period. 
1. Anti-diabetic medications other than the allocated oral hypoglycemic drug 
2. Glucocorticoids (medications for local effect such as external preparations are excluded) 
3. Estrogen preparations 
4. HMG-CoA reductase inhibitors* other than those used at the time of informed consent 
*Dosage of HMG-CoA reductase inhibitors those used at the time of informed consent may 
not be changed.  
5. Acetaminophen 
 [Rational for prohibited concomitant drugs] 
1 to 5. Set as it may affect evaluation of drug efficacy. 
7.3.2 Restricted concomitant drugs 
The following drugs those used at the time of informed consent are permitted from the start of 
observation period to end of treatment period. However, change of dosage, addition of or change to a 
new drug for those drugs is prohibited unless the principal investigator and investigator consider 
necessary due to adverse events. 
1. Lipid lowering agents other than HMG-CoA reductase inhibitors 
2. Anti-hypertensive drug 
7.4 
Research Subject Management 
The principal investigator and investigator shall instruct the research subject the items below. 
(1) Give instructions to take allocated oral hypoglycemic drug as directed. If poor compliance with 
study treatment (e.g., < 75% of the prescribed dose) after the previous visit has been found and 
does not improve, the research subject may be withdrawn from the research if appropriate for 
the circumstances. 
(2) If hypoglycemia symptom (hunger abnormal, feeling of weakness, trembling of hands and 
fingers, cold sweat, palpitations, etc.) is observed, take glucose or sucrose (sugar), and if it does 
not improve give instructions to visit promptly. 
(3) For dietetic therapy and exercise therapy (if performed), the principal investigator and 
investigator shall make sure prescriptions (instructions for calories, etc.) are consistent 
throughout the research period, and instruct the research subject to adhere to the dietetic therapy 
and exercise therapy (if performed). 


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(4) When CGM is being conducted, the principal investigator and investigator shall instruct 
exercise therapy (if performed) that may be performed under the same conditions every day, 
and instruct the research subject to adhere to it. 
(5) When CGM is being conducted, give instruction to photograph every meal contents. 
(6) Instruct the research subject not to eat high-sugar, high-calorie food or beverage between meals 
during CGM. 
(7) When CGM is being conducted, give instructions to note necessary items into the research 
subject diary. 
(8) On visit days for planned laboratory tests, give instructions not to take oral hypoglycemic drug 
scheduled to be taken on that day. Further, at each visit, have the research subject report if drug 
has been taken or not the day before, and on the day of visit. 
(9) On visit days for planned laboratory tests, give instructions for fasting ≥ 10 hours before visit. 
(10) For research subjects of childbearing potential, give instructions to use adequate contraception. 
If pregnancy is discovered, have the research subject report promptly, and discontinue the 
research immediately. 
(11) The principal investigator and investigator shall instruct the research subject to adhere to 
instructed prohibited concomitant drugs. When drugs are taken other than the drugs prescribed 
by the principal investigator and investigator, have the research subject report its content. 
(12) Regarding subjective symptoms/objective findings, have the research subject report at visit the 
necessary items from its contents, onset date, degree, outcome and date of outcome. 
7.5 
Criteria for discontinuation or withdrawal of a research subject 
The principal investigator or investigator shall record the main reason for discontinuation of protocol 
treatment on the case report form according to the classification described below. Refer section 
9.1.12 for discontinuation case before randomization. 
1. Adverse event 
When the research subject had an adverse event that requires withdrawal of the research subject 
from the study because continued participation in the study would impose an unacceptable risk 
to the research subject’s health, or when the research subject is unwilling to continue study 
participation because of the pretreatment event or adverse event. 
2. Major protocol deviation 
When it is discovered after randomization that a research subject does not meet the eligibility 
criteria or is not adhering to the protocol, and continued participation in the research would 
impose an unacceptable risk to the research subject’s health.  
3. Lost to follow-up 
When the research subject failed to make visits and could not be contacted. The attempts that 
were made to contact the research subject shall be recorded in the source documents. 


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4. Voluntary termination 
When the research subject wishes to withdraw from the research. The reason for discontinuation 
shall be recorded on the CRF when it is clarified. 
5. Research termination 
When the sponsor or a committee such as the IEC or regulatory authority has decided to 
terminate the study. Refer to Section 6.3.1 for details. 
6. Pregnancy 
When a female research subject is found to be pregnant. 
Note: Research participation shall be immediately discontinued when pregnancy is known. 
Refer to Section 9.1.11 for procedure. 
7. Others 
Note: The specific reasons should be recorded on the CRF. 
7.6 
Procedures for discontinuation of individual research subjects 
The principal investigator or investigator shall terminate a research subject’s research participation 
when the research subject meets the criteria described in Section 7.5. Individual research subjects 
may discontinue their research participation without giving a reason at any time during the research. 
Should a research subject’s participation be discontinued, the primary reason for termination shall be 
recorded on the CRF by the principal investigator or investigator. In addition, efforts shall be made 
to perform all tests/observations/evaluations scheduled at the time of discontinuation. 


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8.0 
RESEARCH TREATMENT 
This section indicates the treatment regimen of this clinical research. See the latest package insert for 
details and handling of each drug. 
8.1 
Treatment with the study drug 
8.1.1 Study drug 
(1) Study drug: 
Generic name: Trelagliptin Succinate 
Chemical name: 2- ({6- [（3R）-3-Aminopiperidin-1-yl] -3-methyl-2, 4-dioxo-3, 4- 
dihydropyrimidin -1 (2H)-yl} )methyl-4-fluorobenzonitrile monosuccinate 
Generic name: Alogliptin benzonate 
Chemical name:2- ({6- [(3R) -3-Aminopiperidin-1-yl] 
-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1 (2H) –yl} methyl) benzonitrile 
monobenzoate 
8.1.2 Dose and administration method 
Trelagliptin 100 mg (once weekly) or alogliptin 25 mg (once daily) shall be administered orally 
before breakfast. However, the drug shall be administered as described below at the start of the 
treatment period (VISIT 2: Day 1) or during the treatment period (VISIT 3: Day 21). 
At the start of the treatment period (VISIT 2: Day 1): The drug shall be administered after required 
tests/observations, etc. 
During the treatment period (from VISIT 3 to VISIT 5):  
Trelagliptin 100 mg/week group shall insert the sensor on the day before Trelagliptin 
administration day.  Trelagliptin 100 mg/week shall be administered before breakfast on 
the next day of the sensor insertion day. The next administration of Trelagliptin 100 mg is 
after the sensor removal.  
Alogliptin 25 mg/day shall be administered after required tests/observations, etc at every 
VISIT without taking study drug. Research subjects shall take study drug prior to the every 
breakfast at home.  
Duration of treatment shall be start of treatment period (Day 1) to end of treatment period (Day 29). 
Dose and administration method for each administration group are shown in table 8.a. 
Table8.a Administration group and administration method 
Administration group 
Dose 
Route of 
Administration method 


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administration: 
Trelagliptin group 
Trelagliptin 100 mg 
Oral 
administration 
Once weekly, before 
breakfast  
Alogliptin group 
Alogliptin 25 mg  
Oral 
administration 
Once daily, before 
breakfast 
8.1.3 Overdose 
Overdose is defined as intentional or accidental administration of the study drug at a higher dose 
than that specified in the protocol, either by a health professional or by the research subject. 
To consistently collect important safety information about overdose, the principal investigator or 
investigator(s) shall record all cases of overdose on the “Overdose” page of the CRF, 
irrespective of the presence or absence of accompanying adverse event. Adverse events associated 
with overdose shall be recorded on the “Adverse events” page of the CRF, in accordance with the 
procedures described in Section 10.0, “ADVERSE EVENTS.” 
In addition, serious adverse events associated with overdose shall be recorded in accordance with the 
procedures described in Section 10.2.2, “Collection and reporting of SAEs.” 
In the event of overdose, the principal investigator or investigator shall treat the subject as required 
based on symptoms. 
8.2 
Medication other than the study drug 
Prohibited concomitant drugs (refer to Section 7.3.1) may not be used. Also, restricted drugs (refer 
to Section 7.3.2) may be used if used at the time of informed consent. However, dose change for 
those restricted drugs or addition of or change to a new drug shall be prohibited unless the principal 
investigator and investigator consider necessary due to adverse events. Other treatments shall be 
conducted under normal medical practice 
8.3 
Allocation and prescription of the study drug and administration procedure 
The principal investigator or its designee shall access the web case enrollment system to allocate 
research subjects. In addition the principal investigator or its designee shall notify information 
necessary for allocation such as the research subject ID number. Thereafter, the drug to be 
administered to the research subjects shall be notified by the web case enrollment system. The 
principal investigator and investigator shall prescribe the study drug according to the notification and 
record the drug information into the CRF of each research subject. 
8.4 
Preparation and storage of allocation list 
The person responsible for allocation (designated by the sponsor) shall create an allocation list. 


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Allocation shall be conducted at the enrollment center using web case enrollment system at start of 
treatment period (Day 1) with "HbA1c at the start of the observation period (< 7.5% or ≥ 7.5%)" and 
age (< 65 or ≥ 65) as a stratification factor for randomization. The enrollment center shall use the 
allocation list for stratified randomization created by the allocation responsible person. 
Information on the allocation shall be kept in a safe place and shall not be available to anyone other 
than authorized persons, to secure independency from the clinical research. 


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9.0 
CLINICAL STUDY PROTOCOL 
9.1 
Research procedures 
The principal investigator or investigator shall collect data in accordance with the procedure below. 
The same principal investigator or investigator shall perform tests/observations/evaluation of 
research subjects, in principle. The study schedule is provided in Appendix A. 
9.1.1 Informed consent procedure 
The procedures for obtaining informed consent are described in Section 15.3. 
Consent shall be obtained from the research subject before initiation of research procedures. 
Research subject ID code is given to each research subject from whom informed consent was 
acquired and who was randomized. The research subject ID code shall be used throughout the 
research period and shall not be changed. 
9.1.2 Demographic data, medical history, and previous therapeutic drugs 
(1) Demographic information 
Demographic data shall be collected regarding birth, gender, smoking history, drinking history, 
time (year/month) of onset (or diagnosis of diabetes). 
(2) Medical history 
Medical history data shall be collected regarding clinically problematic diseases or symptoms 
that disappeared within 1 year or were terminated from the start of observation period. When 
the symptoms or disease continues, it shall be considered as a concurrent disease (Refer to 
Section 9.1.6). 
(3) Pre-treatment 
Regarding pre-treatment, name of drug, route of administration and date of final administration 
shall be collected for all anti-diabetic medication (including injections) that ended use ≤ 12 
weeks before start of observation period. 
9.1.3 Physical examination 
All subsequent physical examinations after the start of the treatment period shall be assessed for 
clinically significant changes from the baseline examination. 
9.1.4 Weight, height and BMI 
Body weight shall be measured to one decimal place in kilograms.  


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Height shall be measured or asked to the nearest whole number in centimeters.  
BMI shall be calculated by the sponsor using the following formula and shown to one decimal place:  
Body Mass Index:  BMI = weight (kg) / (height (m))2 
Example: 
Height = 176 cm, weight = 79.2 kg, BMI = 79.2/1.762 = 25.6 kg/m2  
9.1.5 Concomitant drugs 
Concomitant drugs are all drugs to be given in addition to the study drug. Drugs prescribed by 
doctors or the over-the-counter medicines purchased by the research subjects shall be included. At 
every hospital visit of the research subject, the status of use of drugs (name of drug, route of 
administration) other than the allocated oral hypoglycemic drug, from start of observation period to 
the completion of the clinical research shall be monitored. 
9.1.6 Concurrent disease 
A concurrent disease is defined as a disease or symptom that is present at the start of the observation 
period or that develops between the start of the observation period and the start of study treatment. 
Clinically significant abnormalities, including laboratory test data and physical examination findings, 
observed in tests and physical examinations at the start of study treatment shall be considered as a 
concurrent disease at the discretion of the principal investigator or investigator. The content of 
concurrent disease (diagnosis) shall be investigated. 
9.1.7 Laboratory tests 
Laboratory tests in table 9.a shall be measured at clinical laboratory instituions according to the 
observation schedule (Appendix A). Regarding tests at fasting, blood sampling shall be conducted 
after ≥ 10 hours of fasting. The principal investigator and investigator shall evaluate and keep the 
reported laboratory test results. 


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Table 9.a 
Laboratory tests 
Serum chemistry 
 
Fasting blood glucose 
Fasting insulin 
Fasting glucagon 
Fasting proinsulin 
FastingGLP-1 
Fasting GIP 
Glycoalbumin 
1,5-AG 
 
The principal investigator shall keep laboratory test reference values, including the historical data. 
9.1.8 HbA1c (NGSP value) 
Measured at research implementing entities to confirm eligibility of research subject at start of 
observation period. The principal investigator and investigator shall evaluate and keep the reported 
laboratory test results. 
9.1.9 Continuous glucose monitoring (CGM)  
Conducted according to Schedule of Research Procedures (Appendix A) Details shall be specified 
separately in the operation procedures manual. 
(1) Device used in this study 
, leased from the sponsor. 
(2) Self-measurement of blood glucose (SMBG)  
Use device leased from sponsor 
Research subjects shall measure blood glucose levels every day during CGM in the observation 
and treatment periods. At least, blood glucose levels shall be measured at three time points on 
the first day of CGM ([1] at least 2 hours after the recorder is connected and [2] 2 hours after 
the first is measured. [3] at bedtime) and at four time points from the second day onward ([1] 
before breakfast, (2) before lunch, (3) before evening meal, and (4) at bedtime).  
The glucose levels from SMBG shall be used for correction of glucose levels obtained from 
CGM. 
(3) Observation period 
A sensor shall be inserted at the start of the observation period (Day -2) and removed at the start 
of treatment (Day 1) 


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(4) Treatment period 
A sensor shall be inserted (VISIT 3: Day 21), exchanged (VISIT 4: Days 24 to 26), and 
removed (VISIT 5: Day 29) during the treatment period. 
(5) Dietetic therapy and exercise therapy 
Research subjects shall present photographs of all meals to the principal investigator or 
investigator during CGM. Also, the meal provided by the sponsor shall be taken according to 
the calories prescribed by the sponsor for each research subject at the meal times shown below. 
Time point of provision of meals: evening meal at start of observation period (Day-2), evening 
meal on first and seventh of CGM to be performed from Day21 for 9 days.  
Research subjects shall only conduct exercise therapy feasible (if performed) under the same 
conditions every day during CGM. 
The principal investigator or investigator shall prescribe consistent dietetic therapy and exercise 
therapy (if performed) throughout the research period. Compliance with dietetic therapy and 
exercise therapy(if performed) shall be investigated and rated on a four-point scale as follows: 
1. 
Compliant (compliance rate ≥ 90%)  
2. 
Almost compliant (compliance rate ≥ 70%)  
3. 
Generally compliant (compliance rate ≥ 50%)  
4. 
Minimally compliant (compliance rate < 50%) 
(6) Research subject diary 
Research subjects shall complete the subject diary every day during CGM and submit the diary 
to the principal investigator or investigator. 
The following information shall be recorded in the subject diary: date and time of dosing, time 
of SMBG and blood glucose levels, meal time and contents, exercise time, wake-up time, 
bedtime, etc.  
9.1.10 Contraception 
Women of childbearing potential (e.g., women who have not undergone surgical sterilization, 
women who have not reached menopause) shall use appropriate contraception during participation in 
this clinical research from the time of informed consent. During the informed consent process, 
appropriate contraceptive methods and the necessity of avoiding pregnancy during participation in 
the clinical research shall be fully explained to women of childbearing potential with the use of the 


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informed consent form and information sheet, and the research subjects shall fully understand these 
explanations before providing consent. 
9.1.11 Pregnancy 
If pregnancy of a female research subject or a partner of male research subject is found during the  
participation in this clinical research, the principal investigator or investigator shall inform the 
sponsorwith pregnancy sheetincluded the detail information as possible. 
9.1.12 Record of cases withdrawn before randomization 
The consent form shall be signed, and a CRF shall be created for all research subjects who are 
withdrawn before randomization. 
The following items are to be described on the CRF. 
• 
Informed consent procedure 
• 
<MMM/DD/YYYY> 
• 
Sex 
• 
Eligibility 
• 
Reason for discontinuation 
The primary reason for withdrawal before randomization shall be recorded on the CRF according to 
the following classification: 
• 
Not meeting inclusion criteria or meeting exclusion criteria 
• 
Serious deviation from protocol 
• 
Lost to follow-up 
• 
Voluntary discontinuation (specify the reason) 
• 
Premature termination criteria of entire clinical research 
• 
Others (specify the reason) 
Research subject ID numbers assigned to research subjects withdrawn from the research before 
randomization shall not be reused. 
9.1.13 Record of randomization 
Research subjects to be randomized shall meet all of the inclusion criteria and shall not meet any of 
the exclusion criteria according to Section 8.3. The principal investigator or investigator shall 
specify the reason why the subject cannot be randomized to the treatment period. 


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9.2 
Drug-taking status of the research subjects 
The principal investigator or investigator shall confirm the treatment compliance and the date and 
time of dosing during CGM with the research subject at every visit. At the end of study drug 
administration, Treatment compliance shall be rated on a two-point scale as follows: 
1. Compliant (compliance rate ≥ 75%) 
2. Not compliant (compliance rate < 75%) 
Medication instruction shall be given to research subjects throughout the clinical research period. If 
poor compliance with study treatment (e.g., < 75% of the prescribed dose) after the previous visit 
has been found and does not improve, the research subject may be withdrawn from the research if 
appropriate for the circumstances. 
9.3 
Implementation time point of the test and observation items 
The schedule for all tests, observations, and evaluations is shown in Appendix A. The principal 
investigator or investigator shall perform the tests, observations, and evaluations at the time points 
shown below. 
9.3.1 Start of observation period (Visit 1: Day -2)  
After consent is obtained, physical examination/tests are to be conducted for research enrollment. 
Eligibility of research subjects shall be determined in accordance with the inclusion and exclusion 
criteria as described in section 7.0. Refer to section 9.1.12 for the recording of research subjects who 
are withdrawn before randomization. 
Tests and observations to be performed and endpoints to be assessed during the observation period 
(VISIT 1: Day -2) are shown below. 
• 
Informed consent procedure 
• 
Demographic information 
• 
Medical history, pre-treatment 
• 
Physical examination 
• 
Height 
• 
Concomitant drugs 
• 
Concurrent disease 
• 
Prescription of and compliance with dietetic therapy and exercise therapy 


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Tests and observations to be performed and endpoints to be assessed during the observation period 
VISIT 1(Day -2) are shown below. 
• 
Physical examination 
• 
Body weight 
• 
Laboratory tests 
• 
HbA1c 
• 
CGM  (remove sensor) 
• 
Self-measurement of blood glucose (self-measured by research subject) 
9.3.2 At start of treatment period (Visit 2: Day 1) 
Research subjects whose eligibility has been confirmed shall be randomized according to section 8.3 
following the results of test, observation and endpoints implemented before start of treatment period. 
Randomization is performed at the visit when the principal investigator or investigator is considered 
as necessity. 
The test, observation, and endpoints to be implemented at the start of treatment period (Visit 2: Day 
1) are shown below. 
• 
Physical examination 
• 
Concomitant drugs 
• 
Compliance with dietetic therapy and exercise therapy 
• 
CGM (remove sensor) 
• 
SMBG (research subject perform by own) 
• 
Adverse Event 
9.3.3 Treatment period (Visit 3: Day 21) 
The test, observation, and endpoints to be implemented during the treatment period (Visit 3: Day 21) 
are shown below. 
• 
Physical examination 
• 
Body weight 
• 
Concomitant drugs 
• 
Laboratory tests 


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• 
Treatment status 
• 
Compliance with dietetic therapy and exercise therapy 
• 
CGM (remove) 
• 
Self-measurement of blood glucose (self-measured by research subject) 
• 
Adverse event 
9.3.4 Treatment period (Visit 4: Day 24) 
The test, observation, and endpoints to be implemented during the treatment period (Visit 4: Day 24) 
are shown below. 
• 
Physical examination 
• 
Concomitant drugs 
• 
Drug-taking status 
• 
Compliance with dietetic therapy and exercise therapy 
• 
CGM (exchange sensor) 
• 
Self-measurement of blood glucose (self-measured by research subject) 
• 
Adverse event 
9.3.5 At end of treatment period (Visit 5: Day 29) or discontinuation during 
treatment period 
The test, observation, and evaluation items to be implemented during at the end of treatment period 
(Visit 5: Day 29) are shown below. 
• 
Physical examination 
• 
Body weight 
• 
Concomitant drugs 
• 
Laboratory tests 
• 
Drug-taking status 
• 
Compliance with dietetic therapy and exercise therapy 
• 
CGM (remove sensor) 
• 
Self-measurement of blood glucose (self-measured by research subject until removal of 
CGM sensor) 


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• 
Adverse event 
The test, observation, and endpoints to be implemented at discontinuation of treatment period are 
shown below. 
• 
Physical examination 
• 
Body weight 
• 
Concomitant drugs 
• 
Laboratory tests 
• 
Drug-taking status 
• 
Compliance with dietetic therapy and exercise therapy 
• 
Adverse event 
• 
Reason of discontinuation  
The status of all randomized research subjects at the end of the clinical research shall be recorded on 
the CRF. 


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10.0 
ADVERSE EVENT 
10.1 
Definitions 
10.1.1 Adverse event 
An adverse event is defined as any untoward medical occurrence in a patient or a research subject 
receiving a pharmaceutical product (including the study drug). It does not necessarily have an 
apparent causal relationship with this pharmaceutical product (including study drug). 
An adverse event can therefore be any unfavorable or unintended sign (e.g., clinically significant 
laboratory abnormality), symptom, or disease temporally associated with the use of a pharmaceutical 
product (including the study drug), regardless of whether it is considered related to the 
pharmaceutical product (including the study drug) or not. 
10.1.2 Considerations for adverse events 
Generally unfavorable findings are described below: 
• 
Newly diagnosed disease or unexpected aggravation of existing symptom (intermittent 
event of an existing symptom is not considered an adverse event) 
• 
Requiring action or medical practice 
• 
Requiring invasive diagnostic treatment 
• 
Requiring discontinuation or a change in the dose of the study drug or a concomitant 
medication 
• 
Considered unfavorable by the principal investigator or the investigator 
Diagnosis name and signs/symptoms: 
Adverse events shall be recorded by diagnosis name. Accompanying signs (including abnormal 
laboratory values, abnormal ECG findings) and symptoms shall not be recorded as adverse events. If 
an adverse event could not be expressed by a diagnosis name, the signs or symptoms shall be 
recorded as the adverse event. 
Laboratory test values and ECG findings: 
Abnormal laboratory values and ECG findings shall be recorded as adverse events when the 
principal investigator or investigator judges the results are clinically problematic (in other words, 
when certain action or medical practice is required, or when the principal investigator or the 
investigator judges the change has exceeded the normal physiological variation range of the research 
subject). Retest and/or continued monitoring of an abnormality are not considered medical practice. 


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Also, repeated or additional conduction of non-invasive tests for verification, evaluation, and 
monitoring of an abnormality are not considered medical practice. 
However, when abnormal laboratory values and ECG findings are the accompanying symptoms of a 
disease diagnosed as an adverse event (e.g., increased creatinine due to renal dysfunction, etc.), the 
adverse event shall be handled by its diagnosis name. 
Pre-existing conditions (disease or symptom that has been present since before the start of study 
treatment): Pre-existing disease or symptom that has been present since before the start of study 
treatment shall be regarded as a concurrent disease and not an adverse event. When a concurrent 
medical condition is aggravated, the aggravation shall be determined as an adverse event and the 
principal investigator or the investigator shall record on the CRF that the adverse event is an 
aggravation of the concurrent disease (e.g., “aggravation of hypertension,” etc.). 
If a research subject has a pre-existing episodic condition (e.g., asthma, epilepsy), each episode shall 
be recorded as an adverse event if the episodes become more frequent, serious, or severe in nature. If 
a research subject has a chronic concurrent condition (e.g., cataracts, rheumatoid arthritis), 
worsening of the condition shall be recorded as adverse event if the degree of the worsening exceeds 
that which would be expected. The principal investigator or investigator shall ensure that the adverse 
event term to be recorded represents the change in the condition from baseline (e.g. “worsening 
of…”). 
Worsening of adverse events:  
If a research subject experiences a worsening of the adverse event after a change to the study drug, 
or secondary signs and symptoms are caused by the adverse event, the worsening or the secondary 
signs and symptoms shall be recorded as a new adverse event on the CRF. The principal investigator 
or investigator shall use an adverse event term that explicitly means a change of the condition (e.g., 
“worsening of…”). 
Change of severity of adverse events:  
If the research subject experiences changes in the severity of an adverse event, the event shall be 
recorded once, at its peak severity. 
Previously planned surgery or treatment:  
Preplanned surgeries or interventions that were scheduled before study treatment shall not be 
considered adverse events. However, when the existing symptom is aggravated to a degree requiring 
emergency surgery or treatment, the condition or the event shall be considered an adverse event. A 
concurrent disease that resulted from previously planned surgery shall be reported as an adverse 
event. 


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Non-urgent surgery or treatment:  
Non-urgent surgery or treatment that does not induce a change in the condition of a research subject 
(cosmetic surgery, etc.) shall not be considered an adverse event; However, it shall be recorded in 
the source documents. Concurrent diseases due to a non-urgent surgery shall be reported as an 
adverse event. 
The insufficient clinical response (lack of efficacy): insufficient clinical response, efficacy, or 
pharmacological action shall not be recorded as an adverse event. The principal investigator or 
investigator shall make the distinction between worsening of a pre-existing condition and lack of 
therapeutic efficacy. 
Overdose of the study drug:  
Overdose of any medication without onset of event shall not be recorded as an adverse event, but the 
overdose shall be recorded on the “Overdose” page of the CRF. Any onset of event shall be recorded 
as adverse events on the “Adverse events” of the CRF. 
10.1.3 Serious adverse event 
Of all unfavorable medical events that develop after administration of a pharmaceutical product 
(including the study drug) (irrespective of dose), a serious adverse event is an event that: 
1. results in death, 
2. is life threatening*, 
3. requires inpatient hospitalization or prolongation of existing hospitalization, 
4. results in persistent or significant disability/incapacity, 
5. leads to a congenital anomaly/birth defect, or 
6. Medically important event that causes a risk to the research subject even if it is not 
immediately life-threatening and does not result in death or hospitalization, or requires an 
action or treatment to prevent the results described in 1 to 5 above. Points described in the 
Takeda Medically Significant Adverse Event List (Table 10.a) are included in this section. 
* The term “life threatening” refers to an event in which the research subject was at risk of death at 
the time of the event; it does not refer to an event that hypothetically might have caused death if it 
were more severe. 


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Table 10.a 
Takeda Medically Significant AE List 
Acute respiratory failure/acute respiratory 
distress syndrome (ARDS) 
Torsades de pointes/ ventricular 
fibrillation/ventricular tachycardia 
Malignant hypertension 
Convulsive seizure (including convulsion 
and epilepsy) 
Agranulocytosis 
Aplastic anemia 
Toxic epidermal necrolysis/ 
Oculomucocutaneous syndrome 
(Stevens-Johnson syndrome) 
Hepatic necrosis 
Acute hepatic failure 
Anaphylactic shock 
Acute renal failure  
Pulmonary hypertension 
Pulmonary fibrosis (including interstitial 
pneumonia) 
Neuroleptic malignant syndrome/ malignant 
hyperpyrexia 
Spontaneous abortion/ stillbirth and fetal death 
Confirmed or suspected transmission of 
infection by a medicinal product 
Confirmed or suspected endotoxin shock 
10.1.4 Adverse events of special interest (specific adverse events) 
An AE of Special Interest (AESI) (serious or non-serious) is one of scientific and medical concern 
specific to the study drug, for which ongoing monitoring and rapid communication by the principal 
investigator or investigator to Takeda may be appropriate. Such events may require further 
investigation in order to establish assessment, and instructions provided to investigators on how and 
when they should be reported to the sponsor are described in Section 10.2.1.3. 
AESIs: Hypoglycemia-related AEs, intestinal obstruction-related AEs and acute pancreatitis-related 
AEs (for both Trelagliptin and Alogliptin), QT/QTc interval prolongation-related AEs (for 
Trelagliptin), and Liver dysfunction or jaundice-related AEs (for Alogliptin). 
<For both Trelagliptin and Alogliptin> 
[Hypoglycemia-related AEs] 
Hypoglycemia-related AEs are designated as AESIs because, in general, attention should be paid to 
the events in the treatment of diabetes mellitus. 
[Intestinal obstruction-related AEs] 
Intestinal obstruction-related AEs are designated as AESIs because there are accumulated reports of 
intestinal obstruction as an adverse reaction to similar incretin-related drugs (GLP-1 receptor 
agonists and other DPP-4 inhibitors). 
[Acute pancreatitis-related AEs] 


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Acute pancreatitis-related AEs are designated as AESIs because there are accumulated reports of 
acute pancreatitis as an adverse reaction to similar incretin-related drugs. 
<For Trelagliptin> 
[QT/QTc interval prolongation-related AEs] 
QT/QTc interval prolongation-related AEs are designated as AESIs because, in the QT/QTc 
assessment study conducted during the development, QT/QTc interval prolongation was reported in 
the trelagliptin 800 mg group although it did not occur in the trelagliptin 200 mg group. 
<For Alogliptin> 
【Liver dysfunction or jaundice-related AEs】 
Liver dysfunction or jaundice-related AEs are designated as AESIs because there are accumulated 
reports as serious adverse reaction. 
10.1.5 Severity of adverse events 
The severity of adverse events shall be classified and defined as shown below. 
Mild 
The event is transient and easily 
tolerated by the subject. 
Moderate 
The event interrupts the subject’s usual 
activities. 
Severe 
The 
event 
causes 
considerable 
interference with the subject’s usual 
activities. 
10.1.6 Causality of adverse events 
The causal relationship of each adverse event to the study drug shall be classified and defined as 
shown below. 
Related 
An adverse event that follows an apparent temporal sequence (including clinical course 
after discontinuation). An adverse event the causal relationship could not be denied and 
there is reasonable possibility due to the study drug, although other factors such as 
underlying disease, concurrent diseases, or concomitant drugs/treatment are also 
suspected. 
Not 
related 
An adverse event that does not follow an apparent temporal sequence from 
administration of the study drug. Very likely due to other factors such as underlying 


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disease, concurrent diseases, or concomitant drugs/treatment. 
10.1.7 Relationship to study procedures 
The relationship shall be recorded as “Yes” if the principal investigator or investigator considers that 
there is reasonable possibility that an adverse event is due to a study procedure. Otherwise, the 
relationship shall be recorded as “No.” 
10.1.8 Date of onset 
The date of onset of adverse events shall be determined according to the following rules: 
Adverse event 
Date of onset 
Signs, symptoms, diseases 
(diagnoses) 
The date on which the first signs/symptoms were noted by the 
research subject and/or the principal investigator or investigator. 
Asymptomatic diseases 
The date on which a diagnosis was confirmed through a test(s). 
The date on which a diagnosis was confirmed, even when the test 
results indicate an old sign(s) of the disease or an approximate time 
of its onset. 
Exacerbation of concurrent 
diseases 
The date on which the first worsening of diseases/symptoms was 
noted by the research subject and/or the principal investigator or 
investigator. 
Onset of a test abnormality after 
the start of the study drug 
administration 
The date on which a clinically significant laboratory abnormality 
was detected. 
Worsening of a baseline test 
abnormality after initiation of 
study treatment 
The date on which a clear increase/decrease in a laboratory 
parameter was clinically confirmed based on the time profile of the 
parameter. 
10.1.9 Date of resolution 
The date of resolution of an adverse event is the date on which the research subject recovered 
(including resolution with sequelae). If a research subject died due to the adverse event concerned, it 
shall be the date of death. The adverse event shall be recorded as “ongoing” if the research subject 
has not yet recovered by the end of the study. 
10.1.10 Actions taken for the study drug 
Actions taken for the study drug shall be classified or defined as shown below. 
Drug withdrawn 
The study drug is discontinued because of an adverse event (including withdrawal 
by the research subject at his/her own discretion). 
When the treatment with the study drug is continued after withdrawal from the 
study, it shall be defined as “Dose not changed.” 


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Dose not changed 
If the dose was unchanged after the onset of the adverse event it shall be defined 
as “Dose not changed.” 
If the study drug was discontinued, reduced, or increased because of another 
adverse event it shall be defined as “Dose not changed.” 
If the study drug was discontinued or reduced for a reason other than for the 
adverse event, e.g., inadvertence of the research subject, it shall be defined as 
“Dose not changed”. 
Unknown 
It has not been possible to determine what action has been taken because the 
research subject is lost to follow-up. 
Not Applicable 
The study treatment had already been completed or discontinued before the onset 
of the adverse event. 
Dose reduced 
The dose of the study drug was reduced because of the adverse event (including 
dose reduction by the research subject at his/her own discretion). 
Dose increased 
The dose of the study drug was increased because of the adverse event (including 
dose increase by the research subject at his/her discretion). 
Washout 
If the study treatment is suspended (i.e., interrupted) (including 
suspension/interruption by the research subject at his/her discretion) because of 
the adverse event but resumed thereafter, shall be defined as “washout”. 
10.1.11 Outcome 
Outcome of adverse events is classified as follows: 
Category 
Criteria 
Recovered 
Disappearance or recovery of symptoms and findings 
Laboratory values returned to normal or baseline 
Improved 
The intensity is lowered by one or more stages 
Symptoms or findings mostly disappeared 
Laboratory values improved, but have not returned to normal or baseline 
The research subject died from a cause other than the concerned adverse event while 
the condition was resolving (recording of the date of death unnecessary) 
Not recovered 
No change in symptoms, findings, or laboratory data 
The symptoms, findings, or laboratory data on the final day of observable period 
were aggravated compared with the date of onset 
Irreversible congenital anomaly 
The research subject died from another cause before resolution of the concerned 
adverse event (recording of the date of death unnecessary) 
Recovered 
with sequelae 
Disability that disturbs daily life 


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Death 
Direct relationship between death and the concerned adverse event 
“Direct relationship” means that the concerned adverse event was the cause of 
death, or the concerned adverse event was clearly responsible for death. 
Outcome of an adverse event which was not determined (judged, presumed) a direct 
cause of death observed in the same research subject is not considered as death. 
If outcome is death, the date of death shall be recorded. 
Unknown 
Follow-up specified in the protocol after the date of onset was not possible due to 
change of hospitals or relocation, etc. 
10.2 
Procedures 
10.2.1 Collection and reporting of adverse events 
10.2.1.1 Adverse event collection period 
Collection of the adverse events shall commence at the start of administration of the study drug (Day 
1) and shall conitue until end of treatment (Day 29). 
10.2.1.2 Reporting of adverse events 
At each study visit, the principal investigator or investigator shall check for the presence of any 
onset of subjective symptoms. A neutral question, such as “How have you been feeling since your 
last visit?” may be asked to collect any adverse events that occurred between the previous and 
present visits. 
The principal investigator or investigator shall follow up all research subjects experiencing an 
adverse event irrespective of the causal relationship with the study drug, until the symptom resolves, 
or any clinically significant abnormal laboratory values have returned to baseline or there is a 
satisfactory explanation for the change (permanent or irreversible adverse events). All adverse 
events shall be entered on the CRF. Adverse event term, onset date, resolution date, severity, causal 
relationship with the study drug (i.e. "Unrelated" or "Related"), action taken for the study drug, 
outcome, causal relationship with any study procedure (with specific procedure if assessed to be 
causally related), and seriousness shall be entered. 
Follow-up period of adverse events shall be until recovery of the adverse events, or the time when 
the principal investigator or investigator judges that further follow-up would be unnecessary. 
10.2.1.3 Reporting of adverse events of special interest (specific adverse events) 
If AESI occurring during the AE collection period is considered to be clinically significant based on 
the criteria below, it should be reported to the sponsor (refer to the attachment  for contact 
information) within 1 business day of first onset, or subject’s notification of the event by the 


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principal investigator or investigator. AESI Form should be completed and signed (or signed and 
sealed) by the principal investigator and reported to the sponsor within 10 business days. 
The criteria for AESIs (hypoglycemia-related AEs, intestinal obstruction-related AEs, acute 
pancreatitis-related AEs, and QT/QTc interval prolongation-related AEs) are as shown below. If any 
other AEs potentially related to the study drug occur, it will be considered whether to include them 
in the AESIs. 
[Hypoglycemia-related AEs] 
AEs related to hypoglycemia 
[Intestinal obstruction-related AEs] 
Intestinal obstruction, ileus, subileus, obstruction of the digestive tract, gastrointestinal motility 
disorder, impaired gastric emptying, and AEs related to these conditions 
[Acute pancreatitis-related AEs] 
AEs related to pancreatitis or acute pancreatitis 
[QT/QTc interval prolongation-related AEs] 
Torsade de pointes, sudden death, ventricular tachycardia, ventricular fibrillation, ventricular flutter, 
consciousness disturbed, convulsion, ECG QT prolonged, and AEs related to these conditions 
【Liver dysfunction or jaundice-related AEs】 
Adverse events corresponding to ' Liver dysfunction related to drug - comprehensive search' in 
MedDRA standard search formula.  
The AESIs have to be recorded as AEs in the CRF. A report along with all other required 
documentation must be submitted to the sponsor. 
10.2.2 Collection and reporting of serious adverse events 
When a serious adverse event develops during the period of collecting adverse events, it shall be 
reported according to the following procedures. At the time of onset of a serious adverse event or 
notification of the onset by the research subject, the principal investigator shall report the serious 
adverse event to the chief executive of the research implementing entity immediately, and the 
sponsor or CRO to whom the sponsor has entrusted responsibility shall notify the principal 
investigator of the research implementing entity. 
The principal investigator shall then report the serious adverse event to the sponsor (for the contact 
information, refer to the attachment) within 1 day of notification of the event onset. Further, the 
principal investigator shall submit a formal report within 10 calendar days to the sponsor. 


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Furthermore, it shall be mandatory to include the contents below in the report to be submitted to the 
sponsor within 1 working day, and other items shall be reported as far as possible. 
• 
Brief description of adverse event and the reason for why it was determined as serious 
• 
Research subject ID number 
• 
Name of principal investigator or the investigator 
• 
Name of the study drug 
• 
Determined causal relationship 
The principal investigator or investigator shall report spontaneously reported serious adverse events 
that are collected even after the adverse event collection period to the sponsor. 
10.2.3 Reporting of additional information concerning adverse events 
If the sponsor requests provision of additional information concerning adverse events for reporting 
to regulatory authorities, the principal investigator or the investigator shall confirm the necessary 
additional information and enter in the EDC system or submit a report within the period specified by 
the sponsor. 
10.3 
Follow-up of serious adverse events 
When information that was not included in the detailed report was obtained later, the principal 
investigator or investigator shall state it in the copy of the report on serious adverse events, or create 
another document and submit it to the contact address shown on the attached sheet. Relevant data 
collected at the research implementing entity (e.g., ECG charts, laboratory test values, discharge 
summary, postmortem results) shall be sent to the sponsor or the committee such as the IEC upon 
request. 
The investigator or the subinvestigator shall follow-up all serious adverse events, etc., until recovery 
is confirmed, or the final outcome is determined. 
10.3.1 Reporting of serious adverse events to Ethics Review Committee, etc., and 
regulatory authorities 
When the chief executive of the research implementing entity receives a report of a serious adverse 
event from the principal investigator, the chief shall consult the Ethics Review Committee, etc., and 
notify the research implementing entities that are conducting the clinical research through the 
sponsor or the CRO consigned by the sponsor. 
If the serious adverse event reported by the principal investigator in which direct causal relationship 
cannot be denied with this study (the study drug) and is unexpected, the chief executive of the 


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research implementing entity shall prepare a written report of the unexpected serious adverse event 
containing the information reported by the principal investigator plus the information below, and 
submit the report to the Minister of Health, Labor and Welfare, and notify other clinical research 
implementing entities. (Reporting to the Minister of Health, Labor and Welfare via the sponsor, or 
notification to other clinical research implementing entities via the sponsor may also be possible) 
• 
Actions taken for serious adverse events (discontinuation of new enrollment, revision of 
informed consent form, re-consents to other research subjects, etc.) 
• 
Date of review, summery of review, result, necessary action, etc., related to Ethics Review 
Committee, etc. 
• 
Notification to other research implementing entities 
The sponsor shall report, in accordance with regulations, unexpected serious adverse drug reactions 
and other serious adverse events that are subject to emergency reporting to regulatory authorities, the 
principal investigators, and chief executives of the research implementing entities. 
From the time point of first acknowledging the event or receiving additional information, the 
sponsor or the CRO consigned by the sponsor shall comply with regulatory required time frames for 
reporting, and make emergency reports concerning unexpected serious adverse drug reactions and 
expected serious adverse drug reactions to regulatory authorities. Also, the sponsor shall, in the same 
way, make an emergency report of other critical safety information that may have a major effect on 
the study drug risk-benefit, continuation of study drug administration, or continuation of clinical 
research. The research implementing entity shall submit copies of emergency report documents to 
the Ethics Review Committee, etc. 


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11.0 
COMMITTEES ESTABLISHED FOR THIS STUDY 
In this clinical research, none of Clinical Research Steering Committee, Data and Safety Monitoring 
Committee, or Central Assessment Committee shall be established. 


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12.0 
DATA MANAGEMENT AND STORAGE OF RECORDS 
Data management operations shall be performed according to the standard operating procedure by 
the data management department of the sponsor independent from the medical affairs department. 
Adverse events, medical history, and concurrent conditions shall be coded using MedDRA. Drugs 
shall be translated using the WHO Drug Dictionary. 
12.1 
Case report form 
The principal investigator or investigator shall complete a CRF for each research subject who has 
signed the informed consent form. 
The sponsor or its designee shall provide research implementing entities with access authorization to 
the electronic CRF. Before use of the electric CRF system, the sponsor shall provide training to the 
principal investigator, investigators, and study collaborators. The CRF shall be used to report the 
information collected during the study period to the sponsor. The CRF shall be made in Japanese. 
Data shall be directly entered in preparing the CRF. 
A change or correction of the CRF shall be recorded as an audit trail that records the information 
before and after the change or correction, the person who made the change or correction, date of 
change or correction, and its reason. 
The principal investigator shall ensure the accuracy and completeness of the CRF, and provide an 
electronic signature on the relevant page of the case report form. The principal investigator shall bear 
full responsibility for the accuracy and reliability of all data entered on the CRF. 
The following data shall be recorded on the CRF directly. (Except if there is a description in the 
source material) 
• 
Eligibility, end state, reason of termination, severity, degree, the causal relationship with the 
study drug or the study procedures, outcome of the adverse event. 
The following data shall not be recorded on the CRF directly. 
• 
Measurement results of CGM 
• 
Laboratory result tested at central. 
When the principal investigator or the investigator makes a change or correction in the data entered 
on the CRF after fixation of clinical data base, a record (Data Clarification Form) of change or 
correction on the CRF provided by the sponsor shall be used. The principal investigator shall 
confirm that the record of change or correction on the CRF is accurate and complete, and sign or 
write name/ affix a seal, and date it. 


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The sponsor or its designee shall confirm that CRFs have been made appropriately according to the 
procedures defined for each study. The sponsor or its designee shall have access to the medical 
records of the research subjects and in-house records to ensure the accuracy of the CRF as necessary. 
The completed CRF is the property of the sponsor, and the principal investigator or investigator shall 
not disclose the information to a third party without a written permission from the sponsor. 
12.2 
Timing of data entry into the electronic CRF system 
The sponsor or its designee shall request the principal investigator and investigator to promptly enter 
data into the EDC at enrollment of the research subject, each visit during study treatment, 
completion/discontinuation of study treatment, and follow-up period. Details of deadlines for data 
entry shall be specified separately in a procedure manual. 
12.3 
Storage of records 
The principal investigator or the chief executive of research implementing entity shall store the 
following materials, including those specified in section 12.1, and study-specific documents to be 
used by the regulatory authority and the sponsor or its designee for investigation and audit. The 
documents include research subject ID code, medical records, clinical study worksheets (if used), 
original signed and dated informed consent forms, the change and fix record of CRF (copy) and 
electric copies of electronic CRF including audit trail. The principal investigator and the chief 
executive of the research implementing entity shall appropriately retain the material/information 
related to this study for at least 5 years from the date of reporting the end of the research by the 
principal investigator, or for 3 years from the date of reporting final publication of the study result, 
whichever date is later. However, when the sponsor requires a longer storage period, the chief 
executive of the research implementing entity shall discuss the period and methods of storage with 
the sponsor. 
 


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13.0 
STATISTICAL ANALYSIS METHODS 
The person responsible for statistical analysis and the designee (a person employed by a CRO 
independent of the sponsor; the person in charge of analysis) shall conduct analyses. The sponsor will 
not be involved in statistical analyses. 
13.1 
Statistical and analytical plans 
The person in charge of analysis shall prepare a statistical analysis plan (hereinafter referred to as 
SAP) before the acquisition of the informed consent of the earliest research subject, and issue the 
first edition. Detailed definition of endpoints and analysis methods should be specified in the SAP to 
deal with all the purposes of the research. 
13.1.1 Analysis set 
Two analysis sets, “full analysis set” and “Safety data analysis set” are used in this study. The “full 
analysis set" used as a primary analysis set in the efficacy analysis shall be defined as "the research 
subjects who were randomized and given at least one dose of the study drug." The “Safety data 
analysis set” shall be defined as "the research subjects who are given at least one dose of the study 
drug." 
13.1.2 Analysis of demographic and other baseline characteristics 
From the “full analysis set” primary research subject background items will be tabulated by each 
treatment group and by merging the treatment groups. 
13.1.3 Efficacy analysis 
[Primary endpoints] 
• 
Changes in the SD of 24-hour blood glucose values (mg/dL) for each 7-day period between 
Week 3 and Week 4 (between Day 22 and Day 28) of the treatment period, calculated from the 
value at the start of the observation period  
(Analysis method) 
•For the “full analysis set”, summary statistics (number of subjects, mean, SDs, maximum values, 
minimum values, quartiles [same apply hereafter]) and 95% confidence interval (two sides) of mean 
shall be calculated for each treatment group at each evaluation point (each day), and illustrating 
changes in mean and SD in order to evaluate changes in the SD of 24-hour blood glucose values 
(mg/dL) for each 7-day period between Week 3 and Week 4 (between Day 22 and Day 28) of the 
treatment period, calculated from the value at the start of the observation period for treagliptin or 
alogliptin separately. 
•Preliminary, for the “full analysis set”, calculate point estimation and 95% confidence interval (two 


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sides) in difference of mean in treatment groups (trelagliptin 100 mg group – alogliptin 25 mg 
group) in order to examine the influence of the once-weekly administration and blood glucose 
fluctuations due to the difference in the daily administration exploratory. 
•As well, for the “full analysis set ,” conduct analysis of covariance at each evaluation point with 
changes in the SD of 24-hour blood glucose values between Week 3 and Week 4 from the value at 
the start of the observation period as dependent variable, treatment groups as independent variable, 
HbA1c (NGSP value) at the start of the observation period, changes in the SD of 24-hour blood 
glucose values at the start of the observation period, and age as covariates, and calculate point 
estimation and 95% confidence interval (two sides) in difference of adjusted mean for each group. 
•Preliminary, “full analysis set ,” calculate point estimation and 95% confidence interval (two sides) 
in difference of adjusted mean in treatment groups (trelagliptin 100 mg group – alogliptin 25 mg 
group)  
[Secondary endpoints] 
• 
Changes in AUC over time when specific blood glucose levels ( 110, 140, 160, or 180 mg/dL) 
are observed during the 3 hour time period after breakfast, lunch and evening meal*1, 2 
• 
Change in AUC over time during periods when blood glucose 140, 160, or 180 mg/dL 
(hyperglycemia) is observed*1, 2 
• 
Changes in blood glucose 140, 160, or 180 mg/dL (hyperglycemia) over time*1, 2 
• 
Changes in AUC over time during periods when blood glucose < 70 mg/dL (hypoglycemia) is 
observed*1,2 
• 
Change in peak postprandial glucose levels over time 3 hours after breakfast, lunch, and evening 
meal*1, 2 
• 
Change in maximum variation of blood glucose levels over time between before and after 
breakfast, lunch, and evening meal *1, 2 
• 
Changes in MAGE*1, 2 
• 
Changes in mean 24-hour blood glucose levels *1, 2 
• 
Changes in mean daytime blood glucose levels*1, 2 
• 
Changes in mean nocturnal blood glucose levels*1, 2 
• 
Changes in AUC*1, 2 
• 
Changes in AUC over time during periods when blood glucose 110 mg/dL is observed*1,2  
• 
Changes in the SD of 24-hour blood glucose values*1,2 
• 
Changes in the SD of mean daytime blood glucose values*1,2 
• 
Changes in the SD of mean nocturnal blood glucose values*1,2 
*1: Measured value and percent changes for the each 7-day period between Week 3 and Week 4 
(between Day 22 and Day 28) of the treatment period calculated from the value at the start of 


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the observation period (however changes in the SD of 24-hour blood glucose values shall be 
measured value only)  
*2: Percent change from the value at the start of the observation period to the mean value during 
the 7-day period between Week 3 and Week 4 (between Day 22 and Day 28) of the treatment 
period 
 
(Analysis method) 
• 
Conduct the same analysis as the primary endpoints for *1 and *2 of the above endpoint section. 
However, for changes in mean/SD, only measured values of *1 and *2 shall be illustrated. 
[Other endpoints] 
• 
Glycoalbumin 
• 
1,5-AG 
• 
Fasting blood glucose 
• 
Fasting insulin 
• 
Fasting glucagon 
• 
Fasting proinsulin 
• 
FastingGLP-1 
• 
Fasting GIP 
(Analysis method) 
• 
Calculate summary statistics and 95% confidence interval (two sides) of mean at each 
evaluation point (the start of the observation period by each treatment group, first and ninth of 
CGM which is to be performed for 9 days from Day 21) in measured values and changes from 
the start of the observation period, and illustrate changes in mean and SD  
13.1.4 Conversion method of data and handling of missing data 
Details shall be specified separately in the statistical analysis plan. 
13.1.5 Significance level and confidence coefficient 
 Confidence coefficient: 95% (two-sided estimation) 
13.1.6 Safety analysis 
[Secondary endpoints] 
• 
Adverse event 


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(Analysis method) 
• 
Adverse events shall be reported using MedDRA terminology and summarized using the 
Preferred Term (PT) and System Organ Class (SOC) of the MedDRA. For the “safety data 
analysis set”, frequency tabulation shall be conducted for adverse events after start of treatment 
with study drug by each treatment group. 
 
Frequency tabulation of all adverse events 
 
Frequency tabulation of adverse events that causal relationship is “related” to study drug. 
 
Frequency tabulation of the degree of all adverse events 
 
Frequency tabulation of degree of adverse events that causal relationship is “related” to 
study drug. 
 
Frequency tabulation of adverse events that were “discontinued” as a measurement 
concerning study drug. 
 
Frequency tabulation of serious adverse events 
13.2 
Criteria for interim analysis and premature discontinuation 
No interim analysis is planned. 
13.3 
Determination of the number of planned research subject 
Planned number of research subjects that are evaluable for primary endpoints in each group is as 
follows. 
Trelagliptin 100 mg group: 15 
Alogliptin 25 mg group: 15 
Set in consideration with the feasibility of the number of research subjects for exploring the effects 
of trelagliptin 100 mg and alogliptin 25 mg on glycemic variation. It is not based on statistical power 
calculation.  


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14.0 
QUALITY CONTROL AND QUALITY ASSURANCE 
14.1 
Monitoring of the research implementing entity 
The sponsor or its designee shall perform periodic monitoring of research implementing entities 
during the research to confirm that the research is conducted in accordance with all specifications in 
the research protocol. The data recorded on the CRF will be checked by comparing them with those 
in the source documents. Source documents are the original documents, data and records. The 
principal investigator and the chief executive of the research implementing entity shall ensure that 
the sponsor or its designee and the Ethics Review Committee, etc., have access to the source 
documents. 
The sponsor or its designee shall access the records, including the list of research subject ID 
numbers, medical records of the research subjects, and signed and dated original consent forms to 
confirm that the research is appropriately conducted in compliance with the research protocol. Also, 
confirm the consistency between CRF and the related source documents. The principal investigator, 
investigator, and other personnel involved in the research shall spare sufficient time to facilitate 
monitoring procedures during visits to the research implementing entity. 
Detailed procedures for monitoring shall be be specified separately in a procedure manual. 
14.2 
Deviation from the Ethical Guidelines for Medical and Health Research 
Involving Human Subjects and the research protocol. 
The principal investigator or investigator shall record all deviations from Ethical Guidelines for 
Medical and Health Research Involving Human Subjects, and research protocol. 
If any deviation is found, the principal investigator shall promptly notify the chief executive of the 
research implementing entity for the clinical research and the sponsor. As necessary, the principal 
investigator will discuss protocol revisions with the sponsor to reach agreement. For protocol 
revisions, draft revisions should be submitted as early as possible to the chief executive of the 
research implementing entity for approval of the committee such as the IEC. 
14.3 
Quality assurance audits and regulatory agency inspections 
The research implementing entity may be subject to audits by the sponsor or its designee. In such a 
case, the auditor designated by the sponsor shall contact the research implementing entity in advance 
to determine the date of audit. The auditor may ask to visit the facilities where laboratory specimens 
are collected and any other facilities used during the clinical research. In addition, this research may 
be inspected by regulatory agencies, including those of foreign governments (e.g., the Food and 
Drug Administration [FDA], the United Kingdom Medicines and Healthcare products Regulatory 
Agency [MHRA]). If the research implementing entity is contacted for an inspection by a regulatory 


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body, the sponsor should be notified promptly. The principal investigator and the chief executive of 
the research implementing entity shall ensure that the auditor has access to all the research-related 
source documents. 


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15.0 
ETHICAL CONDUCT OF CLINICAL RESEARCH 
This research shall be conducted with the highest respect for the individual participants (i.e., 
research subjects) according to the research protocol, and the ethical principles that have their origin 
in the Declaration of Helsinki, Ethical Guidelines for Medical and Health Research Involving 
Human Subjects. Each principal investigator shall conduct the study according to regulatory 
requirements and in accordance with “Responsibilities of the Investigator” in Appendix B. 
15.1 
Approval of the Ethical Review Board, etc. 
The Ethical Review Board, etc., shall be constituted in accordance with the regulations. 
The sponsor or its designee should obtain the document listing the name and title of each committee 
member. When a committee member directly participates in this clinical research, the document 
describing that he/she is not participating in deliberation or voting for the study shall be obtained. 
The sponsor or its designee shall provide related documents for review and approval of the research 
protocol to the Ethical Review Board, etc. In addition to the research protocol, a copy of the 
informed consent form and information sheet, written materials related to research subject 
recruitment, advertisement, and other documents required by regulations, when necessary, shall be 
submitted to the central committee or a research implementing entity committee such as the Ethics 
Review Committee to obtain approval. The sponsor or its designee shall obtain records of approval 
by the Ethical Review Board, etc., for the research protocol and the informed consent form and 
information sheet before the start of the protocol therapy. The records of approval by the Ethical 
Review Board, etc., shall include the clinical research title, protocol number, preparation / revision 
date of the research protocol, and version number and approval date of other reviewed documents 
(example: informed consent and information sheet). The sponsor shall notify the research 
implementing entity, the principal investigator, and investigator after confirming the validity of the 
regulatory documents of the research implementing entity. Protocol procedures such as obtainment 
of consent shall not be started until the research implementing entity, the principal investigator, and 
investigator receive notification. 
The research implementing entity shall observe all requirements that the Ethical Review Board, etc. 
prescribe. The requirements may include notifications to committees such as the IEC, for example, 
revision of the protocol, revision of the informed consent form and information sheet, revision of 
materials related to research subject recruitment, reports on safety in accordance with the regulatory 
requirements, reports on status of implementation of the research at intervals determined by a 
research implementing entity committee such as the Ethics Review Committee, and submission of 
the study completion report. The sponsor or its designee shall obtain written approval from a 


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research implementing entity committee such as the Ethics Review Committee related to the above 
mentioned items and all related materials. 
15.2 
Conflict of interest 
This clinical research shall be conducted with the support of the sponsor. 
Prior to the conduction of this clinical research, the investigators involved in this clinical research 
shall ensure appropriate management of any conflicts (COI) in the conduct of the research in 
accordance with the rules of the research implementing entity11-15). 
The research implementing entity shall comply with all requirements specified by a committee such 
as the Ethics Review Committee This includes the COI self-statement form, the research protocol, 
and the informed consent form and information sheet.  
15.3 
Informed consent and information sheet, and the agreement of the research 
subjects 
The informed consent and information sheet form shall contain specific requirements of the 
Declaration of Helsinki, Ethical Guidelines for Medical and Health Research Involving Human 
Subjects and all applicable laws and regulations. The informed consent form and information sheet 
shall specify the use of personal information and medical information of research subjects in this 
clinical research (both in and outside Japan: supply to a third party), and disclosure. The informed 
consent form and the information sheet will explain in detail the nature of the research, its objectives, 
and potential risks and benefits. Also, the informed consent form will detail the requirements for 
participation and the fact that research subject is free to withdraw at any time without giving a 
reason and without any negative effect on the further medical care. 
The principal investigator is responsible for the preparation, contents, and approval of the informed 
consent form and information sheet by the committee such as the IEC. The informed consent form 
and information sheet must be approved by the committee prior to use. 
The informed consent form and information sheet shall be written in language that can be easily 
understood by the potential research subjects. The principal investigator or investigator shall be 
responsible for providing detailed explanation of the informed consent form and information sheet to 
the potential subjects. Information should be given in both oral and written form whenever possible 
and in manner deemed appropriate by the committee such as the IEC. 
The principal investigator or investigator shall ensure that the potential research subjects have (1) an 
opportunity to inquire about the research and (2) sufficient time to decide on their participation. If a 
potential research subject decides he or she is willing to participate in the research, then the informed 
consent form must be signed and dated by the potential research subject prior to entering into the 


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research as a subject. The principal investigator or investigator shall instruct the potential research 
subject to sign using their legal names, not nicknames, using a blue or black ball point ink pen. Also 
the principal investigator or investigator shall sign and date the informed consent form prior to 
potential research subject entering into the research. 
Once signed, the original informed consent form shall be retained by the principal investigator or 
investigator. The principal investigator or investigator shall record the date that the potential research 
subject signed the informed consent form in the subject’s medical record. A copy of the signed 
informed consent form shall be given to the research subject. 
If the informed consent form and information sheet is revised, the principal investigator or 
investigator shall newly obtain re-consent from the concerned research subject by following the 
same procedure as for obtaining the initial consent. The date of obtaining new consent shall be 
recorded in the research subject’s medical record, and a copy of the revised consent form shall be 
provided to the research subject. 
15.4 
Personal information of the research subjects 
The sponsor or the designee shall affirm the principle of the protection of research subjects' 
private/personal information, etc. Throughout this study, research subject ID numbers shall be used 
to link the subject's source data to the sponsor's research database and research-related documents. 
Limited information on research subjects such as gender, age, and date of birth may be used within 
the scope of all applicable laws and regulations for identification of research subjects and 
confirmation of accuracy of research subject ID number. 
For verification of the conduct of the research in compliance with this protocol and the Ethical 
Guidelines for Medical and Health Research Involving Human Subjects, the sponsor shall require 
the principal investigator to provide the research sponsor’s designee, representatives of regulatory 
authorities, designated auditors, and committees such as the Ethical Review Board direct access to 
research subjects’ original medical records (source data or documents), including laboratory test 
results, ECG results, admission and discharge records during a subject’s research participation, and 
autopsy reports. The principal investigator or investigator shall obtain specific authorization from the 
research subject as part of the informed consent process for access to research subject's original 
medical records by research sponsor’s designee and representatives of regulatory authorities (see 
section 15.3). 
When providing a copy of source documents to the sponsor, the principal investigator or investigator 
shall delete information that may lead to identification of an individual (name and address of 
research subject, other personal information not recorded on the CRF of the research subject). 


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15.5 
Consultation windows for the research subjects or persons related to the 
research concerned 
The principal investigator shall establish a contact service to respond to inquiries concerning this 
clinical research from research subjects or concerned people. Details of the contacts for inquiries 
will be described in the informed consent form. 
15.6 
Financial burden or reward to the research subjects 
Of the expenses for this clinical research, the sponsor shall offer compensation for medical treatment 
not covered by health insurance as research expenses. The research subjects shall pay expenses for 
medical treatment covered by ordinary health insurance. 
In addition, the principal investigator shall pay expenses such as transportation expenses for 
participation in this clinical research to the research subjects at each visit from the research funds. 
Details of the financial burden on the research subjects and rewards shall be described in the 
informed consent form. 
15.7 
Benefits and inconveniences to the research subjects 
15.7.1 Benefits to research subjects 
By participating in this clinical research, the research subjects may understand one’s own condition 
of type 2 diabetes mellitus in detail. 
15.7.2 Inconveniences to research subjects 
By participating in this clinical research the burden of the research subject may increase as number 
of visits will increase compared to daily medical care. 
15.8 
Attribution of research results and access rights 
15.8.1 Attribution of research results 
The research results and data obtained from this research shall belong to the sponsor. In addition, 
secondary use (metaanalysis, etc.) of the data obtained in this clinical research may be possible if 
used in such a way that the data shall not be linked to personal identification information. 
15.8.2 Data access rights 
Access rights for all data and information generated from this study will be given to personnel 
approved by the sponsor. 


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15.9 
Reporting of results, publication, disclosure, and clinical research 
registration policy 
15.9.1 Reporting of results, publication and disclosure 
The principal investigator shall report a written summary of results of the research to the chief 
executive of the research implementing entity and provide the sponsor with all the results and data 
obtained from the research. Only the sponsor may disclose the research information to other 
principal investigators, investigators or regulatory authorities during the research period, except 
when required by laws and regulations. The sponsor shall be responsible for publication of the 
research protocol and research-related results (including the public web site) except for other cases 
permitted in the research contract. 
During research period and after the end of research, the sponsor or its designee should promptly 
summarize the results and present it to medical journals and academic conferences, etc. The sponsor 
may publish any data or information obtained from the research (including data and information 
provided by the principal investigator) without obtaining consent of the principal investigator. 
The principal investigator or the investigator should obtain the prior written approval from the 
sponsor when publishing the information obtained in this research at an academic conference, etc. 
15.9.2 Clinical research registration 
To ensure that information on clinical research is made accessible to the public in a timely manner 
and to comply with applicable laws, regulations, and guidelines, Takeda Pharmaceutical Company 
Limited shall register all clinical research being conducted in patients around the world at public trial 
registration sites, including at least the website(s) of ClinicalTrials.gov (and) Japan Pharmaceutical 
Information Center Clinical Trials Information (JAPIC). On such websites, the research location 
(city, country), subject recruitment status, and contact information for Takeda Pharmaceutical 
Company Limited are open to the public. 
15.9.3 Clinical trial results disclosure 
Takeda Pharmaceutical Company Limited shall post the research results, irrespective of the nature of 
the results, at the public trial registration site(s) of Clinical Trials.gov (and) JAPIC in accordance 
with applicable laws and regulations. 
15.10 Insurance and compensation for injury 
The research subjects participating in this research shall be compensated for any injury resulting 
from participation in the research according to local regulations applicable to the research 


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implementing entity. The sponsor or its designee shall buy an insurance policy to compensate for 
health injury in research subjects. 
Healthy injury in a research subject will be compensated as specified in the study contract. 
Compensation-related questions by the principal investigator or investigators should be made to the 
sponsor or its designee. 


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16.0 
REFERENCES 
1. 
Rimei Nishimura, Glucose variability and vascular disease risk. The Journal of the Japanese 
Society of Internal Medicine102: 922-930  
2. 
Gerstein HC. et al; The Action to Control Cardiovascular Risk in Diabetes Study Group. 
Effects of intensive glucose lowering in type 2 diabetes. The New England Journal of 
Medicine. 2008; 358: 2545-2559. 
3. 
Currie CJ, et al. Survival as a function of HbA（1c）in people with type 2 diabetes: a 
retrospective cohort study. Lancet. 2010; 375: 481- 489. 
4. 
Baggio LL, Drucker DJ. Biology of incretins: GLP-1 and GIP. Gastroenterology. 2007; 
132(6): 2131-2157. 
5. 
Monnier L, Mas E, et al; Activation of Oxidative Stress by Acute Glucose Fluctuations 
Compared With Sustained Chronic Hyperglycemia in Patients With Type 2 Diabetes. The 
Journal of the American Medical Association. 2006Apr 12; 295(14): 1681-1687.  
6. 
Klonoff DC, et al;Continuous Glucose Monitoring: roadmap for 21st century diabetes 
therapy. Diabetes Care. 2015 May; 28(5): 1231-1239. 
7. 
Drucker DJ. The biology of incretin hormones. Cell Metabolism. 2006; 3(3):153-165. 
8. 
Kaufman FR, Gibson LC, Halvorson M, et al. A pilot study of the continuous glucose 
monitoring system: clinical decisions and glycemic control after its use in pediatric type 1 
diabetic subjects. Diabetes Care. 2001; 24(12): 2030-2034. 
9. 
Su G, Mi S, et al; Association of glycemic variability and the presence and severity of 
coronary artery disease in patients with type 2 diabetes. Cardiovascular Diabetology. 2011; 
10:19. 
10. Inagaki N, Onouchi H, et al. Once-weekly trelagliptin versus daily alogliptin in Japanese 
patients with type 2 diabetes: a randomised, double-blind, phase 3, non-inferiority study.  
Lancet Diabetes Endocrinol. 2015 Mar; 3(3):191-197.. 
11. Report of the Working Group on Conflict of Interest (Ministry of Education, Culture, Sports, 
Science and Technology dated November 1, 2002) 
12. Guidelines for determining the conflict of interest polity for clinical research (Review group 
for ethical aspects of clinical research and conflict of interest, March 2006) 
13. Guidelines on the Management of Conflict of Interest (COI) in Health and Labour Sciences 
Research (March 31, 2008) 
14. Guidelines for management of COI in medical research (COI Committee of Japan 
Association of Medical Sciences, February 2011) 
15. Common guidelines for conflict of interest (COI) in clinical research (Japanese Society of 
Internal Medicine, Japan Society of Hematology, Japanese Circulation Society, Japan 
Endocrine Society, Japan Diabetes Society, Japanese Respiratory Society, Japanese Society 
of Hematology, Japanese Society of Allergology, Japanese Association for Infectious 
Diseases, Aug 2011) 


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Appendix A 
Schedule of Research Procedures 
 
 
Observation period 
Treatment period 
Time 
of 
Visit 
Week 
 
 
0 
 
 
4 
 
Disconti
nuation(g
) 
Day 
-14 
-2 
1(b) 
21(c) 
24(c) 
29(c) 
- 
Allowable range (Day) 
-28 to -2 
-2 
1 
21 to 35 24~39(f) 29 to 43 
- 
VISIT Number 
 
1 
2 
3 
4 
5 
- 
Informed 
consent 
procedure 
× 
 
 
 
 
 
 
Inclusion/Exclusion 
criteria 
× 
× 
 
 
 
 
 
Demographic 
information 
× 
 
 
 
 
 
 
Medical 
history, 
pre-treatment 
× 
× 
 
 
 
 
 
Physical examination 
× 
× 
(×) 
× 
× 
× 
× 
Body weight, BMI 
 
× 
 
× 
 
× 
× 
Height 
× 
 
 
 
 
 
 
Concomitant drugs 
× 
× 
(×) 
× 
× 
× 
× 
Concurrent disease 
× 
× 
 
 
 
 
 
Laboratory tests (a) 
 
× 
 
× 
 
× 
× 
HbA1c 
 
× 
 
 
 
 
 
Drug -taking status 
 
 
 
× 
× 
× 
× 
Prescription of dietetic 
therapy and exercise 
therapy and assessment 
of compliance 
× 
× 
(×) 
× 
× 
× 
× 
CGM 
 
× (d) 
(Sensor 
insertion) 
×
(d) 
(Sensor 
remove) 
× (d) 
(Sensor  
insertion) 
× (d) 
(Exchange 
sensor) 
×
(d) 
(Sensor 
remove) 
 
Self-measurement of 
blood glucose 
 
× (e) 
× (e) 
× (e) 
× (e) 
× (e) 
 
Adverse event 
monitoring 
 
 
× 
(a) Measured on VISIT1 (Day-2), and the first and ninth days of the 9-day CGM starting on Day 21 
Blood tests: glycoalbumin, 1,5-AG, fasting insulin*, fasting glucagon*, fasting proinsulin*, fasting GLP-1*, fasting GIP* 
(b) The starting day of study treatment in the treatment period is designated as Day 1. The study drug shall be administered after required 
tests/observations, etc. The day before the start of study treatment in the treatment period is designated as Day -1.It is performed at the visit 
when principal investigator or investigator consider as needed. 
(c) Trelagliptin 100 mg/week group shall insert the sensor on the day before Trelagliptin administration day.  Trelagliptin 100 mg/week shall 
be administered before breakfast on the day after the sensor insertion day.  
Alogliptin 25 mg/day shall be administered after required tests/observations, etc at every VISIT without taking study drug. Research 
subjects shall take study drug prior to the every breakfast at home.  
(d) To be performed by study site personnel 
(e) At leaset, blood glucose levels shall be measured at three time points on the first day of CGM ([1] at least 2 hours after the recorder is 


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connected and [2] 2 hours after the first is measured. [3] at bedtime) and at four time points from the second day onward ([1] before 
breakfast, (2) before lunch, (3) before evening meal, and (4) at bedtime).  
(f) After taking trelagliptin 100 mg/week or alogliptin 25 mg/day on the nest day from sensor insertion on Visit3 (Day 21), research subjects 
should visit the study site between the third day and the fifth day. 
(g) To be performed to the extent possible 


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"Protocol No. Trelagliptin-4001"  
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Initial Version 
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CONFIDENTIAL 
Appendix B 
Responsibilities of the sponsor 
1. 
To appropriately conduct the clinical research in compliance with this research protocol and the 
Ethical Guidelines for Medical and Health Research Involving Human Subjects and with the 
highest respect for human rights, safety, and welfare of research subjects. 
2. 
To prepare a list of any other investigators and/or research collaborators when certain important 
research-related activities are divided by investigators and/or research collaborators, and submit 
the list to the sponsor as required. 
3. 
To prepare the informed consent form and revise it as necessary. 
4. 
To check the contents of the study contract. 
5. 
To provide sufficient information on the protocol, drug and duties of each personnel to 
subinvestigators and study collaborators, and give guidance and supervision. 
6. 
To select research subjects who satisfy the inclusion criteria, give explanation using written 
information, and obtain consent in writing. 
7. 
To be responsible for all medical judgments related to the research. 
8. 
Corresponding to request from the chief executive of the research implementing entity, to report 
the latest progress status at least once a year to the chief executive of the research implementing 
entity. 
9. 
To ensure that the most update status is confirmed and comprehended regarding the COI of the 
investigators participating in the clinical research according to the research implementing 
entity. 
10. To ensure, together with the chief executive of the research implementing entity, that sufficient 
medical care is provided to research subjects for all research-related clinically problematic 
adverse events throughout the period of subjects’ research participation and thereafter. 
11. When a research subject is treated at another medical institution or department, to inform the 
acting physician at the medical institution or department in writing of the research subject’s 
study participation and research completion/discontinuation after obtaining the research subject’
s consent, and prepare a record. 
12. When emergency reporting of serious adverse events, is required, to immediately report it in 
writing to the chief executive of the research implementing entity and the sponsor. 
13. To ensure that the CRFs are accurate and complete, electronically sign and submit them to the 
sponsor. 
14. To verify any entries on the CRFs made by the investigator or transcribed by the collaborator 
from source documents, electronically sign and submit them to the sponsor. 
15. To discuss a revision of the protocol, etc., when proposed by the sponsor. 


122/NRP-001 
"Protocol No. Trelagliptin-4001"  
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Initial Version 
March 29, 2016
 
CONFIDENTIAL 
16. To report the research completion in writing to the chief executive of the research implementing 
entity. 

SAP_001.pdf: 
Certain information within this clinical study report has been redacted (ie, specific content is masked 
irreversibly from view with a black 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 and the language in original document was Japanese.


 
 
 
 
 
An exploratory study of the effects of trelagliptin and alogliptin on 
glucose variability in patients with type 2 diabetes mellitus 
(Protocol number: Trelagliptin-4001) 
 
Statistical Analysis Plan 
(Ver.4.0: 25 Oct 2017) 
 
 
Sponsor: Takeda Pharmaceutical Company Limited 
 
 
 
 
 
 
 
Authorizer:  
  
 
  
 
Takeda Pharmaceutical Company Limited 
 
             
      .  
 
Biostatistics Manager: 
 
 
 
 
            
           . 


Contents 
1. 
DEFINITIONS of TERMS ................................................................................................. 1 
2. 
TIME WINDOW ............................................................................................................... 1 
3. 
ANALYSIS SET................................................................................................................ 3 
4. 
CONSIDERATIONS for ANALYSIS .................................................................................. 4 
5. 
OTHER DATA HANDLING .............................................................................................. 4 
6. 
SUBJECTS, DEMOGRAPHIC and OTHER BASELINE CHARACTERISTICS ................... 5 
6.1. Subject Disposition ......................................................................................................... 5 
6.2. Demographics and Other Baseline Characteristics ............................................................. 6 
6.3. Treatment Compliance ................................................................................................... 10 
7. 
EFFICACY EVALUATIONS ............................................................................................ 11 
7.1. Primary Endpoint and the Analytical Methods .................................................................. 11 
7.2. Secondary Endpoints and the Analytical Methods ............................................................ 12 
7.3. Other Analyses .............................................................................................................. 14 
8. 
SAFETY EVALUATION ................................................................................................. 19 
8.1. Frequency of Adverse Event Occurrence ......................................................................... 19 
9. 
LISTING ........................................................................................................................ 21 
10. CONSIDERATIONS on STATISTICAL ANALYSIS ......................................................... 22 
10.1. Adjustments for Covariates .......................................................................................... 22 
10.2. Handling of Dropouts or Missing Data .......................................................................... 22 
10.3. Criteria for Interim Analysis and Early Discontinuation ................................................. 22 
10.4. Multicenter Studies ..................................................................................................... 22 
10.5. Multiple Comparisons/Multiplicity ............................................................................... 22 
10.6. Examination of Subgroups ........................................................................................... 22 
11. REVISION HISTORY ..................................................................................................... 23 
 


 
1 
 
1. 
DEFINITIONS of TERMS 
・ Summary Statistics: Number of subjects, mean, SDs, maximum values, minimum values, 
and quartiles 
・ Treatment Group: Trelagliptin 100 mg group and Alogliptin 25 mg group 
 
2. 
TIME WINDOW 
For each inspection, observation and evaluation item, evaluable data is handled according to the 
following table. When there are multiple data that can be evaluated at the same time point, the 
one with the closest inspection date, observation, and evaluation date to the reference date is 
adopted, and if the difference from the reference date is the same, the later data is adopted. 
 
[CGM] 
Time Point 
Reference Date 
Start of the observation 
period 
4 hours before breakfast to 20 hours after breakfast at “Day -1” 
after the date of administration. 
The 2nd day of the treatment 
period for CGM insertion 
4 hours before breakfast to 20 hours after breakfast at “Day 1” 
after the date of administration after CGM insertion 
The 3rd day of the treatment 
period for CGM insertion 
In 24 hours from the end time of “Day 2” after the date of 
administration after CGM insertion 
The 4th day of the treatment 
period for CGM insertion 
In 24 hours from the end time of “Day 3” after the date of 
administration after CGM insertion 
The 5th day of the treatment 
period for CGM insertion 
In 24 hours from the end time of “Day 4” after the date of 
administration after CGM insertion 
The 6th day of the treatment 
period for CGM insertion 
In 24 hours from the end time of “Day 5” after the date of 
administration after CGM insertion 
The 7th day of the treatment 
period for CGM insertion 
In 24 hours from the end time of “Day 6” after the date of 
administration after CGM insertion 
The 8th day of the treatment 
period for CGM insertion 
In 24 hours from the end time of “Day 7” after the date of 
administration after CGM insertion 
 
[Laboratory Tests] Glycoalbumin, 1,5-AG, Fasting Insulin, Fasting Glucagon, Fasting Proinsulin 
Time Point 
Reference Date 
Time Allowance 
Number of days after the 
first administration 
Start of the observation 
Days after administration: -2 
Applicable for Visit 1 


 
2 
 
Time Point 
Reference Date 
Time Allowance 
Number of days after the 
first administration 
period 
 (Day -4 to Day -2) 
“Day 1” of week 3-4 of the 
treatment period 
Days after administration: 21 
Applicable for Visit 3 
 (Day 19 to Day 35) 
“Day 9” of week 3-4 of the 
treatment period 
The number of days after 
administration is determined as 
follows according to the timing of 
Day 1*1. 
1. 
“Day 1*1” is days 19 - 25 
after administration; 29 
2. 
“Day 1*1” is days 26 - 32 
after administration; 36 
3. 
“Day 1*1” is days 33 - 35 
after administration; 43 
Applicable for Visit 5 
 (Day 1*1 + 1 to Day 43) 
*1  Day1:  Days after administration regarded as “Day 1” of treatment period 3-4 week. 
 
[Laboratory Tests] Fasting GLP-1, Fasting GIP, DPP-4 Activity, Inhibitory Rate of DPP-4 Activity 
Time Point 
Reference Date 
Time Allowance 
Number of days after the 
first administration 
Start of the observation 
period 
Days after administration: -2 
Applicable for Visit 1 
 (Day -4 to Day -2) 
“Day1” of week 3-4 of the 
treatment period 
Days after administration: 21 
Applicable for Visit 3 
 (Day 19 to Day 35) 
“Day 4” to “Day 6” of week 
3-4 of the treatment period 
The number of days after 
administration is determined as 
follows according to the timing of 
Day 1*1.  
1. 
“Day 1*1” is days 19 - 23 
after administration; 24 
2. 
“Day 1*1” is days 24 - 30 
after administration; 31 
3. 
“Day 1*1” is days 31 - 35 
after administration; 38 
Applicable for Visit 4 
 (Day 1*1 + 1 to Day 2*2) 


 
3 
 
Time Point 
Reference Date 
Time Allowance 
Number of days after the 
first administration 
“Day 9” of week 3-4 of the 
treatment period 
The number of days after 
administration is determined as 
follows according to the timing of 
Day 1*1.  
1. 
“Day 1*1” is days 19 - 25 
after administration; 29 
2. 
“Day 1*1” is days 26 - 32 
after administration; 36 
3. 
“Day 1*1” is days 33 - 35 
after administration; 43 
Applicable for Visit 5 
 (Day 1*1 + 1 to Day 43) 
*1  Day1: Days after administration regarded as “Day 1” of treatment period 3-4 week. 
““Day 9” of week 3-4 of the treatment period” will be evaluated prior to ““Day 4” to “Day 6” 
of week 3-4 of the treatment period”  
*2  Day2: Days after administration regarded as “Day 9” of treatment period 3-4 week. 
 
[Treatment Compliance, Dietetic Therapy, Exercise Therapy] 
Time Point 
Reference Date 
Time Allowance 
Number of days after 
administration 
Visit 3 
Visit of the time of actual visit 
- 
Visit 4 
Visit of the time of actual visit 
- 
Visit 5 or time of 
discontinuation 
Visit of the time of actual visit 
- 
・ The reference implementation date and the number of days after administration in the 
treatment period are indicated as “Day -1” for the day before study drug administration and 
“Day 1” for the administration day. 
・ The time points of treatment compliance are only Visit5 and time of discontinuation.  
 
3. 
ANALYSIS SET 
・ Full Analysis Set 
The subjects who were randomized and given at least one dose of the study drug. 
・ Safety Analysis Set 
The subjects who are given at least one dose of the study drug. 


 
4 
 
 
4. 
CONSIDERATIONS for ANALYSIS 
・ Confidence coefficient  
95% (two-sided estimation) 
・ Display digit 
 [Mean, Confidence coefficient, Quartiles] 
Round statistics down to the 1 digits lower than significant digits of the data. 
 [Standard Deviation] 
Round statistics down to the 2 digits lower than significant digits of the data. 
 [Minimum and Maximum Values] 
Display the data at the significant digits.  
 [Proportion, Percentage] 
Round statistics off to 1 decimal places. 
 
 
5. 
OTHER DATA HANDLING 
 [Definition of Daytime] 
・ Time zone from wake-up time to bedtime 
 [Definition of Nocturnal Period] 
・ Time zone from bedtime to wake-up time 
 [Data Handling for Study Drug] 
・ Duration of Treatment 
Duration of Treatment = Date of the Last Dose – Date of the First Dose + 1 
 [Data Handling for Adverse Event] 
・ An adverse event is defined as any untoward medical occurrence in a patient or a subject 
receiving a pharmaceutical product (including the study drug). It does not necessarily have 
an apparent causal relationship with this pharmaceutical product (including study drug). 
・ Adverse events, excluding serious adverse events (protocol 10.1.3), shall be non-serious 
adverse events in the case of an incidence of over 5% in at least one treatment group. 
 [Data Handling for Laboratory Test Results] 
・ Inhibitory Rate of DPP-4 Activity (%) 
Inhibitory rate of DPP-4 activity (%) = (DPP-4 activity at start of observation period – 
DPP-4 activity at each visit of treatment period) / DPP-4 activity at start of observation 
period x 100 
 [Data Handling for Duration of Diabetes (year)] 
・ Duration of Diabetes (year) 


 
5 
 
Duration of diabetes (year) = (Date of Informed Consent (year/month) – Onset Date of 
Diabetes (year/month)) / 12 (rounded off two decimal places) 
If only the month of the onset of diabetes is unknown, the month of the onset of diabetes is 
regarded as “January”. 
 
 
6. 
SUBJECTS, DEMOGRAPHIC and OTHER BASELINE CHARACTERISTICS 
6.1. Subject Disposition 
6.1.1. Study Information 
Analysis Set: All subjects who were obtained informed consent 
Analysis Variables: The earliest date of informed consent 
The latest date of the last date of administration 
Version of MedDRA 
Version of SAS 
Analysis Methods: For the above analysis items, the following analysis is 
performed. 
(1) Show above items. 
 
6.1.2. Eligibility of Subjects 
Analysis Set: All subjects who were obtained informed consent 
Analysis Variables: Randomization into the treatment period of the study 
[Yes, No (and the reason)] 
Analysis Methods: For the above analysis items, the following analysis is 
performed. 
(1) Frequency distribution 
 
6.1.3. Exit Status of Subjects 
Analysis Set: Randomized subjects 
Analysis Variables: Exit status from the study 
[Complete, Incomplete (and the reason)] 
Analysis Methods: For the above analysis items, the following analysis is 
performed for each treatment group and all subjects in the 
analysis set. 
(1) Frequency distribution 
 


 
6 
 
6.1.4. Protocol Deviations and Analysis Datasets 
6.1.4.1. 
Protocol Deviations  
Analysis Set: Randomized subjects 
Analysis Variables: Protocol Deviations 
[Major GCP Violations, Deviations of Protocol Entry Criteria, 
Deviations of Discontinuation Criteria, Deviations Related to 
Treatment Procedure or Dose, Deviations Concerning 
Excluded Medication or Therapy, Deviations to Avoid 
Emergency Risk, Other Deviations] 
Analysis Methods: For the above analysis items, the following analysis is 
performed for each treatment group and all subjects in the 
analysis set. 
(1) Frequency distribution 
Summarize the number of subjects who have deviated from 
the protocol, classify the deviations into above category, and 
show the breakdown of deviations. Subjects applicable for 
multiple categories will be counted once in each category. 
 
6.1.4.2. Datasets Analyzed 
Analysis Set: Randomized subjects 
Analysis Variables: Subjects excluded from analysis datasets [Reason of exclusion] 
Full Analysis Set    [Adopted] 
Safety Analysis Set  [Adopted] 
Analysis Methods: For the above analysis items, the following analysis is 
performed for each treatment group (both (1) and (2)) and all 
subjects (for (2)) in the analysis set. For analysis (1), Subjects 
applicable for multiple categories will be counted once in 
each category. 
(1) Frequency distribution in each analysis set about 
handling for subjects 
(2) Frequency distribution in each analysis set of adopted 
subjects. 
 
6.2. Demographics and Other Baseline Characteristics 
6.2.1. Distribution of Demographics Items 
Analysis Set: Full Analysis Set 


 
7 
 
Analysis Variables:  
Age (years old) [Min<= - <65, 65<= - <75, 75<= - <=Max] 
Sex          [Male, Female] 
Height (Start of the observation period) (cm) 
[Min<= - <150, 150<= - <160,  
160<= - <170, 170<= - <=Max] 
Weight (Start of the observation period) (kg) 
[Min<= - <50.0, 50.0<= - <60.0, 
60.0<= - <70.0, 70.0<= - <80.0, 
80.0<= - <=Max] 
BMI (Start of the observation period) (kg/m2) 
[Min<= - <18.5, 18.5<= - <25.0,  
25.0<= - <=Max] 
Smoking Classification [Never Smoked, Current Smoker, Ex-Smoker] 
Drink Alcohol Almost Every Day?  [Yes, No] 
Duration of Diabetes Mellitus (Years)  [Min<= - <5, 5<= - <10,  
10<= - <=Max] 
HbA1c (NGSP) (Start of the observation period) (%) 
[Min<= - <7, 7<= - <8, 8<= - <=Max] 
 
AUC over time when blood glucose 110 mg/dL is observed during the 3 
hour time period after breakfast (Start of the observation period) 
AUC over time when blood glucose 140 mg/dL is observed during the 3 
hour time period after breakfast (Start of the observation period) 
AUC over time when blood glucose 160 mg/dL is observed during the 3 
hour time period after breakfast (Start of the observation period) 
AUC over time when blood glucose 180 mg/dL is observed during the 3 
hour time period after breakfast (Start of the observation period) 
AUC over time when blood glucose 110 mg/dL is observed during the 3 
hour time period after lunch (Start of the observation period) 
AUC over time when blood glucose 140 mg/dL is observed during the 3 
hour time period after lunch (Start of the observation period) 
AUC over time when blood glucose 160 mg/dL is observed during the 3 
hour time period after lunch (Start of the observation period) 
AUC over time when blood glucose 180 mg/dL is observed during the 3 
hour time period after lunch (Start of the observation period) 


 
8 
 
AUC over time when blood glucose 110 mg/dL is observed during the 3 
hour time period after evening meal (Start of the observation period) 
AUC over time when blood glucose 140 mg/dL is observed during the 3 
hour time period after evening meal (Start of the observation period) 
AUC over time when blood glucose 160 mg/dL is observed during the 3 
hour time period after evening meal (Start of the observation period) 
AUC over time when blood glucose 180 mg/dL is observed during the 3 
hour time period after evening meal (Start of the observation period)  
AUC over time during periods when blood glucose 140 mg/dL is 
observed (start of the observation period) 
AUC over time during periods when blood glucose 160 mg/dL is 
observed (Start of the observation period) 
AUC over time during periods when blood glucose 180 mg/dL is 
observed (Start of the observation period)  
Cumulative time during periods when blood glucose 140 mg/dL is 
observed (Start of the observation period) 
Cumulative time during periods when blood glucose 160 mg/dL is 
observed (Start of the observation period) 
Cumulative time during periods when blood glucose 180 mg/dL is 
observed (Start of the observation period) 
AUC over time during periods when blood glucose <70 mg/dL is 
observed (Start of the observation period) 
Peak postprandial glucose over time 3 hours after breakfast (Start of the 
observation period) 
Peak postprandial glucose over time 3 hours after lunch (Start of the 
observation period)  
Peak postprandial glucose over time 3 hours after evening meal (Start of 
the observation period) 
Maximum variation of blood glucose over time between before and 
after breakfast (Start of the observation period) 
Maximum variation of blood glucose over time between before and 
after lunch (Start of the observation period) 
Maximum variation of blood glucose over time between before and 
after evening meal (Start of the observation period) 
MAGE (Start of the observation period)  
Mean 24-hour blood glucose (Start of the observation period)   


 
9 
 
Mean daytime blood glucose (Start of the observation period)                   
Mean nocturnal blood glucose (Start of the observation period) 
AUC (Start of the observation period) 
AUC over time during periods when blood glucose 110 mg/dL is 
observed (Start of the observation period) 
SD of 24-hour blood glucose (Start of the observation period) 
SD of daytime blood glucose (Start of the observation period) 
SD of nocturnal blood glucose (Start of the observation period) 
Glycoalbumin (Start of the observation period)     
1,5-AG (Start of the observation period)  [Min<= - <10, 10<= - <14, 
14<= - <=Max] 
Fasting blood glucose (Start of the observation period)          
Fasting insulin (Start of the observation period)     
Fasting glucagon (Start of the observation period)     
Fasting proinsulin (Start of the observation period) 
Fasting GLP-1 (Start of the observation period)         
Fasting GIP (Start of the observation period)            
DPP-4 Activity (Start of the observation period)         
Analysis Methods: For the above analysis items, the following analysis is 
performed for each treatment group and all subjects in the 
analysis set. 
(1) Frequency distribution for discrete variables and summary 
statistics for continuous variables 
 
6.2.2. Medical History and Concurrent Disease 
Analysis Set: Safety Analysis Set 
Analysis Variables: Medical history, Concurrent disease 
Analysis Methods: For the above analysis items, the following analysis is 
performed for each treatment group. Analysis variables will 
be coded using the MedDRA dictionary and be summarized 
into SOC and PT. SOCs will be sorted in alphabetical order, 
then PTs will be sorted in frequency order. 
(1) Frequency of medical history by SOC/PT 
(2) Frequency of concurrent disease by SOC/PT 
     The method of accounting for the frequency is as follows. 


 
10 
 
     [Number of subjects with AE] 
Within each summary, subjects with one or more events within a level 
of SOC term is counted only once in that level. Similarly, subjects with 
one or more events within a level of PT term is counted only once in 
that level. 
 
6.2.3. Prior and Concomitant Medication 
Analysis Set: Safety Analysis Set 
Analysis Variables: Prior medication 
Concomitant medication 
Analysis Methods: For the above analysis items, the following analysis is 
performed for each treatment group. Analysis variables will 
be coded using the WHO (World Health Organization) Drug. 
Coded medications will be sorted in frequency order. 
Medications used more than once within a subject will be 
counted only once for the subject. 
(1) Frequency of prior medication 
(2) Frequency of concomitant medication 
 
6.3. Treatment Compliance 
6.3.1. Study Medication Compliance 
Analysis Set: Safety Analysis Set 
Analysis Variables: Study medication compliance   
 [Fully Complied (75% or More),  
Not Compliant (Less than 75%)]  
Time Point: Visit 5 or time of discontinuation 
Analysis Methods: For the above analysis items, the following analysis is 
performed for each treatment group and all subjects in the 
analysis set by time point.  
(1) Frequency 
 
6.3.2. Diet Therapy Compliance 
Analysis Set: Safety Analysis Set 
Analysis Variables: Diet therapy     [Yes, No] 
Diet therapy compliance  [Fully complied (90% or More), 
Almost complied (70% or more), 


 
11 
 
Occasionally complied (50% or more), 
Rarely complied (Less than 50%)] 
Time Point: Visit3, Visit4, Visit 5 or time of discontinuation 
Analysis Methods: For the above analysis items, the following analysis is 
performed for each treatment group and all subjects in the 
analysis set by time point.  
(1) Frequency 
 
6.3.3. Exercise Therapy Compliance 
Analysis Set: Safety Analysis Set 
Analysis Variables: Exercise therapy      [Yes, No] 
Exercise therapy compliance   
[Fully complied (90% or more), 
Almost complied (70% or more), 
Occasionally complied (50% or more), 
Rarely complied (Less than 50%)] 
Time Point: Visit3, Visit4, Visit 5 or time of discontinuation 
Analysis Methods: For the above analysis items, the following analysis is 
performed for each treatment group and all subjects in the 
analysis set by time point.  
(1) Frequency 
             
6.3.4. Study Medication Exposure 
Analysis Set: Safety Analysis Set 
Analysis Variables: Duration of exposure (days) 
Analysis Methods: For the above analysis items, the following analysis is 
performed for each treatment group and all subjects in the 
analysis set. 
(1) Summary statistics of continuous variables 
      
7. 
EFFICACY EVALUATIONS 
7.1. Primary Endpoint and the Analytical Methods 
Analysis Set: Full Analysis Set 
Analysis Variables: Changes in the standard deviation (SD) of 24-hour blood 
glucose values 
Time Point: Start of the observation period, CGM in treatment period (Day 2, Day 3, 


 
12 
 
Day 4, Day 5, Day 6, Day 7, Day 8) 
Covariate: HbA1c (NGSP) at start of the observation period (%)  
[Continuous variable] 
SD of 24-hour blood glucose at start of the observation period 
[Continuous variable] 
Age (years old)                           [< 65, 65 <=Max] 
Analysis Methods: For the above analysis items, the following analysis is 
performed. 
(1) Summary statistics and two-sided 95% confidence interval (CI) by 
time point (each Day) will be calculated by treatment group. The 
time course will be presented graphically using the mean change 
and SD. Then, point estimates of the difference of mean between 
treatment groups (Trelagliptin 100 mg group - Alogliptin 25 mg 
group) and its two-sided 95% CI will be calculated. 
(2) To estimate adjusted mean and two-sided 95% CI of each 
treatment group, adjusted difference of mean between treatment 
groups (Trelagliptin 100 mg group - Alogliptin 25 mg group) and 
its two-sided 95% CI, analysis of covariance (ANCOVA) will be 
performed by time point using change from start of the observation 
period of SD of 24-hour blood glucose as a dependent variable, 
treatment group as an independent variable, HbA1c (NGSP) and 
SD of 24-hour blood glucose at start of the observation period and 
age as covariates. 
 
7.2. Secondary Endpoints and the Analytical Methods 
Analysis Set: Full Analysis Set 
Analysis Variables:  
AUC over time when blood glucose 110 mg/dL is observed during the 3 
hour time period after breakfast 
AUC over time when blood glucose 140 mg/dL is observed during the 3 
hour time period after breakfast 
AUC over time when blood glucose 160 mg/dL is observed during the 3 
hour time period after breakfast 
AUC over time when blood glucose 180 mg/dL is observed during the 3 
hour time period after breakfast 
AUC over time when blood glucose 110 mg/dL is observed during the 3 


 
13 
 
hour time period after lunch 
AUC over time when blood glucose 140 mg/dL is observed during the 3 
hour time period after lunch 
AUC over time when blood glucose 160 mg/dL is observed during the 3 
hour time period after lunch 
AUC over time when blood glucose 180 mg/dL is observed during the 3 
hour time period after lunch 
AUC over time when blood glucose 110 mg/dL is observed during the 3 
hour time period after evening meal 
AUC over time when blood glucose 140 mg/dL is observed during the 3 
hour time period after evening meal 
AUC over time when blood glucose 160 mg/dL is observed during the 3 
hour time period after evening meal 
AUC over time when blood glucose 180 mg/dL is observed during the 3 
hour time period after evening meal  
AUC over time during periods when blood glucose 140 mg/dL is 
observed 
AUC over time during periods when blood glucose 160 mg/dL is 
observed 
AUC over time during periods when blood glucose 180 mg/dL is 
observed  
Cumulative time during periods when blood glucose 140 mg/dL is 
observed 
Cumulative time during periods when blood glucose 160 mg/dL is 
observed 
Cumulative time during periods when blood glucose 180 mg/dL is 
observed 
AUC over time during periods when blood glucose <70 mg/dL is 
observed 
Peak postprandial glucose over time 3 hours after breakfast 
Peak postprandial glucose over time 3 hours after lunch 
Peak postprandial glucose over time 3 hours after evening meal 
Maximum variation of blood glucose over time between before and 
after breakfast 
Maximum variation of blood glucose over time between before and 
after lunch 


 
14 
 
Maximum variation of blood glucose over time between before and 
after evening meal 
MAGE 
Mean 24-hour blood glucose 
Mean daytime blood glucose 
Mean nocturnal blood glucose 
AUC 
AUC over time during periods when blood glucose 110 mg/dL is 
observed 
SD of 24-hour blood glucose 
SD of daytime blood glucose 
SD of nocturnal blood glucose 
Time Point: Start of the observation period, CGM in treatment period (Day 2, Day 3, 
Day 4, Day 5, Day 6, Day 7, Day 8) 
Covariate: HbA1c (NGSP) at start of the observation period (%)  
[Continuous variable] 
SD of 24-hour blood glucose at start of the observation period 
[Continuous variable] 
Age (years old)                           [< 65, 65 <=Max] 
Analysis Methods: For the above analysis items, the following analysis is 
performed 
(1) The same analyses described in 7.1(1) and (2) will be performed 
on measurement values and changes from start of the observation 
period at each time point. For the SD of 24-hour blood glucose, 
only the measured value will be shown.  
(2) The same analyses described in 7.1(1) and (2) will be performed 
on means of 7days and changes from start of the observation 
period during Week 3-4 at treatment period. The time course will 
be presented graphically using only means and SDs of each 
treatment group.  
 
7.3. Other Analyses 
7.3.1. Clinical Laboratory Test 
Analysis Set: Full Analysis Set 
Analysis Variables: Glycoalbumin 
1,5-AG 


 
15 
 
Fasting blood glucose 
Fasting insulin 
Fasting glucagon 
Fasting proinsulin 
Fasting GLP-1  
Fasting GIP 
DPP-4 Activity 
Inhibitory Rate of DPP-4 Activity 
Time Point: Start of the observation period, Week 3-4 of the treatment period (Day 
1, Day 4-6, Day 9) 
Analysis Methods: For the above analysis items, the following analysis is 
performed 
(1) For measurement values and changes from start of the observation 
period, summary statistics and two-sided 95% CI by time point 
(each Day) will be calculated by treatment group. The time course 
will be presented graphically using the mean change and SD.  
 
7.3.2. Relationship Between Secondary Endpoints and Covariate 
Analysis Set: Full Analysis Set 
Analysis Variables: AUC over time when blood glucose 110 mg/dL is observed 
during the 3 hour time period after breakfast 
AUC over time when blood glucose 140 mg/dL is observed 
during the 3 hour time period after breakfast 
AUC over time when blood glucose 160 mg/dL is observed 
during the 3 hour time period after breakfast 
AUC over time when blood glucose 180 mg/dL is observed 
during the 3 hour time period after breakfast 
AUC over time when blood glucose 110 mg/dL is observed 
during the 3 hour time period after lunch 
AUC over time when blood glucose 140 mg/dL is observed 
during the 3 hour time period after lunch 
AUC over time when blood glucose 160 mg/dL is observed 
during the 3 hour time period after lunch 
AUC over time when blood glucose 180 mg/dL is observed 
during the 3 hour time period after lunch 


 
16 
 
AUC over time when blood glucose 110 mg/dL is observed 
during the 3 hour time period after evening meal 
AUC over time when blood glucose 140 mg/dL is observed 
during the 3 hour time period after evening meal 
AUC over time when blood glucose 160 mg/dL is observed 
during the 3 hour time period after evening meal 
AUC over time when blood glucose 180 mg/dL is observed 
during the 3 hour time period after evening meal  
AUC over time during periods when blood glucose 140 mg/dL is 
observed 
AUC over time during periods when blood glucose 160 mg/dL is 
observed 
AUC over time during periods when blood glucose 180 mg/dL is 
observed  
Cumulative time during periods when blood glucose 140 mg/dL 
is observed 
Cumulative time during periods when blood glucose 160 mg/dL 
is observed 
Cumulative time during periods when blood glucose 180 mg/dL 
is observed 
AUC over time during periods when blood glucose <70 mg/dL is 
observed 
Peak postprandial glucose over time 3 hours after breakfast 
Peak postprandial glucose over time 3 hours after lunch 
Peak postprandial glucose over time 3 hours after evening meal 
Maximum variation of blood glucose over time between before 
and after breakfast 
Maximum variation of blood glucose over time between before 
and after lunch 
Maximum variation of blood glucose over time between before 
and after evening meal 
MAGE 
Mean 24-hour blood glucose 
Mean daytime blood glucose 
Mean nocturnal blood glucose 
AUC 


 
17 
 
AUC over time during periods when blood glucose 110 mg/dL is 
observed 
SD of 24-hour blood glucose 
SD of daytime blood glucose 
SD of nocturnal blood glucose 
Time Point: Start of the observation period, CGM in treatment period (Day 2, Day 3, 
Day 4, Day 5, Day 6, Day 7, Day 8) 
Covariate: HbA1c at start of the observation period (NGSP) (%)  
[Continuous variable] 
SD of 24-hour blood glucose at start of the observation period 
[Continuous variable] 
Age (years old)                        [Continuous variable] 
Analysis Methods: For the above analysis items, the following analysis is 
performed 
(1) 
Correlation coefficients between secondary endpoints and 
covariates will be calculated by time Point. 
 
7.3.3. Individual Profiles of Blood Glucose Obtained from CGM 
Analysis Set: Full Analysis Set 
Analysis Variables: Blood Glucose Obtained from CGM 
Time Point: CGM in treatment period (Day 2, Day 3, Day 4, Day 5, Day 6, Day 7, 
Day 8) 
Analysis Methods: For the above analysis items, the following analysis is 
performed 
(1) 
The time course will be presented graphically by subject by 
treatment group. 
 
7.3.4. Effect on mean 24-hour blood glucose 
Analysis Set: Full Analysis Set 
Analysis Variables: Change from start of the observation period of mean 24-hour  
blood glucose 
Covariate: HbA1c (NGSP) at start of the observation period (%)  
[Continuous variable] 
SD of 24-hour blood glucose at start of the observation period 
[Continuous variable] 
Age (years old)                        [< 65, 65 <=Max] 


 
18 
 
Background Factor:  
Gender                              [Male, Female] 
Height (Start of the observation period) (cm) [Continuous variable] 
Weight (Start of the observation period) (cm) [Continuous variable] 
BMI (Start of the observation period) (kg/m2) [Continuous variable] 
Smoking Classification  [Never Smoke, Current Smoker, Ex-Smoker] 
Drink Alcohol Almost Every Day?         [Yes, No] 
Duration of Diabetes Mellitus (Years)       [Continuous variable] 
HbA1c (NGSP) (Start of the observation period) (%)  
[Continuous variable] 
Time Point : CGM in treatment period (Day 2, Day 3, Day 4, Day 5, Day 6, Day 7, 
Day 8) 
Analysis Methods: For the above analysis items, the following analysis is 
performed 
(1) 
To estimate parameter estimates of background factors and its 
confidence intervals, ANCOVA will be performed by background 
factor using change from start of the observation period of mean  
24-hour blood glucose as a dependent variable, treatment group as 
an independent variable, HbA1c (NGSP) and SD of 24-hour blood 
glucose at start of the observation period, age and each background 
factor as covariates.  
(2) 
Perform the same analysis as (1) with the covariate including the 
treatment group × each background factor (one factor).  
 
7.3.5. Proportion of Frequency for Blood Glucose Obtained from CGM  
Analysis Set: Full Analysis Set 
Analysis Variables: Blood glucose level obtained by CGM  
Time Point: Start of the observation period, CGM in treatment period (Day 2, Day 3, 
Day 4, Day 5, Day 6, Day 7, Day 8) 
Analysis Methods: For the above analysis items, the following analysis is 
performed 
(1) 
Calculate proportion of frequency and graphically show 
distribution of the data using proportion of frequency as vertical 
axis and blood glucose level as horizontal axis. 
 
 


 
19 
 
8. 
SAFETY EVALUATION 
8.1. Frequency of Adverse Event Occurrence 
8.1.1. Brief Summary of Adverse Events 
Analysis Set: Safety Analysis Set 
Analysis Variables: Adverse Event 
Category Classification:  
Causal relationship with the investigational products  [related, unrelated] 
        Severity                             [Mild, Moderate, Severe] 
For the above analysis items, the following analyses of frequency distribution is 
performed. 
(1) All of the TEAEs 
(2) TEAEs Related to Investigational Drug 
(3) TEAEs by Severity 
(4) TEAEs Related to Investigational Drug by Severity 
(5) TEAEs leading to Discontinuation of Administration of 
Investigational Drug 
(6) Serious TEAEs 
(7) Non-serious TEAEs 
(8) Serious TEAEs Related to Investigational Drug 
(9) Serious TEAEs leading to Discontinuation of Administration of 
Investigational Drug 
(10) TEAEs Leading to Death 
 Incidence rates will be calculated as following on each analysis. 
   [Frequency of Subjects] 
   ・Frequency by Severity 
Subjects with one or more adverse events within a level of MedDRA term 
is counted only once in that level using the most severe incident. The 
denominator when calculating the incidence of adverse events is the 
number of subjects of safety analysis set. 
    
   ・Analyses Other Than the Above 
Subjects with one or more adverse events within a level of MedDRA term 
is counted only once for that MedDRA term. The denominator when 
calculating the incidence of adverse events is the number of subjects of 
safety analysis set. 
 


 
20 
 
8.1.2. Display of TEAE 
Analysis Set: Safety Analysis Set 
Analysis Variables: TEAE 
Category Classification:  
Causal relationship with the investigational products  [related, unrelated] 
        Severity                             [Mild, Moderate, Severe] 
Analysis Methods: For the above analysis items, the following analysis is 
performed for each treatment group. Analysis variables will be coded using the 
MedDRA dictionary and be summarized into SOC and PT. SOCs will be sorted in 
alphabetical order, then PTs will be sorted in frequency order. 
1) 
All of the TEAEs (by SOC/PT) 
2) 
TEAEs Related to Investigational Drug (by SOC/PT) 
3) 
TEAEs by Severity (by SOC/PT) 
4) 
TEAEs Related to Investigational Drug by Severity (by 
SOC/PT) 
5) 
TEAEs leading to Discontinuation of Administration of 
Investigational Drug (by SOC/PT) 
6) 
Serious TEAEs (by SOC/PT) 
7) 
Non-serious TEAEs (by SOC/PT) 
8) 
Serious TEAEs Related to Investigational Drug (by SOC/PT) 
9) 
Serious TEAEs leading to Discontinuation of Administration 
of Investigational Drug (by SOC/PT) 
10) TEAEs Leading to Death (by SOC/PT) 
  Incidence rates will be calculated as following on each analysis. 
   [Frequency of Subjects] 
   ・Frequency (by SOC/PT) 
Within each summary, subjects with one or more adverse events within a 
level of SOC term is counted only once in that level. Similarly, subjects 
with one or more adverse events within a level of PT term is counted only 
once in that level. The denominator when calculating the incidence of 
adverse events is the number of subjects of safety analysis set. 
   ・Frequency by Severity (by SOC/PT) 
Subjects with one or more adverse events within a level of SOC/PT term 
is counted only once in that level using the most severe incident. The 
denominator when calculating the incidence of adverse events is the 
number of subjects of safety analysis set. 


 
21 
 
 
 
9. 
LISTING 
Following lists will be create for randomized subjects 
・Demographics 
 
 


 
22 
 
10. CONSIDERATIONS on STATISTICAL ANALYSIS 
10.1. Adjustments for Covariates 
ANCOVA will be performed on primary and secondary endpoints using treatment group as 
independent variables, HbA1c (NGSP) at the start of the observation period and SD of 24-hour 
blood glucose at the start of observation period as covariate. Details are described in 7.1, 7.2 and 
7.3.4. 
 
10.2. Handling of Dropouts or Missing Data 
For laboratory test, a value below determination limit are treated as zero. 
 
10.3. Criteria for Interim Analysis and Early Discontinuation 
Interim analysis will not be performed. 
 
10.4. Multicenter Studies 
Analyses for consideration of medical institution will not be performed. 
 
10.5. Multiple Comparisons/Multiplicity 
It does not adjust multiplicity. 
 
 
10.6. Examination of Subgroups 
Subgroup analysis will not be performed. 
 
 


 
23 
 
11. REVISION HISTORY 
Ver. 
Date 
Author 
Revised Content 
Reason for Revision 
1.0 
12 JUL 2016 
 
- 
 
2.0 
24 JUL 2017 
 
 [2.TIME WINDOW] 
・Modification on some 
reference 
implementation date of 
CGM 
・Modification on 
description of time 
window of Laboratory 
Tests 
・To avoid doble count of evening meal 
 
・To make a distinction between items 
measured 
three 
times 
and 
items 
measured twice and to reflect updated 
protocol 
 
 
 
 
 [5.OTHER DATA 
HANDLING] 
・Modification on 
Definition of 
“Daytime” and 
“Nocturnal Period” 
・Modification on 
Definition of 
Non-seriousAE 
・Add definition of 
inhibitory rate of 
DPP-4 activity 
・Add definition of 
duration of diabetes 
・To follow specification document of 
CGM database 
 
・Requirement of Clinical Trial.gov 
 
・To reflect updated Protocol 
 
・Clarification 
 
 
 
 [6.2.1.Distribution of 
Demographics items] 
・Add items that were 
not described as 
Demographics items in 
secondary evaluation 
items 
・Additional items 


 
24 
 
Ver. 
Date 
Author 
Revised Content 
Reason for Revision 
 
 
 
 [6.3.2. 
Diet Therapy 
Compliance and 
6.3.3.Exercise Therapy 
Compliance] 
・Clarification 
 
 
 
 [7.3.1. Clinical 
Laboratory Test] 
・Add DPP-4activity a 
nd inhibitory rate of 
DPP-4 activity   
・Add Day 4-6 as time 
point 
・To reflect updated protocol 
 
 
 
 [7.3.5. Proportion of 
Frequency for Blood 
Glucose Obtained from 
CGM] 
・Delete the description 
in the second edition, 
"Add analysis as 
necessary". 
・Clerical corrections 
 
 
 
 [8.1.1.Brief Summary 
of Adverse Events and 
8.1.2.Display of TEAE] 
・Add analysis of 
frequency distribution 
of non-serious adverse 
events, deleted analysis 
of frequency 
distribution count by 
onset time point. 
・Requirement of Clinical Trial.gov 
・Remove unnecessary items 
 
 
 
 [9.2. Handling of 
Dropout or Missing 
Value] 
・Add treatment of 
values below 
quantitation limit 
・Clarification 


 
25 
 
Ver. 
Date 
Author 
Revised Content 
Reason for Revision 
3.0 
28 JUL 2017 
 
 [6.1.3. Exit Status of 
Subjects] 
・Remove “Exit status 
from the treatment of 
study drug” and add 
“Exit status from the 
study” 
・Clerical corrections 
4.0 
25 JUL 2017 
 
 [Title page] 
・Modification on 
organization name 
・Clerical corrections 
・Organizational change 
 
 
 
 [9. Listing] 
・Add listing of 
background factor 
・Addition of listing