Clinical trial NCT03014479
Conditions: Type 2 Diabetes
Sponsor: Takeda
Start date: 2017-02-18; Completion date: 2017-10-21
Enrollment: 219 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to assess the reduction in treatment burden during 12 weeks of trelagliptin administration in patients with type 2 diabetes on diet and exercise therapy only.

Detailed description:
The purpose of this study is to assess the reduction in treatment burden during 12 weeks of trelagliptin administration in patients with type 2 diabetes on diet and exercise therapy only. Eligible participants will be randomized to either the study drug (trelagliptin) group or the comparative drug (daily DPP-4 inhibitor) group. Treatment burden will be assessed using Diabetes Therapy Related -QOL (DTR-QOL) questionnaire and Diabetes Treatment Satisfaction Questionnaire (DTSQ).

Arms: arm 1: Trelagliptin 100 mg, orally, once weekly for up to 12 weeks. Trelagliptin 50 mg, orally, once weekly for up to 12 weeks in patients with moderate renal impairment. arm 2: An inhibitor orally administered at the dosage and administration in the package inserts for each drug, for up to 12 weeks.
Interventions: intervention 1: Trelagliptin intervention 2: Daily DPP-4 inhibitor
Intervention descriptions: intervention 1: Trelagliptin 100 mg or 50 mg intervention 2: Alogliptin, anagliptin, linagliptin, saxagliptin, sitagliptin, teneligliptin or vildagliptin

Protocol documents:
Prot_000.pdf: 
 
 
Title: Study of the QOL evaluation of Trelagliptin in patient with type 2 Diabetes 
mellitus (TRENDS) 
 
NCT Number: NCT03014479 
Protocol Approve Date: 05-Jul-2017 
 
Certain information within this protocol has been redacted (ie, specific content is 
masked irreversibly from view with a black/blue bar) to protect either personally 
identifiable information or company confidential information. 
 
This may include, but is not limited to, redaction of the following: 
 
Named persons or organizations associated with the study. 
 
Patient identifiers within the text, tables, or figures or in by-patient data listings. 
 
Proprietary information, such as scales or coding systems, which are considered 
confidential information under prior agreements with license holder. 
 
Other information as needed to protect confidentiality of Takeda or partners, 
personal information, or to otherwise protect the integrity of the clinical study. 
 
If needed, certain appendices that contain a large volume of personally identifiable 
information or company confidential information may be removed in their entirety if it 
is considered that they do not add substantially to the interpretation of the data (eg, 
appendix of investigator’s curriculum vitae). 
 
Note; This document was translated into English as the language on original version 
was Japanese. 


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PROTOCOL 
 
 
 
 
 
Study of the QOL evaluation of TRElagliptiN in patient with type 2 DiabeteS mellitus 
(TRENDS)  
 
 
 
 
 
 
 
Sponsor 
Takeda Pharmaceutical Company Limited 
12-10 Nihonbashi 2-chome, Chuo-ku, Tokyo 
Protocol number 
Trelagliptin-4002 
Version number/Revision number 
Version 2.0 
Study drug 
Trelagliptin 
Creation date 
July 5, 2017 
 
 
 
 
 


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CONFIDENTIAL PROPERTY 
This document is a confidential communication of Takeda. Acceptance of this document constitutes 
agreement by the potential recipient 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 study 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 
STUDY ADMINISTRATIVE INFORMATION AND CLINICAL STUDY 
PRINCIPLES 
1.1 
Clinical study principles 
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: International Conference on 
Harmonization of Technical Requirement for Registration on Pharmaceuticals for Human Use. 
E6) 
• 
All applicable laws and regulations, including, without limitation, data privacy laws and conflict 
of interest guidelines. 
 
1.2 
Clinical study implementation system 
This study will be conducted in accordance with the requirements of this clinical study protocol 
designed and prepared by the sponsor and also in accordance with the following. Other study 
administrative structures are shown in the separate documents. 
Sponsor 
Japan Medical Affairs, Japan Pharma Business Unit, Takeda Pharmaceutical Company Limited 
The sponsor shall be responsible for matters related to planning/preparation, 
implementation/operation, and results/reporting in this clinical study. Methods of supervision of the 
contractor entrusted with the services related to this clinical study will be described in the procedure 
to be prepared separately. 
Expenses* required for the operation of this clinical study will be paid by the sponsor. 
* :  Based on the “Consignment Service Contract,” expenses incurred for the services of Office of 
Clinical Study, monitoring, registration/allocation center, and statistical processing shall be paid 
to the contractor entrusted with services related to this clinical study. Expenses agreed by the 
study site shall be paid to the site based on the “Research Expense Standard.” 
 
 


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Chair of the Clinical Study Steering Committee: 
 
Terms in this protocol are defined as follows: 
Study site: 
A corporation, governmental agency and sole proprietor conducting the study, excluding cases 
where only a part of the services related to storage of samples/information, statistical processing 
and other studies are entrusted. 
Investigators: 
Principal investigators and other parties involved in conduction of the study (including operations 
at institutions involved in collection/distribution of samples/information). Those involved only in 
providing existing samples/information outside the study sites and those engaged in part of the 
entrusted operations related to the study are excluded. 
Principal Investigator: 
An investigator who is engaged in implementation of the study and integrates the operations 
involved in this study at an affiliated study site. 
Chief executive of the study site: 
A representative of a corporation, head of a governmental agency, or a sole proprietor 
Study subject: 
A subject (including a dead subject) who meets any of the following:  
1. 
Subjects being studied (including those who have been asked to be studied)  
2. 
Subjects from whom existing samples/information to be used in the study have been 
obtained. 
 
PPD


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Table of Contents 
1.0 
STUDY ADMINISTRATIVE INFORMATION AND CLINICAL STUDY 
PRINCIPLES ........................................................................................................... 3 
1.1 
Clinical study principles .................................................................................... 3 
1.2 
Clinical study implementation system ............................................................... 3 
2.0 
STUDY SUMMARY ............................................................................................ 10 
3.0 
ABBREVIATION ................................................................................................. 17 
4.0 
INTRODUCTION ................................................................................................. 18 
4.1 
Background ...................................................................................................... 18 
4.2 
Rationale for the proposed study ..................................................................... 18 
5.0 
STUDY OBJECTIVES AND ENDPOINTS ........................................................ 20 
5.1 
Objectives ........................................................................................................ 20 
5.2 
Definition of endpoints .................................................................................... 20 
5.2.1 Primary endpoints ...................................................................................... 20 
5.2.2 Secondary endpoints .................................................................................. 20 
5.2.3 Other Endpoints ......................................................................................... 21 
6.0 
CLINICAL STUDY DESIGN............................................................................... 22 
6.1 
Clinical study design ....................................................................................... 22 
6.2 
Rationale for the clinical study design ............................................................ 24 
6.3 
Premature termination of entire clinical study or premature termination 
of clinical study at a study site ........................................................................ 24 
6.3.1 Premature termination criteria of entire clinical study .............................. 24 
6.3.2 Criteria for premature termination of study sites....................................... 25 
6.3.3 Procedures of clinical study suspension and premature termination of 
entire clinical study or clinical study at a study site .................................. 25 
6.4 
Procedures for protocol revision ..................................................................... 25 
7.0 
SELECTION AND WITHDRAWAL CRITERIA OF STUDY SUBJECTS ....... 26 
7.1 
Inclusion criteria .............................................................................................. 26 
7.2 
Exclusion criteria ............................................................................................. 26 
7.3 
Prohibited concomitant drugs and permitted concomitant drugs .................... 28 
7.4 
Study subject management .............................................................................. 28 


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7.5 
Criteria for discontinuation or withdrawal of a study subject ......................... 28 
7.6 
Procedures for discontinuation of individual study subjects ........................... 29 
8.0 
STUDY TREATMENT ......................................................................................... 31 
8.1 
Study drug and Comparative drug ................................................................... 31 
8.1.1 Study drug ................................................................................................. 31 
8.1.2 Comparative drug ...................................................................................... 31 
8.2 
Overdose of the study drug .............................................................................. 32 
8.3 
Medication other than the study drug and the comparative drug .................... 32 
8.4 
Allocation of the study drug and administration procedure ............................ 33 
8.5 
Preparation and storage of allocation list ........................................................ 33 
9.0 
CLINICAL STUDY PROTOCOL ........................................................................ 34 
9.1 
Clinical study procedures ................................................................................ 34 
9.1.1 Informed consent ....................................................................................... 34 
9.1.2 Demographic data and medical history ..................................................... 34 
9.1.3 Physical examination ................................................................................. 34 
9.1.4 Body weight, height, and BMI .................................................................. 34 
9.1.5 Concomitant drugs ..................................................................................... 34 
9.1.6 Comorbidities ............................................................................................ 35 
9.1.7 Laboratory tests ......................................................................................... 35 
9.1.8 The Basic Information on Study Subject (Your Basic Profile) ................. 36 
9.1.9 DTR-QOL Questionnaire .......................................................................... 36 
9.1.10 DTSQ ......................................................................................................... 37 
9.1.11 Treatment Compliance .............................................................................. 38 
9.1.12 Hospitalization for type 2 diabetes ............................................................ 38 
9.1.13 Contraception ............................................................................................ 38 
9.1.14 Pregnancy .................................................................................................. 38 
9.1.15 Record of study subjects who are withdrawn before randomization......... 39 
9.1.16 Record of randomization ........................................................................... 39 
9.2 
Implementation time point of the tests and observation .................................. 39 
9.2.1 Screening period (Week -4) ....................................................................... 39 
9.2.2 Treatment period (Week 0)........................................................................ 40 


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9.2.3 Treatment period (Week 4)........................................................................ 40 
9.2.4 Treatment period (Week 12) or discontinuation........................................ 41 
10.0 
ADVERSE EVENTS ............................................................................................ 42 
10.1 
Definitions ....................................................................................................... 42 
10.1.1 Adverse events ........................................................................................... 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 ......................................................................... 45 
10.1.6 Causality of adverse events ....................................................................... 45 
10.1.7 Relationship to study procedures ............................................................... 46 
10.1.8 Date of onset .............................................................................................. 46 
10.1.9 Date of resolution ...................................................................................... 46 
10.1.10Actions taken for the study drug or comparative drug .............................. 47 
10.1.11Outcome .................................................................................................... 47 
10.2 
Procedures ....................................................................................................... 48 
10.2.1 Collection and reporting of adverse events and its coverage .................... 48 
10.2.2 Collection and reporting of serious adverse events ................................... 49 
10.2.3 Reporting of additional information concerning adverse events ............... 50 
10.3 
Follow-up of serious adverse events ............................................................... 50 
10.3.1 Reporting of serious adverse events to Ethical Review Board, etc., 
and regulatory authorities .......................................................................... 50 
11.0 
COMMITTEES ESTABLISHED FOR THIS STUDY ........................................ 52 
11.1 
Clinical Study Steering Committee ................................................................. 52 
12.0 
DATA MANAGEMENT AND STORAGE OF RECORDS ............................... 53 
12.1 
Case report form .............................................................................................. 53 
12.2 
Timing of data entry into the EDC system ...................................................... 54 
12.3 
Storage of records ............................................................................................ 54 
13.0 
STATISTICAL ANALYSIS METHODS ............................................................. 55 
13.1 
Statistical and analytical plans ......................................................................... 55 
13.1.1 Analysis set ................................................................................................ 55 


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13.1.2 Analysis of demographic and other baseline characteristics ..................... 55 
13.1.3 Efficacy analysis ........................................................................................ 55 
13.1.4 Safety analysis ........................................................................................... 57 
13.2 
Criteria for interim analysis and premature discontinuation ........................... 57 
13.3 
Determination of the number of planned study subject ................................... 57 
14.0 
QUALITY CONTROL AND QUALITY ASSURANCE .................................... 59 
14.1 
Monitoring of the study site ............................................................................ 59 
14.2 
Deviation from the Ethical Guidelines for Medical and Health Research 
Involving Human Subjects and the study protocol .......................................... 59 
14.3 
Quality assurance audits and regulatory agency inspections........................... 59 
15.0 
ETHICAL CONDUCT OF CLINICAL STUDY .................................................. 61 
15.1 
Approval of the Ethical Review Board, etc. .................................................... 61 
15.2 
Conflict of interest ........................................................................................... 62 
15.3 
Informed consent form and information sheet, and the agreement of the 
study subjects ................................................................................................... 62 
15.4 
Personal information of the study subjects ...................................................... 63 
15.5 
Consultation windows for the study subjects or persons related to the 
study concerned ............................................................................................... 63 
15.6 
Financial burden or reward to the study subjects ............................................ 63 
15.7 
Benefits and inconveniences to the study subjects .......................................... 64 
15.7.1 Benefits to study subjects .......................................................................... 64 
15.7.2 Inconveniences to study subjects ............................................................... 64 
15.8 
Attribution of study results and access rights .................................................. 64 
15.8.1 Attribution of study results ........................................................................ 64 
15.8.2 Data access rights ...................................................................................... 64 
15.9 
Reporting of results, publication, disclosure, and clinical study 
registration policy ............................................................................................ 64 
15.9.1 Reporting of results, publication and disclosure ....................................... 64 
15.9.2 Clinical study registration .......................................................................... 65 
15.9.3 Clinical trial results disclosure .................................................................. 65 
15.10 Insurance and compensation for injury ........................................................... 65 
16.0 
REFERENCES ...................................................................................................... 66 


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LIST OF IN-TEXT TABLES 
Table 8.a  
Daily DPP-4 inhibitor ................................................................................ 32 
Table 9.a 
Laboratory tests ......................................................................................... 36 
Table 10.a 
Takeda Medically Significant AE List ...................................................... 45 
LIST OF IN-TEXT FIGURES 
Figure 6.a 
Outline of the clinical study design ........................................................... 24 
 


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2.0 
STUDY SUMMARY 
Sponsor: 
Takeda Pharmaceutical Company Limited 
Study drug: 
Trelagliptin  
Study title:  
Study of the QOL evaluation of Trelagliptin in patients with type 2 diabetes mellitus 
Protocol number: Trelagliptin-4002 
Clinical study design: 
This is a multi-center, randomized, open-label, parallel-group comparison study to assess the 
reduction in treatment burden during the administration of a DPP-4 inhibitor (trelagliptin or a daily 
DPP-4 inhibitor) for 12 weeks in patients with type 2 diabetes on diet and exercise therapy only. 
Subjects who are determined to be eligible based on the results of eligibility assessment after 
informed consent has been obtained will be randomized to either the study drug (trelagliptin) group 
or the comparative drug (daily DPP-4 inhibitor) group. Randomization was stratified by the total 
score (<80% (score 139.4), ≥80% (score 139.4)*)) for total score of the “Diabetes Therapy-Related 
QOL (DTR-QOL) Questionnaire” and “HbA1c (<8.0%, ≥8.0%)” at the start of the screening period. 
* A scale of 1 to 7 with 7 as the best was used for each QOL question item, and total score 
calculated by adding up scores of each question was expressed as a percentage of the maximum total 
score (i.e., the best score [203] = 100%; the worst score [29] = 0%.) 
Objectives: 
The objective is to assess the reduction in treatment burden during 12 weeks of trelagliptin 
administration in patients with type 2 diabetes on diet and exercise therapy only 
Subjects:  
Patients with type 2 diabetes on diet and exercise therapy alone 
Planned number of study subjects: 
As the number of randomized subjects: 
The study drug (Trelagliptin) group 120 subjects 
The comparative drug (daily DPP-4 inhibitor) group 
120 subjects 
Number of study sites: 
Approximately 15 
Dose and method of administration: 
The study drug (Trelagliptin) group: Trelagliptin 100 
mg is orally administered once weekly. Trelagliptin 
Route of administration: 
Oral 


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50 mg is orally administered once weekly in patients 
with moderate renal impairment. 
The comparative drug (Daily DPP-4 inhibitor) group: 
An inhibitor is orally administered at the dosage and 
administration in the package inserts for each drug. 
Duration of treatment: 
12 weeks 
Duration of evaluation: 
16 weeks 
(Screening period: 4 weeks; treatment 
period: 12 weeks) 
Inclusion criteria: 
Eligibility of study subjects shall be determined in accordance with the following criteria. 
1. 
Patients diagnosed as type 2 diabetes. 
2. 
Patients with a stable diet and exercise therapy only for at least 12 weeks prior to the start of the 
screening period. 
3. 
Patients who require a DPP-4 inhibitor treatment. 
4. 
Patients with HbA1c ≥6.5 % and <10.0 % at the start of the screening period. 
5. 
Patients who completed DTR-QOL questionnaire at the start of the screening period. 
6. 
Patients who have receive less than 2 types of medication for treatment of comorbidities (such 
as hypertension or dyslipidemia) at the start of the screening period (any number of daily 
doses). 
7. 
Patients who, in the opinion of the principal investigator or the investigator, are capable of 
understanding the content of the clinical study and complying with the study protocol 
requirements. 
8. 
Patients who can provide the written informed consent prior to the initiation of any study 
procedures. 
9. 
Patients aged ≥20 years at the time of informed consent. 
10. Outpatient. 
Exclusion criteria: 
Study subjects meeting any of the criteria below shall not be included in this study. 
1. 
Patients who are receiving any oral anti-diabetic medication for the treatment of type 2 diabetes 
at the start of the screening period. 
2. 
Patients diagnosed as type 1 diabetes. 


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3. 
Patients with severe renal impairment or renal failure (e.g., eGFR <30 mL/min/1.73 m2 or on 
dialysis). 
4. 
Patients with serious heart disease or cerebrovascular disorder, or serious pancreatic, blood, or 
other disease. 
5. 
Patients with a history of gastrointestinal resection. 
6. 
Patient with a proliferative diabetic retinopathy. 
7. 
Patient with malignancy. 
8. 
Patients with a history of hypersensitivity or allergy to DPP-4 inhibitors. 
9. 
Pregnant, lactating or postmenopausal women. 
10. Patients who may need to add or discontinue concomitant medication or change the dose during 
the study period. 
11. Patients who will require treatment with a prohibited concomitant medication during the study 
period. 
12. Patients participating in other clinical studies. 
13. Patients assessed ineligible in the study by the principal investigator or the investigator. 
ENDPOINTS: 
<Primary endpoint> 
Change from baseline (Week 0) in total score for all question items in the DTR-QOL Questionnaire 
at the end of the treatment period (Week 12). 
 
<Secondary endpoints> 
Efficacy assessment: 
• 
Changes in the total score for each factor provided through the DTR-QOL Questionnaire 
[Factor 1: Burden on social activities and daily activities (13 questions in all), Factor 2: Anxiety 
and dissatisfaction with treatment (8 questions in all), Factor 3: Hypoglycemia (4 questions in 
all) and Factor 4: Treatment satisfaction (4 questions in all)] at each assessment time point. 
• 
Change in the total score for all questions in the DTR-QOL Questionnaire at each assessment 
time point. 
• 
Change in the total score for treatment satisfaction in the Diabetes Treatment Satisfaction 
Questionnaire (DTSQ) at each assessment time point. 
• 
Changes in the total scores for all questions in the DTR-QOL Questionnaire and the total score 


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for treatment satisfaction in the DTSQ, stratified by the following factors at the start of the 
treatment period (Week 0) within each treatment group. 
 
Use of medication for treatment of comorbidities 
 
Number of daily doses of medication for treatment of comorbidities (<2 times or ≥2 times) 
 
Total number of daily tablets of medication for treatment of comorbidities (<2 tablets or 
≥2 tablets) 
 
Number of doses of the study drug or comparative drug (once weekly, once daily or twice 
daily) 
• 
Changes in the scores per question in the DTR-QOL Questionnaire at each assessment time 
point. 
• 
Changes in the scores per question in the DTSQ at each assessment time point. 
 
Safety assessment: 
• 
Adverse events 
• 
Incidence of hypoglycemia 
• 
Hospitalization for type 2 diabetes (duration and number, excluding educational hospitalization 
without worsening of diabetes) 
 
<Other Endpoints> 
• 
Laboratory tests [HbA1c, fasting blood glucose, fasting insulin, fasting glucagon, 
glycoalbumin, 1,5-AG, serum creatinine, urinary 8-OHdG (using a correction value of uric 
creatinine (8-OHdG/creatinine)) and urinary creatinine] 
• 
Treatment compliance 
• 
The Basic Information on Study Subject (Your Basic Profile) 
STATISTICAL ANALYSIS METHODS: 
<Analysis Sets> 
Two analysis sets comprising the “Full Analysis Set (FAS)” and the “Safety Population” will be 
established. The FAS used as the main efficacy analysis set is defined as “randomized subjects who 
receive at least one dose of trelagliptin or daily DPP-4 inhibitor.”  The safety population is defined 
as “subjects who receive at least 1 dose of trelagliptin or daily DPP-4 inhibitor.” 
 
<Primary endpoint> 


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• 
Change from baseline (Week 0) in total score for all question items in the DTR-QOL 
Questionnaire at the end of the treatment period (Week 12). 
(1) A comparison between the treatment groups will be carried out based on the ANCOVA 
model using a change in the total score by the end of treatment [the end of the treatment 
period (Week 12) - baseline (Week 0)] as a dependent variable; the total score at the 
baseline (Week 0), the total score of the DTR-QOL Questionnaire (<80% or ≥80%) at the 
start of the screening period and HbA1c (<8.0% or ≥8.0%) at the start of the screening 
period as covariates; and a treatment group as an independent variable. The level of 
significance will be 5% (two-sided). 
<Secondary endpoints> 
Efficacy endpoints: 
• 
Change in the total score for each factor provided through the DTR-QOL Questionnaire 
[“Factor 1: Burden on social activities and daily activities (13 questions in all)”, "Factor 2: 
Anxiety and dissatisfaction with treatment (8 questions in all)", “Factor 3: Hypoglycemia (4 
questions in all)”, and “Factor 4: Treatment satisfaction (4 questions in all)”] at each assessment 
time point. 
• 
Change in the total score for all questions in the DTR-QOL Questionnaire at each assessment 
time point. 
• 
Change in the total score for treatment satisfaction in the DTSQ at each assessment time point. 
(1) Summary statistics [sample size, mean, standard deviation (SD), maximum, minimum and 
quantile] and the two-sided 95% confidence interval (CI) for means per treatment group at 
each assessment time point will be calculated to plot the changes in means and SDs. Point 
estimates and the two-sided 95% CI for differences between the treatment groups will also 
be calculated. 
(2) Changes from the baseline (Week 0) to each assessment time point will be calculated to be 
similarly analyzed to 1) above. 
(3) The analyses below carried out on the total score for each factor provided through the 
DTR-QOL Questionnaire, and on the total score for treatment satisfaction in the DTSQ: 
A comparison between the treatment groups will be carried out based on the ANCOVA 
model using a change in the total score by the end of treatment [the end of the treatment 
period (Week 12) - baseline (Week 0)] as a dependent variable; the total score at the 
baseline (Week 0), the total score of "the DTR-QOL Questionnaire (<80% or ≥80%)" at 
the baseline (Week 0) and "HbA1c (<8.0% or ≥8.0%)" at the baseline (Week 0) as 
covariates; and a treatment group as an independent variable. The level of significance will 


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be 5% (two-sided). Note that the total score for all questions in the DTR-QOL is out of the 
scope of the analysis. 
(4) To indicate the changes in the total scores for all questions in the DTR-QOL Questionnaire 
and the total score for treatment satisfaction in the DTSQ, the summary statistics and 
two-sided 95% CI for means per treatment group will be calculated, with stratification by 
the following factors at the start of the treatment period (Week 0): 
 
Use of medication for treatment of comorbidities 
 
Number of daily doses of medication for treatment of comorbidities (<2 times or ≥2 
times) 
 
Total number of daily tablets of medication for treatment of comorbidities (<2 tablets 
or ≥2 tablets) 
 
Number of doses of the study drug or comparative drug (once weekly, once daily or 
twice daily) 
• 
Changes in the scores per question in the DTR-QOL Questionnaire at each assessment time 
point. 
• 
Changes in the scores for per question in the DTSQ at each assessment time point. 
(1) Summary statistics for measurements and the changes from the baseline (Week 0) will be 
calculated per treatment group. 
Safety endpoints: 
Frequency tables will be prepared for the incidences of adverse events, hypoglycemia, and 
hospitalization (duration and number) for type 2 diabetes after the first administration of the study 
drug or comparative drug in the “safety population” in each treatment group. 
 
<Other Endpoints> 
Summarizations below will be performed in the "full analysis set" (FAS). 
• 
Laboratory tests 
Summary statistics for measurements and the changes from the baseline (Week 0) will be 
calculated per treatment group to plot the changes in means and SDs. 
• 
Treatment compliance 
Treatment compliance of each study subject will be calculated and summary statistics of 
compliance per treatment group will be presented. 
• 
The Basic Information on Study Subject (Your Basic Profile) 
Frequency of answers to each question at each visit will be analyzed per treatment group. 


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Rationale for the number of planned study subjects: 
In this clinical study, to discuss the changes in the total score for all questions in the DTR-QOL 
Questionnaire from the baseline (Week 0) to the end of the treatment period, as the primary 
endpoint, mean changes in the daily DPP-4 inhibitor and trelagliptin groups were assumed as 14.4% 
and 19.0%, respectively. The mean change in the daily DPP-4 inhibitor group was assumed by 
reference to the data on a sodium glucose transporter 2 (SGLT2) inhibitor, from the previous 
research; and that in trelagliptin group was assumed by reference to the data from the validation trial 
of the DTR-QOL Questionnaire. The common SD was assumed as 12.1 % considering the former 
assumption. When 5% of significance level (two-sided) is based for the analysis of the primary 
endpoint, 110 subjects per group would be needed to ensure 80% power in comparisons between the 
trelagliptin group and daily DPP-4 inhibitor group. As this is a study on treatment for type 2 diabetes 
with DPP-4 inhibitors currently used in the medical setting, the number of randomized subjects was 
established as 120 subjects per group, for a total of 240 subjects, assuming a type 2 diabetes 
treatment discontinuation rate of 8%*. 
 
*Based on the results for Topic 2 of the “Strategic Studies on the Prevention of Diabetes” 
(JDOIT-2), the annual discontinuation rate for the “usual care group” without intervention is 
approximately 8%. 


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3.0 
ABBREVIATION 
AE 
adverse event 
COI 
conflict of interest 
CRO 
contract research organization 
DTSQ 
Diabetes Treatment Satisfaction Questionnaire 
DTR-QOL 
Diabetes Therapy-Related QOL 
FDA 
US Food and Drug Administration 
GCP 
Good Clinical Practice 
ICH 
International Conference on Harmonization of Technical 
Requirement for Registration on Pharmaceuticals for Human Use 
MHRA 
Medicines and Healthcare Products Regulatory Agency 
MedDRA 
Medical Dictionary for Regulatory Activities 
QOL 
Quality Of Life 
SAE 
serious adverse event 
SAP 
statistical analysis plan 


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4.0 
INTRODUCTION 
4.1 
Background 
 The aim of diabetes treatment is to maintain Quality of Life (QOL) similar to that of healthy people 
and continue the same QOL for life as that of healthy people 1). Well controlled blood glucose, lipid 
and blood pressure levels to prevent complications in the early stages and greatly influence the 
patients' QOL and prognoses. One of the characteristics of diabetes is a tendency of frequent 
treatment discontinuation because a patient tends to be unaware of his/her disease even after a 
diagnosis of diabetes due to limited subjective symptoms during the early stages without notable 
complications. However, in diabetes treatment, prevention of complications or slow disease 
progression cannot be expected unless the patient is committed to the treatment; therefore, the key 
point in diabetes treatment is to improve the patients' QOL to enable continued management of 
diabetes. On the other hand, discontinuation of diabetes treatment leads to progression of disease 
complications and poor QOL. Patients' understanding of the treatment and the relationship between 
patients and medical personnel are important 2). The research using an auto-recording system 
captured medication use reported that the level of compliance is decreased as dosing frequency 
increased 3). In this context, to minimize the dosing frequency (number of tablets) is expected to 
contribute to the improvement in the QOL and treatment satisfaction. 
Dipeptidyl peptidase 4 (DPP-4) inhibitors inhibit degradation of gastrointestinal hormones GIP and 
GLP-1, and thereby, enhance incretin effects glucose-level-dependently, and consequently decrease 
blood glucose. In Japan, the first DPP-4 inhibitor was approved in December 2009. Since then, many 
"daily-dosing" DPP-4 inhibitors have been approved one after another which required to be taken 
every day. In March 2015, trelagliptin was approved as the world's first "weekly-dosing" DPP-4 
inhibitor. In the use of trelagliptin, benefits of improving medication adherence are expected due to 
less frequent dosing compared with existing oral glucose-lowering medications, especially in 
patients who are starting oral glucose-lowering monotherapy. 
4.2 
Rationale for the proposed study 
QOL study in patients with type 2 diabetes starting treatment with oral glucose-lowering 
medications can be expected to provide useful rationales in choosing a therapeutic medication 
corresponding to various lifestyles of patients. DPP-4 inhibitors, including "daily-dosing" products, 
have presented limited evidence regarding effects on the QOL of diabetes patients. 
Accordingly, this study has been proposed to assess trends in the reduction of treatment burden using 
the Diabetes Treatment Satisfaction Questionnaire (DTSQ). Also, to assess changes and trends in the 
QOL at pre- and post-treatment of trelagliptin or a daily DPP-4 inhibitor in diabetes patients solely 


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controlled by diet/exercise therapy, comparing the "weekly-dosing" product with "daily-dosing" 
products, using the Diabetes Therapy-Related QOL (DTR-QOL) Questionnaire. 


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5.0 
STUDY OBJECTIVES AND ENDPOINTS 
5.1 
Objectives 
The objective is to assess the reduction in treatment burden during 12 weeks of trelagliptin 
administration in patients with type 2 diabetes on diet and exercise therapy only. 
5.2 
Definition of endpoints 
5.2.1 Primary endpoints 
Change from baseline (Week 0) in total score for all question items in the DTR-QOL Questionnaire 
at the end of the treatment period (Week 12) . 
5.2.2 Secondary endpoints 
5.2.2.1 Efficacy assessment: 
• 
Changes in the total score for each factor provided through the DTR-QOL Questionnaire 
[Factor 1: Burden on social activities and daily activities (13 questions in all), Factor 2: Anxiety 
and dissatisfaction with treatment (8 questions in all), Factor 3: Hypoglycemia (4 questions in 
all) and Factor 4: Treatment satisfaction (4 questions in all)] at each assessment time point. 
• 
Change in the total score for all questions in the DTR-QOL Questionnaire at each assessment 
time point. 
• 
Change in the total score for treatment satisfaction in the Diabetes Treatment Satisfaction 
Questionnaire (DTSQ) at each assessment time point. 
• 
Changes in the total scores for all questions in the DTR-QOL Questionnaire and the total scores 
for treatment satisfaction in the DTSQ, stratified by the following factors at the start of the 
treatment period (Week 0) within each treatment group. 
 Use of medication for treatment of comorbidities 
 Number of daily doses of medication for treatment of comorbidities (<2 times or ≥2 times) 
 Total number of daily tablets of medications for treatment of comorbidities (<2tablets or 
≥2 tablets) 
 
Number of doses of the study drug or comparative drug (once weekly, once daily or twice 
daily) 
• 
Changes in the score per question in the DTR-QOL Questionnaire at each assessment time 
point. 


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• 
Changes in the score per question in the DTSQ at each assessment time point. 
5.2.2.2 Safety endpoints 
• 
Adverse events 
• 
Incidence of hypoglycemia 
• 
Hospitalization for type 2 diabetes (duration and number, excluding educational 
hospitalization without worsening of diabetes) 
5.2.3 Other Endpoints 
• 
Laboratory tests [HbA1c, fasting blood glucose, fasting insulin, fasting glucagon, glycoalbumin, 
1,5-AG, serum creatinine, urinary 8-OHdG (using a correction value of uric creatinine 
(8-OHdG/creatinine)) and urinary creatinine] 
• 
Treatment compliance 
• 
The Basic Information on Study Subject (Your Basic Profile) 


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6.0 
CLINICAL STUDY DESIGN 
6.1 
Clinical study design 
<Clinical study design> 
This is a multi-center, randomized, open-label, parallel-group comparison study to assess the 
reduction in treatment burden during the administration of a DPP-4 inhibitor (trelagliptin or a daily 
DPP-4 inhibitor) for 12 weeks in patients with type 2 diabetes on diet and exercise therapy only. 
Eligible study subjects as a result of eligibility assessment after giving informed consent will be 
randomized to either of the study drug (trelagliptin) group or the comparative drug (daily DPP-4 
inhibitor) group as specified in Section 8.4. 
< Dosage and Administration> 
The study drug group: Trelagliptin 100 mg is orally administered once weekly. Trelagliptin 50 
mg is orally administered once weekly in patients with moderate renal 
impairment. 
The comparative drug group: An inhibitor is orally administered at the dosage and administration in 
the package inserts for each drug. 
<Evaluation period and visit frequency for study subjects> 
Evaluation period: 16 weeks (Screening period: 4 weeks; treatment period: 12 weeks) 
Number of visits: total 4 visits 
A study subject will visit to his/her study site at the start of the screening period (Visit 1; 
Week -4), at the start of the treatment period (Visit 2; Week 0 of the treatment period), 
during the treatment period (Visit 3; Week 4 of the treatment period) and at the end of 
the treatment period (Visit 4; Week 12 of the treatment period). 
<Planned number of study subjects> 
As the number of randomized subjects: 
The study drug (Trelagliptin) group 120 subjects 
The comparative drug (daily DPP-4 inhibitor) group 120 subjects 
<Number of study sites> 
Approximately 15 
Figure 6 (a) shows an outline of the clinical study design. Refer to Appendix A for schedule of 
examinations, observations, and evaluations. 


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Visit
Week
Time window
21 to 35
On diet and exercise therapy only
Informed consent procedure
Eligibility tests
Start of study
drug
administration
1
2
3
Daily DPP-4inhibitor
The comparative drug (Daily
DPP-4inhibitor) group
4
-4
0
4
12
70 to 97
Screening period
Treatment
　Trelaglipin 100 mgor50 mg/week
The study drug (Trelagliptin)
group
-29 to -1
0
DTR-QOL
DTR-QOL
DTR-QOL
DTR-QOL
DTSQ
DTSQ
DTSQ


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Figure 6.a 
Outline of the clinical study design 
<Outline of the clinical study> 
Duration of treatment: 12 weeks 
Number of visits: 4 visits 
6.2 
Rationale for the clinical study design 
(1) Rationale for the clinical study design 
The study was designed as an open-label, parallel-group comparative study, to assess impact 
of trelagliptin on QOL of type 2 diabetes compared with Daily DPP-4 inhibitors. In 
conducting this parallel-group comparative study, randomization with stratification will be 
performed, using "the total score for all factors (1-4) in the DTR-QOL Questionnaire (<80% 
or ≥80%)" and "HbA1c (<8.0% or ≥8.0%)" as stratification factors, for the purpose of 
adjusting effects on the reduction level of diabetes treatment burdens in patients controlled 
by diet/exercise therapy during Visit 1. 
(2) Rationale for the study period 
The treatment period was designed as 12 weeks, because switch to other treatment including 
combination therapy with other medications is recommended for a case fails to achieve the 
therapeutic target following three-month continuous administration, as the evaluation on 
responses to treatment with oral diabetic medications 1), and in a study which investigate 
changes in DTR-QOL score during treatment with sodium glucose transporter 2 (SGLT2) 
inhibitor, statistically significant increase in the score was observed at 12 weeks of treatment 
and scores at 12 weeks and 24 weeks was comparable. 
(3) Rationale for the number of planned study subjects 
See Section 13.3. 
6.3 
Premature termination of entire clinical study or premature termination of 
clinical study at a study site 
6.3.1 Premature termination criteria of entire clinical study 
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 study subject participation in the study. 


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 
When there is serious deviation from Ethical Guidelines or ICH-GCP for medical and health 
study involving human subjects. 
6.3.2 Criteria for premature termination of study sites 
Termination of involvement of a study site in the study may be requested prematurely at the 
discretion of the sponsor if the entity (e.g., principal investigator) is found to have significant 
violation of the ethical guidelines, protocol, or contractual agreement for medical and health study 
involving human subjects or becomes unable to ensure proper conduct of the study, or otherwise as 
specified in the contractual agreement. 
6.3.3 Procedures of clinical study suspension and premature termination of 
entire clinical study or clinical study at a study site 
In the event that the sponsor or a study site committee such as an Ethical Review Board decides to 
prematurely suspend or terminate the entire clinical study or clinical study at a study site, a 
study-specific procedure shall be provided by the sponsor. The procedure shall be followed by 
applicable study sites 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 study site shall be informed of the details of each protocol revision. 
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 study site shall submit the revised contents to 
committees such as the Ethical Review Board, 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 STUDY SUBJECTS 
The principal investigator or investigator shall check for all the inclusion/exclusion criteria including 
the test results prior to randomization. 
7.1 
Inclusion criteria 
Eligibility of study subjects shall be determined in accordance with the following criteria. 
1. 
Patients diagnosed as type 2 diabetes. 
2. 
Patients with a stable diet and exercise therapy only for at least 12 weeks prior to the start 
of the screening period. 
3. 
Patients who require a DPP-4 inhibitor treatment. 
4. 
Patients with HbA1c ≥6.5 % and <10.0 % at the start of the screening period. 
5. 
Patients who completed DTR-QOL questionnaire at the start of the screening period. 
6. 
Patients who have receive less than 2 types of medication for treatment of comorbidities 
(such as hypertension or dyslipidemia) at the start of the screening period (any number of 
daily doses). 
7. 
Patients who, in the opinion of the principal investigator or the investigator, are capable of 
understanding the content of the clinical study and complying with the study protocol 
requirements. 
8. 
Patients who can provide the written informed consent prior to the initiation of any study 
procedures. 
9. 
Patients aged ≥20 years at the time of informed consent. 
10. Outpatient. 
 [Rationale for the inclusion criteria] 
1-3: These were set to specify a study subject applicable to achieve objective of this  study. 
4: 
The lower and upper limits were set to include a study subject whom treatment with oral 
glucose-lowering medications is considered to require and who is suitable for 
glucose-lowering monotherapy. 
5: 
This was set because total score of DTR-QOL questionnaire at the start of the screening 
period is stratifying factor of randomization. 
6: 
This was set to minimize influences on drug taking behavior by medications for 
comorbidities in the QOL study. 
7-10: These were set as fundamentals for this study. 
7.2 
Exclusion criteria 
Study subjects meeting any of the criteria below shall not be included in this study. 


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1. Patients who are receiving any oral anti-diabetic medication for the treatment of type 2 
diabetes at the start of the screening period. 
2. Patients diagnosed as type 1 diabetes. 
3. Patients with severe renal impairment or renal failure (e.g., eGFR <30 mL/min/1.73 m2 or on 
dialysis). 
4. Patients with serious heart disease or cerebrovascular disorder, or serious pancreatic, blood, or 
other disease. 
5. Patients with a history of gastrointestinal resection. 
6. Patient with a proliferative diabetic retinopathy. 
7. Patient with malignancy. 
8. Patients with a history of hypersensitivity or allergy to DPP-4 inhibitors. 
9. Pregnant, lactating or postmenopausal women. 
10. Patients who may need to add or discontinue concomitant medication or change the dose 
during the study period. 
11. Patients who will require treatment with a prohibited concomitant medication during the study 
period. 
12. Patients participating in other clinical studies. 
13. Patients assessed ineligible in the study by the principal investigator or the investigator. 
 [Rationale for the exclusion criteria] 
1, 10: 
These were set to exclude influences on senses of burden against treatment using 
concomitant medications including diabetic medications other than the allocated oral 
glucose-lowering medication. 
2: 
This was set to exclude patients with type 1 diabetes, because the indications of 
trelagliptin and daily DPP-4 inhibitors are for "type 2 diabetes." 
3: 
This was set to exclude patients with severe renal dysfunction or renal failure, because 
trelagliptin is contraindicated in such patients. 
4-8, 11: These were set in consideration of patient safety. 
9: 
This was set because trelagliptin should not be administered in pregnant or possibly 
pregnant females unless potential therapeutic benefits outweigh risks, and because 
excretion of trelagliptin and alogliptin into milk was observed in the non-clinical studies. 
12, 13: These were set as fundamentals for this study. 


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7.3 
Prohibited concomitant drugs and permitted concomitant drugs 
The use of diabetic medications other than allocated oral glucose-lowering medication will 
be prohibited during from the start of the screening period (Week -4) until the end of the 
treatment period (Week 12). 
<Rationale of prohibited concomitant drugs> 
It was designed due to potential influences on the assessment of this clinical study. 
7.4 
Study 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. 
(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) 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. 
(4) On visit days for planned laboratory tests, give instructions for fasting ≥ 10 hours before visit 
(excluding start of observation period). 
(5) 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. 
(6) 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. 
(7) 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 study subject 
The principal investigator or investigator shall record the main reason for discontinuation of protocol 
treatment on the case report form (CRF) according to the classification described below. Refer to 
Section 9.1.15 for study subjects who withdraw from the study before randomization. 
1. Adverse events 
When the study subject had an adverse event that requires withdrawal of the study subject from 
the study because continued participation in the study would impose an unacceptable risk to the 


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study subject’s health, or when the study subject is unwilling to continue study participation 
because of the adverse event. 
2. Major protocol deviation 
When it is discovered after randomization that a study subject does not meet the eligibility 
criteria or is not adhering to the protocol, and continued participation in the study would impose 
an unacceptable risk to the study subject’s health. 
3. Lost to follow-up 
When the study subject failed to make visits and could not be contacted despite the attempts to 
contact the study subject. 
4. Voluntary termination 
When the study subject wishes to withdraw from the study. The reason for discontinuation shall 
be obtained to the extent possible. 
5. Study termination 
When the sponsor or a committee such as the Ethical Review Board or regulatory authority has 
decided to terminate the study. Refer to Section 6.3.1 for details. 
6. Pregnancy 
When a female study subject was found to be pregnant. 
Note: The study subject must discontinue the study immediately after she was found to be 
pregnant. Refer to Section 9.1.13 for the procedures. 
7. Lack of efficacy  
When efficacy of the study drug is not evident and continuation of the study may pose an 
unacceptable risk to the study subjects in the opinion of the principal investigator or 
investigator. 
8. Others 
When the principal investigator or investigator determined to terminate the study for other 
reasons. 
The specific reasons should be recorded on the CRF. 
7.6 
Procedures for discontinuation of individual study subjects 
The principal investigator or investigator shall terminate a study subject’s study participation when 
the study subject meets the criteria described in Section 7.5. Individual study subjects may 
discontinue their study participation without giving a reason at any time during the study. Should a 


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study 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 
STUDY 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 
Study drug and Comparative drug 
8.1.1 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 
<Dose and administration method> 
Trelagliptin: Trelagliptin 100 mg is orally administered once weekly. Trelagliptin 50 mg is oraly 
administered once weekly in patients with moderate renal impairment. 
8.1.2 Comparative drug 
Daily DPP-4 inhibitor: Inhibitors shown in Table 8.a are orally administered at the dosage and 
administration instructed in the package inserts of each drug. 


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Table 8.a 
Daily DPP-4 inhibitor 
Inhibitors 
Dosage and Administration 
Sitagliptin:
Vildagliptin:
Alogliptin
Linagliptin:
Teneligliptin:
Anagliptin:
Saxagliptin
Take orally in accordance 
with the instructions in the 
package inserts. 
8.2 
Overdose of the study drug 
Overdose is defined as intentional or accidental administration of the study drug or comparative drug 
at a higher dose than that specified in the package inserts, either by a health professional or by the 
study 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 serious adverse events.” 
In the event of overdose, the principal investigator or investigator shall treat the subject as required 
based on symptoms. 
8.3 
Medication other than the study drug and the comparative drug 
Prohibited concomitant drugs (refer to Section 7.3.1) may not be used. Other treatments shall be 
conducted under normal medical practice. 
In principle, concomitant medications cannot be added or withdrawn, and the dosages of 
concomitant medications cannot be changed during this clinical study period (refer to the section 
7.2). However, the addition of concomitant medications will be allowed as long as the principal 
investigator or investigator considers its necessity due to reasons such as adverse events. The 
principal investigator or investigator shall provide directions to study subjects not to take any 
medications (including over-the-counter drugs) other than the medications instructed to use without 
prior consultation. 
CCI
CCI
CCI
CCI
CCI
CCI
CCI


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8.4 
Allocation of the study drug and administration procedure 
The principal investigator or the designee  shall access the Case Registration Web System to 
allocate the study subjects. The principal investigator or the designee shall notify the information 
required for allocation in addition to the study subject identification (ID) code. Then, drugs that 
should be administered to each study subject will be notified through the Case Registration Web 
System. The principal investigator or investigator shall prescribe the study drug or comparative drug 
according to the notification, and record the drug information (the name, dose per administration, 
number of daily administration and number of tablets per administration) into the CRF of each 
research subject. 
8.5 
Preparation and storage of allocation list 
The allocation responsible person (designated by the sponsor) shall create an allocation list. 
Study subjects will be allocated at the Case Registration Center through the Case Registration Web 
System, using "the total score for the DTR-QOL Questionnaire [<80% (<168.2 as a score) or ≥80% 
(≥168.2 as a score※)]" and "HbA1c (<8.0% or ≥8.0%)" at the start of the screening period as 
stratification factors. The Case Registration Center will use the allocation list for stratification 
prepared by the allocation responsible person in operating the treatment allocation. 
※ Refer to the section 9.1.9 for the calculation method of the total score for the DTR-QOL 
Questionnaire. 
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 
Clinical study procedures 
The principal investigator or investigator shall collect data in accordance with the procedure below. 
In principle, all the tests, observations, and evaluations of study subjects shall be performed by the 
same principal investigator or investigator with the exception of the specific 20-lipoprotein fraction. 
The study schedule is provided in Appendix A. 
9.1.1 Informed consent 
The procedures for obtaining informed consent are described in Section 15.3. 
Consent shall be obtained from the study subject before initiation of study procedures. 
A study subject ID code will be given to each study subject who provided informed consent, and 
then the study subject is to be de-identified. The study subject ID code shall be used throughout the 
study period and shall not be changed. 
9.1.2 Demographic data and medical history 
The following data will be collected as demographic data: 
- 
Date of birth, sex, smoking history, alcohol intake history, the time (month and year) of diabetes 
onset (or a diabetes diagnosis) 
As medical history, the information on clinically problematic diseases and symptoms 
resolved/recovered within a year before the start of the screening period will be collected. A 
continuous disease/symptom will be considered as a comorbidity. 
9.1.3 Physical examination 
The presence/absence of clinically significant abnormalities at subsequent physical examinations 
during the course of this study treatment will be determined compared with the baseline physical 
examination. 
9.1.4 Body weight, height, and BMI 
Body weight shall be measured to one decimal place in kilograms. 
Height shall be measured to the nearest whole number in centimeters. 
The sponsor will calculate BMI using the formula below, showing one decimal place. 
Body Mass Index: BMI=body weight (kg)/[height(m)]2 
9.1.5 Concomitant drugs 
Concomitant drugs are all drugs to be given in addition to the study drug or comparative drug. Drugs 
prescribed by physicians or the over-the-counter medicines purchased by the study subjects shall be 
included. At every visit of the study subject, any use of drugs (name, dosage/administration, route of 


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administration, duration of use, and intended use) shall be investigated and recorded on the CRF 
from the start of the screening period to the completion of the clinical study. In addition, the 
followings shall be recorded on the CRF; any use of therapeutic drugs for comorbidity *; number of 
daily doses of therapeutic drugs for comorbidities (<2 times or ≥2 times); and total number of daily 
tablets of therapeutic drugs for comorbidity (<2 tablets or ≥2 tablets) from the start of the screening 
period to the completion of the clinical study. 
* For recording of any use of therapeutic drugs for comorbidity; number of daily doses of 
therapeutic drugs for comorbidity (<2 times or ≥2 times); and total number of daily tablets of 
therapeutic drugs for comorbidity (<2 tablets or ≥2 tablets), drugs for as-needed use and topical use 
and supplements are not be included. For drugs for once-weekly use, the numbers shall be divided 
by 7 for recording. 
9.1.6 Comorbidities 
A comorbidity shall be defined as a disease or symptom present at the start of the screening period or 
observed from the start of the screening period until before the start of study drug or comparative 
drug administration. Clinically problematic laboratory tests and abnormal physical examination 
findings, etc. observed through the first tests and physical examination at the start of the screening 
period shall be considered as comorbidities at the discretion of the principal investigator or 
investigator. The details of comorbidities (diagnoses) shall be investigated. 
9.1.7 Laboratory tests 
The laboratories will perform the tests shown below in accordance with the Schedule for Study 
Procedures (Appendix A). The tests will be performed under the ≥10-hour fasting condition 
(excluding start of observation period). The principal investigator or investigator will retain the 
reported results of laboratory tests along with evaluating them.. 


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Table 9.a 
Laboratory tests 
Serum chemistry  
・ HbA1c 
 
Glycoalbumin 
・ Fasting blood glucose  
・ 1,5-AG 
・ Fasting insulin  
・ serum creatinine 
・ Fasting glucagon  
 
Urinalysis  
・ urinary 8-OHdG 
 
Urinary creatinine 
The principal investigator shall keep laboratory test reference values, including the historical data. 
9.1.8 The Basic Information on Study Subject (Your Basic Profile) 
Study subjects will answer the ''Your Basic Profile'' regarding their diabetes therapy at each 
assessment time point during the screening period and treatment period. The principal investigator or 
investigator will provide directions to the study subjects to answer all questions truthfully and 
recorded the answer of each question on the CRF. Of note, in the column "Other drugs than diabetic 
drugs (e.g., for hypertension)" in the ''Your Basic Profile'', drugs prescribed in a medical institution 
shall be recorded. (Supplements and medicines for as-needed use are not included, even though it 
was prescribed in a medical institution.) 
9.1.9 DTR-QOL Questionnaire 
Subjects will answer the DTR-QOL Questionnaire (all 29 questions) 5) regarding the diabetes 
therapy being conducted at each assessment time point during the screening period and treatment 
period. The investigator will instruct the subjects to answer all questions truthfully and record the 
answer of each question of the DTR-QOL Questionnaire (29 questions in total) on the CRF. 
[Calculation of the total score based on answers of the DTR-QOL Questionnaire] 
 
Calculation method of the total score of Factor 1: "burden on social activities and daily 
activities" (13 questions in all) 
Every score of the question number 1-13 will be simply added up, and the total figure will be 
subsequently converted to percentage [the best (91) and worst (13) scores will be equivalent to 
100% and 0%, respectively]. 
 
Calculation method of the total score of Factor 2: "anxiety and dissatisfaction with treatment" 
(8 questions in all) 


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Every score of the question number 14 and 19-25 will be simply added up, and the total figure 
will be subsequently converted to percentage [the best (56) and worst (8) scores will be 
equivalent to 100% and 0%, respectively]. 
 
Calculation method of the total score of Factor 3: "hypoglycemia" (4 questions in all) 
Every score of the question number 15-18 will be simply added up, and the total figure will be 
subsequently converted to percentage [the best (28) and worst (4) scores will be equivalent to 
100% and 0%, respectively]. 
 
Calculation method of the total score of Factor 4: "treatment satisfaction" (4 questions in all) 
Each score of the question number 26-29 will be converted into reverse (i.e., 1 will be 
converted to 7, 7 will be converted to 1, and so on. The converted scores, where 7 is the best 
and 1 is the worst, have the opposite sequence of the original scores). Then, the converted 
scores will be simply added up, and the total figure will be subsequently converted to 
percentage [the best (28) and worst (4) scores will be equivalent to 100% and 0%, respectively]. 
 
Calculation method of the total score of all questions 
Each score of the question number 26-29 will be converted into reverse, as described above, 
and then these converted scores and original scores of the question number 1-25 will be simply 
added up. Subsequently, the total figure will be converted to percentage [the best (203) and 
worst (29) scores will be equivalent to 100% and 0%, respectively]. 
If some answers of a questionnaire are unavailable (i.e., missing data), the scores will be handled in 
the manner below: 
Factor 1-4: As for a factor associated with <50% missing data, the mean value calculated from 
available answers will be applied to cover the missing data. 
The total score for a factor with ≥50% missing data should not be calculated. 
The total score of whole questions should not be calculated as well, if a total score of any of the four 
factors is unavailable. 
9.1.10 DTSQ 
Subjects will answer the DTSQ (all 8 questions) 6), 7) regarding the diabetes therapy being conducted 
at each assessment time point during the treatment period. The investigator will instruct the subjects 
to answer all questions truthfully and record the answer of each question of the DTSQ (8 questions 
in total) on the CRF. 


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9.1.11 Treatment Compliance 
Throughout the study period, instructions for treatment will be given to subjects. If instructions were 
given for treatment incompliance, the details will be recorded on the source document. At each visit, 
the investigator will check with subjects the treatment compliance status with study drug or 
comparative drug. 
The investigator will instruct the subjects to record study drug or comparative drug usage on a 
“Diabetes Treatment Medication Record Card*.” The subjects will also be instructed to bring empty 
sheets allowing compliance and usage to be checked along with the “Diabetes Treatment Medication 
Record Card*” at each visit. The treatment compliance status with the study drug or comparative 
drug (administration time and quantity of the study drug or comparative drug prescribed and unused) 
will be recorded on the CRF throughout the study period. 
*: Diabetes Treatment Medication Record Card: The card contains an electronic circuit board, and 
the times that medication is taken are electronically recorded by pressing a button when medication 
is taken. 
9.1.12 Hospitalization for type 2 diabetes 
The investigator will check with study subjects any hospitalization for type 2 diabetes after the first 
administration of the study drug or comparative drug (excluding educational hospitalization without 
worsening of diabetes). The admission-discharge date will be recorded on CRF. 
9.1.13 Contraception 
Female subjects of childbearing potential (e.g., nonsterilized or premenopausal female subjects) 
must use adequate contraception from signing on the informed consent throughout the study period. 
At the time of acquisition of informed consent from an applicable study subject, signature on the 
informed consent should be acquired only after explanation is made about what is the adequate 
contraception and that the subject must avoid to be pregnant during the study period by use of the 
informed consent form until the subject thoroughly understands them. 
9.1.14 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. 


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9.1.15 Record of study subjects who are withdrawn before randomization 
A CRF shall be created for all study subjects who have signed the consent form and withdrawn 
before randomization. 
The following items are to be described on the CRF. 
• 
Date of consent obtainment 
• 
Date of birth 
• 
Gender 
• 
Eligibility 
• 
Reason for discontinuation 
The primary reason for withdrawal before randomization shall be recorded on the CRF according to 
the following classification: 
• 
Not satisfying at least one of the inclusion criteria or meeting any of the exclusion criteria 
• 
Major protocol deviation 
• 
Lost to follow-up 
• 
Voluntary discontinuation (specify the reason) 
• 
Study termination 
• 
Pregnancy 
• 
Others (specify the reason) 
Study subject ID codes assigned to study subjects withdrawn from the study before randomization 
shall not be reused. 
9.1.16 Record of randomization 
Study subjects to be randomized shall meet all of the inclusion criteria and shall not meet any of the 
exclusion criteria according to Section 8.4. The principal investigator or investigator shall specify 
the primary reason why the study subject cannot be randomized. 
9.2 
Implementation time point of the tests and observation 
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. 
9.2.1 Screening period (Week -4) 
After obtaining informed consent, the physical examination and tests will be performed for the 
determining eligibility for study enrollment. The eligibility of a patient will be determined based on 
the inclusion/exclusion criteria presented in the section 7.0. Refer to the section 9.1.16 for the 
preparation of records on a study subject withdrawn from the study before randomization. 


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Tests, observations and evaluations performed at the start of the screening period (Visit 1: Day -29 
to -1) are shown below. 
 
Informed consent 
 
Concomitant drugs＊ 
 
Inclusion/ exclusion criteria 
 
Comorbidity＊ 
 
Demographic data, medical history 
 
Laboratory tests (HbA1c only) ＊ 
 
Physical examination＊ 
 
DTR-QOL Questionnaire＊ 
 
Height, body weight and BMI 
 
The Basic Information on Study 
Subject (Your Basic Profile)＊ 
*: To be performed during from Day -29 until Day -14. 
9.2.2 Treatment period (Week 0) 
An eligible study subject in consequence of the tests, observations and evaluations before the start of 
the treatment period will be randomized in accordance with the section 8.4. 
Tests, observations and evaluations performed at the start of the screening period (Visit 2: Week 0) 
are shown below. 
 
Inclusion/ exclusion criteria 
 
DTR-QOL Questionnaire 
 
Physical examination 
 
DTSQ 
 
Concomitant drugs 
 
The Basic Information on Study 
Subject (Your Basic Profile) 
 
Comorbidity 
 
Adverse event# 
 
Laboratory tests (blood chemistry and 
urinalysis) 
 
Hospitalization for type 2 diabetes# 
 
Prescription of the study drug/ or 
comparative drug 
 
 
 
#: To be performed after the first administration (Day 1). 
9.2.3 Treatment period (Week 4) 
Tests, observations and evaluations performed during the treatment period (Visit 3: Week 4) are 
shown below. 
 
Physical examination 
 
DTR-QOL Questionnaire 
 
Concomitant drugs 
 
DTSQ 
 
Laboratory tests (blood chemistry and 
urinalysis) 
 
The Basic Information on Study 
Subject (Your Basic Profile) 
 
Prescription of the study drug/ or 
comparative drug 
 
Adverse event 


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 
Treatment Compliance 
 
Hospitalization for type 2 diabetes 
 
9.2.4 Treatment period (Week 12) or discontinuation 
Tests, observations and evaluations performed at the end of study treatment (Visit 4: Week 12) are 
shown below. 
 
Physical examination 
 
DTR-QOL Questionnaire 
 
body weight 
 
DTSQ 
 
Concomitant drugs 
 
The Basic Information on Study 
Subjects (Your Basic Profile) 
 
Laboratory tests (blood chemistry and 
urinalysis) 
 
Adverse event 
 
Treatment Compliance 
 
Hospitalization for type 2 diabetes 
 
Tests, observations and evaluations performed at the discontinuation are shown below. 
 
Physical examination 
 
DTR-QOL Questionnaire 
 
Concomitant drugs 
 
DTSQ 
 
Laboratory tests (blood chemistry and 
urinalysis) 
 
The Basic Information on Study 
Subject (Your Basic Profile) 
 
Treatment Compliance 
 
Adverse event evaluation 
 
 
 
Hospitalization for type 2 diabetes 
 
 
The reason for the discontinuation 
 


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10.0 
ADVERSE EVENTS 
10.1 
Definitions 
10.1.1 Adverse events 
An adverse event is defined as any untoward medical occurrence in a patient or a study subject 
receiving a pharmaceutical product (including the study drug or comparative drug). It does not 
necessarily have an apparent causal relationship with this pharmaceutical product (including study 
drug or comparative drug). 
An adverse event can therefore be any unfavorable and unintended sign (e.g., a clinically significant 
laboratory abnormality), symptom, or disease temporally associated with the use of a pharmaceutical 
product (including the study drug or comparative drug), regardless of whether it is considered related 
to the pharmaceutical product (including the study drug or comparative 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 comparative 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) 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: 
Abnormal laboratory values shall be recorded as adverse events when the principal investigator or 
the 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 study subject). Retest and/or continued 


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monitoring of an abnormality are not considered medical practice. 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 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 (a disease or symptom that is present at the start of the screening period or 
that is observed from the start of the screening period until before the start of study drug/or 
comparative drug administration): 
A disease or symptom that is present at the start of the screening period or that is observed from the 
start of the screening period until before the start of study drug/ or comparative drug administration 
are considered a comorbidity and not considered an adverse event. When a comorbidity 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 comorbidity 
(e.g., “aggravation of hypertension,” etc.). 
If a study 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 
study 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 the investigator shall ensure that the adverse event 
term to be reported represents the change in the condition from baseline (e.g. “worsening of…”).  
Worsening of adverse events: 
If a study subject experiences a worsening of the adverse event after a change of the study drug or 
comparative 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 the 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 study 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 treatment that were scheduled before the start of study drug or comparative 
drug administration 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 


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considered an adverse event. A complication that resulted from previously planned surgery shall be 
reported as an adverse event. 
Non-urgent surgery or treatment: 
Non-urgent surgery or treatment that does not induce a change in the condition of a study subject 
(cosmetic surgery, etc.) shall not be considered an adverse event; However, it shall be recorded in 
the source documents. Complications 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 the investigator shall make the distinction between worsening of 
a pre-existing condition and lack of therapeutic efficacy. 
Overdose of the study drug or comparative drug: 
Overdose of any medication without manifested symptoms shall not be recorded as an adverse event, 
but the overdose shall be recorded on the “Overdose” page of the CRF. Any manifested symptoms 
shall also be recorded as adverse events on the “Adverse events” of the CRF. 
10.1.3 Serious adverse event 
Of all the unfavorable medical events that develop with administration of a pharmaceutical product 
(including study drug/ or comparative 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. other medically significant condition: a medically important event that causes a risk to a 
study 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. In addition, 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 study 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 was 
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 or comparative 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. 
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 or comparative drug shall be 
classified and defined as shown below. 
Related 
An adverse event that follows a temporal sequence (including clinical course after 
discontinuation), or an adverse event in which there is at least a reasonable 


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probability that a causal relationship to the study drug or comparative drug cannot be 
ruled out, although other factors such as underlying disease, complications, or 
concomitant drugs/treatment are also suspected. 
Not 
related 
An adverse event that does not follow a temporal sequence from administration of 
the study drug or comparative drug. Very likely due to other factors such as 
underlying disease, complications, or concomitant drugs/treatment. 
10.1.7 Relationship to study procedures 
The relationship shall be recorded as “Yes” if the principal investigator or the 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 event shall be determined according to the following rules: 
Adverse events 
Date of onset 
Signs, symptoms, diseases 
(diagnoses) 
The date on which the first signs/symptoms were noted by the 
study 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 complications 
The date on which the first worsening of diseases/symptoms was 
noted by the study subject and/or the principal investigator or 
investigator. 
Onset of a test abnormality 
after the start of study drug 
administration or comparative 
drug administration 
The date on which a clinically significant laboratory abnormality 
was detected. 
Worsening of a baseline test 
abnormality after the start of 
study drug administration or 
comparative drug 
administration  
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 study subject recovered 
(including resolution with sequelae). If a study subject died due to the adverse event concerned, it 


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shall be the date of death. The adverse event shall be recorded as “ongoing” if the study subject has 
not yet recovered by the end of the study. 
10.1.10 Actions taken for the study drug or comparative drug 
Actions taken for the study drug or comparative drug shall be classified or defined as shown below. 
Drug withdrawn 
The study drug or comparative drug is discontinued because of an adverse 
event (including withdrawal by the study subject at his/her own discretion). 
When the study is discontinued but administration of the study drug or 
comparative drug is still continued, the classification should be “Dose not 
changed.” 
Dose not 
changed 
The dose was not changed after the onset of the adverse event. 
The study drug or comparative drug was discontinued, reduced, or increased 
because of another adverse event. 
The study drug was discontinued or reduced for a reason other than the 
adverse event, e.g., inadvertence of the study subject. 
Unknown 
It has not been possible to determine what action has been taken because the 
study subject is lost to follow-up. 
Not Applicable 
The administration of the study drug or comparative drug had already been 
completed or discontinued before the onset of the adverse event. 
Dose reduced 
The dose of the study drug or comparative drug is reduced because of an adverse 
event (including dose reduction by the study subject at his/her own discretion). 
Dose increased 
The dose of the study drug or comparative drug was increased because of the 
adverse event (including dose increase by the study subject at his/her own 
discretion). 
Washout 
If administration of the study drug or comparative drug is suspended (i.e., 
interrupted) (including suspension/interruption by the study subject at his/her own 
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 study subject died from a cause other than the concerned adverse event 
while the condition was resolving (recording of the date of death unnecessary) 


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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 study 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 
Death 
- Direct relationship between death and the concerned adverse event, etc. 
“Direct relationship” means that the concerned adverse event, etc. was the 
cause of death, or the concerned adverse event, etc. 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 study subject is not considered as 
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 and its coverage 
10.2.1.1 Adverse event collection period 
Adverse events shall be collected from the start of administration with the study drug/ or 
comparative drug (day1) until completion of the treatment period (or discontinuation). 
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 study subjects experiencing an adverse 
event irrespective of the causal relationship with the study drug or comparative drug, until the 
symptom resolve, or any clinically significant abnormal laboratory values have returned to baseline 
or there is a satisfactory explanation for the change (permanent and irreversible adverse events, etc.). 
All adverse events shall be recorded in the CRF. For the adverse event, the name, date of onset, date 
of resolution, category, severity, causal relationship with the study procedures (the procedure 
possibly having causal relationship, if applicable), causal relationship with the study drug or 
comparative drug (i.e. "Not related" or "Related"), action taken for the study drug or comparative 
drug, outcome, and seriousness shall be recorded. 


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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 
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 
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 after notification of the onset by the study subject, 
the principal investigator shall report the serious adverse event to the chief executive of the study site 
immediately, and the sponsor or the contract research organization (CRO) to whom the sponsor has 
entrusted responsibility shall notify the principal investigator of the study site. 


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The principal investigator shall then report the serious adverse event to the sponsor (for the contact 
information, refer to the attachment) within 1 working day after notification of the onset. Further, the 
investigator shall submit a formal report within 10 calendar days to the sponsor. 
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 
• 
Study subject ID code 
• 
Name of principal investigator or the investigator 
• 
Name of the study drug or comparative 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 Electronic Data Capture (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, principal 
investigator or the 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 study site (e.g., ECG charts, laboratory test values, discharge summary, 
postmortem results) shall be sent to the sponsor or the committee such as the Ethical Review Board 
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 Ethical Review Board, etc., and 
regulatory authorities 
When the chief executive of study site receives a report of a serious adverse event from the principal 
investigator, the chief executive of study site shall consult the Ethical Review Board, etc., and notify 


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the study sites that are conducting the clinical study through the sponsor or the CRO consigned by 
the sponsor. 
When the principal investigator reported a serious adverse event for which a causal relationship to 
the study (study drug or comparative drug) cannot be ruled out and is unexpected, the chief 
executive of the study site 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 study sites 
conducting the clinical study. (The chief executive of the study site may report it to the Minister of 
Health, Labour and Welfare via the sponsor, and notify it to other clinical study sites via the 
sponsor.) 
• 
Actions taken for serious adverse events 
(discontinuation of new enrollment, revision of informed consent form, re-consents to other 
study subjects, etc.) 
• 
Date of review, summery of review, result, necessary action, etc., related to Ethical Review 
Board, etc. 
• 
Notification to other collaborative study sites 
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 the chief executive of study site. 
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 risk-benefit of the study drug or comparative drug, continuation of administration of the study 
drug or comparative drug, or continuation of clinical study. The study site shall submit copies of 
emergency report documents to the Ethical Review Board, etc. 


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11.0 
COMMITTEES ESTABLISHED FOR THIS STUDY 
11.1 
Clinical Study Steering Committee 
The Clinical Study Steering Committee is composed of the chair and the sponsor. The 
Clinical Study Steering Committee supervise implementation and reporting of the 
clinical study, secure medical guidance of a high degree of professionalism and a 
high-level scientific quality, and revise the study protocol appropriately. The 
responsibilities of the committee shall be prescribed in the procedures of the Clinical 
Study Steering Committee. 
 


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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 comorbidities shall be coded using the MedDRA. Drugs shall 
be coded using the World Health Organization (WHO) Drug Dictionary. 
12.1 
Case report form 
The principal investigator or investigator shall complete a CRF for each study subject who has 
signed the informed consent form. 
The sponsor or the designee shall provide access rights to the EDC system to the study site. Before 
use of the EDC 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. CRF must be completed 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 CRF. 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 (unless recorded in the source document). 
• 
Eligibility, completion status, reason for discontinuation, seriousness of adverse events, 
severity of adverse events and causal relationship between adverse events and the study 
drug or comparative drug or the study procedures, and outcome 
The following data shall not be recorded directly into the CRF. 
• 
Laboratory test values 
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; DCF) 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. 
The sponsor or the designee shall confirm that the CRFs are completed appropriately according to 
the procedures set by study. The sponsor or the designee shall have access to the medical records of 


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the study 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 the 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 EDC system 
The sponsor or the designee shall request the principal investigator and investigator to promptly 
enter data into the EDC following enrolment of the study subject, each visit during treatment with 
the study drug or comparative drug, completion/discontinuation of the study, and follow-up period. 
12.3 
Storage of records 
The principal investigator or the chief executive of the study site shall store the following materials, 
including those specified in Section 12.1, and study-specific documents to be investigated or audited 
by the regulatory authority and the sponsor or the designee. The documents include the list of study 
subject ID code, medical records, clinical study worksheets (if used), original signed and dated 
informed consent forms, the record (copy) of modification or correction on the CRF, and electric 
copies of EDC including audit trail. The principal investigator and the chief executive of the study 
site shall appropriately retain the material/information related to this study for at least 5 years from 
the date of reporting the end of the study 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 study site shall discuss the period and 
methods of storage with the sponsor. 


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13.0 
STATISTICAL ANALYSIS METHODS 
The person in charge of analysis and the designee [analysis personnel, who belongs to CRO 
independent from the sponsor] shall perform the statistical analysis. The sponsor will not be 
involved in the statistical analysis. 
13.1 
Statistical and analytical plans 
The analysis personnel shall prepare a statistical analysis plan (SAP) before the acquisition of the 
informed consent of the earliest study subject, and issue the first edition. Detailed definition of 
endpoints and analytical methods should be specified in the SAP to deal with all the purposes of the 
study. 
13.1.1 Analysis set 
Two analysis sets comprising the “Full Analysis Set (FAS)” and the “Safety Population” will be 
established. The FAS used as the main efficacy analysis set is defined as “randomized subjects who 
receive at least one dose of trelagliptin or daily DPP-4 inhibitor.”  The safety population is defined 
as “subjects who receive at least 1 dose of trelagliptin or daily DPP-4 inhibitor.” 
13.1.2 Analysis of demographic and other baseline characteristics 
From “SAS” primary study subject background items will be tabulated. 
13.1.3 Efficacy analysis 
From FAS the following shall be analyzed. 
<Primary endpoint> 
Change from baseline (Week 0) in total score for all question items in the DTR-QOL 
Questionnaire at the end of the treatment period (Week 12). 
1) 
A comparison between the treatment groups will be carried out based on the ANCOVA model 
using "the change in the total score by the end of treatment [the end of the treatment period - 
baseline (Week 0)]" as a dependent variable; "the total score at the baseline, the total score of 
the DTR-QOL Questionnaire (<80% or ≥80%) at the start of the screening period and HbA1c 
(<8.0% or ≥8.0%) at the start of the screening period as covariates; and "a treatment group" as 
an independent variable. The level of significance will be 5% (two-sided). 
<Secondary endpoints> 
Efficacy endpoints: 


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• 
Changes in the total score for each factor provided through the DTR-QOL Questionnaire 
[“Factor 1: Burden on social activities and daily activities (13 questions in all)”, Factor 2: 
Anxiety and dissatisfaction with treatment (8 questions in all), “Factor 3; Hypoglycemia (4 
questions in all)”, and “Factor 4: Treatment satisfaction (4 questions in all)”] at each assessment 
time point. 
• 
Change in the total score for all questions in the DTR-QOL Questionnaire at each assessment 
time point. 
• 
Change in the total score for treatment satisfaction in the DTSQ (evaluated with the score of 
questions #1, 4, 5, 6, 7, and 8) at each assessment time point. 
1) 
Summary statistics [sample size, mean, standard deviation (SD), maximum, minimum and 
quantile] and the two-sided 95% confidence interval (CI) for means per treatment group at 
each assessment time point will be calculated to plot the changes in means and SDs. Point 
estimates and the two-sided 95% CI for differences between the treatment groups will also 
be calculated. 
2) 
Changes from the baseline (Week 0) to each assessment time point will be calculated to be 
similarly analyzed to 1) above.  
3) 
The analyses below carried out on the total score for each factor provided through the 
DTR-QOL Questionnaire, and on the total score for treatment satisfaction in the DTSQ: 
A comparison between the treatment groups will be carried out based on the ANCOVA 
model using "the change in the total score by the end of treatment [the end of the treatment 
period (Week 12) - baseline (Week 0)]" as a dependent variable; the total score at the 
baseline (Week 0), the total score of "the DTR-QOL Questionnaire (<80% or ≥80%)" at 
the baseline (Week 0) and "HbA1c (<8.0% or ≥8.0%)" at the baseline (Week 0) as 
covariates; and "a treatment group" as an independent variable. The level of significance 
will be 5% (two-sided). Note that the total score for all questions in the DTR-QOL is out 
of the scope of the analysis. 
4) 
To indicate the changes in the total scores for all questions in the DTR-QOL Questionnaire 
and the total scores for treatment satisfaction in the DTSQ, the summary statistics and 
two-sided 95% CI for means per treatment group will be calculated, with stratification by 
the following factors at the start of the treatment period (Week 0): 
 
Use of medication for treatment of comorbidities 
 
Number of daily doses of medication for treatment of comorbidities (<2 times or ≥2 
times) 


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 
Total number of daily tablets of medication for treatment of comorbidities (<2 tablets 
or ≥2 tablets) 
 
Number of doses of the study drug or comparative drug (once weekly, once daily or 
twice daily) 
• 
Changes in the scores per question in the DTR-QOL Questionnaire at each assessment time 
point. 
• 
Changes in the scores for per question in the DTSQ at each assessment time point. 
1) 
Summary statistics for measurements and the changes from the baseline (Week 0) will be 
calculated per treatment group. 
<Other endpoints> 
Summarizations below will be performed in the "full analysis set" (FAS). 
• 
Laboratory tests 
Treatment compliance of each study subject will be calculated and summary statistics of 
compliance per treatment group will be presented. 
• 
Treatment compliance 
Treatment compliance of each study subject will be calculated and summary statistics of 
compliance per treatment group will be presented. 
• 
The Basic Information on Study Subject（Your Basic Profile） 
Frequency of answers to each question at each visit will be analyzed per treatment group. 
13.1.4 Safety analysis 
Frequency tables will be prepared for the incidences of adverse events, hypoglycemia, and 
hospitalization for type 2 diabetes (number and duration of hospitalization) after the first 
administration of the study drug or comparative drug administration in the “safety population” in 
each treatment group. 
13.2 
Criteria for interim analysis and premature discontinuation 
No interim analysis is planned. 
13.3 
Determination of the number of planned study subject  
In this clinical study, to discuss changes in the total score for all questions in the DTR-QOL 
Questionnaire from the baseline (Week 0) to the end of the treatment period, as the primary endpoint, 
mean changes in the daily DPP-4 inhibitor and trelagliptin groups were assumed as 14.4% and 


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19.0%, respectively. The mean change in the daily DPP-4 inhibitor group was assumed by reference 
to the data on SGLT2 inhibitor, from the previous research 4); and that in trelagliptin group was 
assumed by reference to the data from the validation trial of the DTR-QOL Questionnaire 6). The 
common SD was assumed as 12.1 % considering the former assumption. When 5% of significance 
level (two-sided) is based for the analysis of the primary endpoint, 110 subjects per group would be 
needed to ensure 80% power in comparisons between the trelagliptin group and daily DPP-4 
inhibitor group. As this is a study on treatment for type 2 diabetes with DPP-4 inhibitors currently 
used in the medical setting, the number of randomized subjects was established as 120 subjects per 
group, for a total of 240 subjects, assuming a type 2 diabetes treatment discontinuation rate of 8%*.  
*Based on the results for Topic 2 of the “Strategic Studies on the Prevention of Diabetes” (JDOIT-2), 
the annual discontinuation rate for the “usual care group” without intervention is approximately 8% 
2). 


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14.0 
QUALITY CONTROL AND QUALITY ASSURANCE 
14.1 
Monitoring of the study site 
The sponsor or the designee shall perform periodic monitoring of the study site during the study to 
confirm that the study is conducted in accordance with all specifications in the study protocol. In the 
monitoring, 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 study site shall ensure that the sponsor or the designee and 
the Ethical Review Board, etc., have access to the source documents. 
The sponsor or the designee shall access the records, including the list of study subject ID codes, 
medical records of the study subjects, and signed and dated original consent forms to confirm that 
the study is appropriately conducted in compliance with the study protocol. Also, confirm the 
consistency between CRF and the related source documents. The principal investigator, investigator, 
and other personnel involved in the study shall spare sufficient time to facilitate monitoring 
procedures during visits to the study site. 
Detailed procedures for monitoring shall be described separately in the written procedures. 
14.2 
Deviation from the Ethical Guidelines for Medical and Health Research 
Involving Human Subjects and the study protocol 
The principal investigator or investigator shall record all deviations from Ethical Guidelines for 
Medical and Health Research Involving Human Subjects, and study protocol. 
If any deviation is found, the principal investigator shall promptly notify the chief executive of the 
study site for the clinical study 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 study site for approval of the 
committee such as the Ethical Review Board. 
14.3 
Quality assurance audits and regulatory agency inspections 
The sponsor or the designee shall perform audit at the study site as necessary. In such a case, the 
auditor designated by the sponsor shall contact the study site 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 study. In addition, this study 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 study 
site is contacted for an inspection by a regulatory body, the sponsor should be notified promptly. The 


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principal investigator and the chief executive of the study site shall ensure that the auditor has access 
to all the study-related source documents. 


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15.0 
ETHICAL CONDUCT OF CLINICAL STUDY 
This clinical study shall be conducted with the highest respect for the individual participants (i.e., 
study subjects) according to the study protocol, the ethical principles that have their origin in the 
Declaration of Helsinki, and “Ethical Guidelines for Medical and Health Research Involving Human 
Subjects.” Each principal investigator will conduct the study according to regulatory requirements 
and in accordance with “Responsibilities of the Principal 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 the designee should obtain the document listing the name and title of each committee 
member. When a committee member directly participates in this clinical study, the document 
describing that he/she is not participating in deliberation or voting for the study will be obtained. 
The sponsor or the designee shall supply relevant documents for submission to study site committee 
such as the Ethical Review Board for the protocol’s review and approval. In addition to the study 
protocol, a copy of the informed consent form and information sheet, written materials related to 
study subject recruitment, advertisement, and other documents required by regulations, when 
necessary, shall be submitted to the central committee or a study site committee such as the Ethical 
Review Board to obtain approval. The sponsor or the designee must obtain written approval of the 
protocol and the informed consent form and information sheet from the study site committee such as 
the Ethical Review Board before commencement of the study. The study site committee such as the 
Ethical Review Board’s approval must refer to the study by exact protocol title, number and version 
date; identify versions of other documents (e.g., informed consent form and information sheet) 
reviewed; and state the approval date. The sponsor shall notify the study site, the principal 
investigator, and investigator after confirming the validity of the regulatory documents of the study 
site. Protocol procedures such as obtainment of consent shall not be started until the study site, the 
principal investigator, and investigator receive notification. 
The study site shall observe all requirements that the Ethical Review Board, etc. prescribe. The 
requirements may include notifications to committees such as the Ethical Review Board, for 
example, revision of the protocol, revision of the informed consent form and information sheet, 
revision of materials related to study subject recruitment, reports on safety in accordance with the 
regulatory requirements, reports on status of implementation of the study at intervals determined by 
a study site committee such as the Ethical Review Board, and submission of the study completion 
report. The sponsor or the designee shall obtain written approval from the Ethical Review Board, etc. 
related to the above mentioned items and all related materials. 


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15.2 
Conflict of interest 
This clinical study shall be conducted with the support of the sponsor. 
Prior to the conduction of this clinical study, the principal investigators involved in this clinical 
study shall ensure appropriate management of any conflicts of interest (COI) in the conduct of the 
study in accordance with the rules of the study site.9)-13) 
The study site shall observe all requirements that the Ethical Review Board, etc. prescribe. This will 
include self-declaration of COI, clinical study protocol, informed consent form and information 
sheet. 
15.3 
Informed consent form and information sheet, and the agreement of the 
study subjects 
The informed consent 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 study subjects in this clinical study (both in and 
outside Japan: supply to a third party), and disclosure. The informed consent form will explain in 
detail the nature of the clinical study, its objectives, and potential risks and benefits. The informed 
consent form will detail the requirements of the participant and the fact that study subject is free to 
withdraw at any time without giving a reason and without any negative effect on 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 Ethical Review Board. The 
informed consent form and information sheet must be approved by the committee such as the Ethical 
Review Board prior to use. 
The informed consent form shall be written in language that can be easily understood by the 
potential study subjects. The principal investigator or investigator shall be responsible for providing 
detailed explanation of the informed consent form to the potential study subjects. Information should 
be given in both oral and written form whenever possible and in manner deemed appropriate by the 
committee such as the Ethical Review Board. 
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 study 
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 study subject. 
The principal investigator or investigator shall follow the same procedure as for obtaining the initial 
consent when newly obtaining re-consent from the concerned study subject when the informed 


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consent form and information sheet is revised. The date of obtaining new consent shall be recorded 
in the study subject’s medical record, and a copy of the revised consent form shall be provided to the 
study subject. 
15.4 
Personal information of the study subjects 
The sponsor or the designee shall affirm the principle of the protection of study subjects' 
private/personal information. Throughout this study, study subject ID codes shall be used to link the 
subject's source data to the sponsor's study database and study-related documents. Limited 
information on study subjects such as gender, age, and date of birth may be used within the scope of 
all applicable laws and regulations for identification of study subjects and confirmation of accuracy 
of study subject ID code. 
For verification of the conduct of the study 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 study sponsor’s designee, representatives of regulatory 
authorities, designated auditors, and committees such as the Ethical Review Board direct access to 
study subjects’ original medical records (source data or documents), including laboratory test results, 
admission and discharge records during a subject’s study participation, and autopsy reports. The 
principal investigator or investigator shall obtain specific authorization of the study subject as part of 
the informed consent process for access to study subject's original medical records by study 
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 study 
subject, other personal information not recorded on the CRF of the study subject). 
15.5 
Consultation windows for the study subjects or persons related to the study 
concerned 
The principal investigator shall establish a contact service to respond to inquiries concerning this 
clinical study from study subjects or concerned people. Details of the contacts for inquiries will be 
described in the informed consent form and information sheet. 
15.6 
Financial burden or reward to the study subjects 
Of the expenses for this clinical study, the sponsor shall offer compensation for medical treatment 
not covered by health insurance as study expenses. The study 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 study to the study subjects at each visit from the research funds. Details 


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of the financial burden on the study subjects and rewards shall be described in the informed consent 
form and information sheet. 
15.7 
Benefits and inconveniences to the study subjects 
15.7.1 Benefits to study subjects 
Study subjects can deeply learn their own conditions of type 2 diabetes including such as the change 
in the QOL associated with the change in treatment approaches and the level of treatment 
satisfaction, through the study participation 
15.7.2 Inconveniences to study subjects 
Burdens of study subjects may be increased due to requirements of providing answers to the Basic 
Information on Study Subject, DTR-QOL Questionnaire and DTSQ, through the study participation. 
15.8 
Attribution of study results and access rights 
15.8.1 Attribution of study results 
The study results and data obtained from this study shall belong to the sponsor. In addition, 
secondary use (meta-analysis, etc.) of the data obtained in this clinical study 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. 
15.9 
Reporting of results, publication, disclosure, and clinical study registration 
policy 
15.9.1 Reporting of results, publication and disclosure 
The principal investigator shall report a written summary of results of the study to the chief 
executive of the study site and provide the sponsor with all the results and data obtained from the 
study. Only the sponsor may disclose the study information to other principal investigators, 
investigators or regulatory authorities during the study period, except when required by laws and 
regulations. The sponsor shall be responsible for publication of the study protocol and study-related 
results (including the public web site) except for other cases permitted in the study contract. 
During the study period and after the end of study, the sponsor or the designee should promptly 
summarize the results and present it to medical journals and academic conferences, etc. The sponsor 


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may publish any data or information obtained from the study (including data and information 
provided by the principal investigator) without obtaining agreement 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 study at an academic conference, etc. 
15.9.2 Clinical study registration 
To ensure that information on clinical study 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 study 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), before initiation of the clinical study. On 
such websites, the study location (city, country), study 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 study 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 
In case of injuries, each study subject in the clinical study must be insured in accordance with the 
regulations applicable to the study site where the subject is participating. The sponsor or the 
designee shall buy an insurance policy to compensate for health injury in study subjects. 
Healthy injury in a study 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 the designee. 


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16.0 
REFERENCES 
1. 
Treatment Guide for Diabetes 2016-2017. Edited by Japan Diabetes Society. BUNKODO 
Corp. 2016 
2. 
Izumi K, Noda M. In order to reduce the interruption of diabetes treatment. Diabetes Frontier. 
2014;25:709-718. 
3. 
Paes AH, Bakker A, Soe-Agnie CJ. Impact of dosage frequency on patient compliance. 
Diabetes Care. 1997;20:1512-1517. 
4. 
Yamazaki M, Higo N, Kaneko T, et.al. SGLT2 Inhibitors As the Trigger for Diabetes Care: 
Reconfirmed Importance of Behavior Modification After Drug Administration. J.Japan 
Dab.Soc.2015;58:745-752. 
5. 
Ishii H. Development and psychometric validation of the Diabetes Therapy-Related QOL 
(DTR-QOL) questionnaire. J Med Econ. 2012;15:556-563. 
6. 
Bradley C: Diabetes treatment satisfaction questionnaire (DTSQ). In: Handbook of 
psychology and diabetes (ed. by Bradley C.). Harwood Academic Pubi., Chur, 1994 
7. 
Ishii H, Bradley C, Riazi A, et al. The Japanese Version of the Diabetes Treatment 
Satisfaction Questionnaire (DTSQ): translation and clinical evaluation. Journal of Clinical 
and Experimental Medicine. 2000;192:809-14. (A Japanese Journal published in Japanese) 
8. 
Sadamoto K, Takamori H, Sadamoto T, et al. Impact of push-through-packages with 
electronic devices for accurate drug taking. Journal of Scientific and Innovative Research. 
2014;3:288-294. 
9. 
Report of the Working Group on Conflict of Interest (Ministry of Education, Culture, Sports, 
Science and Technology dated November 1, 2002) 
10. Guidelines for determining the conflict of interest polity for clinical research (Review group 
for ethical aspects of clinical study and conflict of interest, March 2006) 
11. Guidelines on the Management of COI in Health and Labor Sciences Research (No. 0331001, 
science, issued on March 31, 2008, and approved by the Chief of the Health Sciences 
Division) 
12. Guidelines for management of COI in medical research (COI Committee of Japan 
Association of Medical Sciences, February 2011) 
13. Common guidelines for conflict of interest (COI) in clinical research (Japanese Society of 
Internal Medicine, Japan Society of Hepatology, 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, Japan Geriatrics Society, Aug 2011) 


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PROTOCOL 
 
 
 
 
 
Study of the QOL evaluation of TRElagliptiN in patient with type 2 DiabeteS mellitus 
(TRENDS)  
 
 
 
 
 
 
 
Sponsor 
Takeda Pharmaceutical Company Limited 
12-10 Nihonbashi 2-chome, Chuo-ku, Tokyo 
Protocol number 
Trelagliptin-4002 
Version number/Revision number 
Version 1.0 
Study drug 
Trelagliptin 
Creation date 
November 2, 2016 
 
 
 
 
 


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CONFIDENTIAL PROPERTY 
This document is a confidential communication of Takeda. Acceptance of this document constitutes 
agreement by the potential recipient 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 study 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 
STUDY ADMINISTRATIVE INFORMATION AND CLINICAL STUDY 
PRINCIPLES 
1.1 
Clinical study principles 
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: International Conference on 
Harmonization of Technical Requirement for Registration on Pharmaceuticals for Human Use. 
E6) 
• 
All applicable laws and regulations, including, without limitation, data privacy laws and conflict 
of interest guidelines. 
 
1.2 
Clinical study implementation system 
This study will be conducted in accordance with the requirements of this clinical study protocol 
designed and prepared by the sponsor and also in accordance with the following. Other study 
administrative structures are shown in the separate documents. 
Sponsor 
Japan Medical Affairs, Japan Pharma Business Unit, Takeda Pharmaceutical Company Limited 
The sponsor shall be responsible for matters related to planning/preparation, 
implementation/operation, and results/reporting in this clinical study. Methods of supervision of the 
contractor entrusted with the services related to this clinical study will be described in the procedure 
to be prepared separately. 
Expenses* required for the operation of this clinical study will be paid by the sponsor. 
* :  Based on the “Consignment Service Contract,” expenses incurred for the services of Office of 
Clinical Study, monitoring, registration/allocation center, and statistical processing shall be paid 
to the contractor entrusted with services related to this clinical study. Expenses agreed by the 
study site shall be paid to the site based on the “Research Expense Standard.” 
 
 


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Chair of the Clinical Study Steering Committee: 
 
Terms in this protocol are defined as follows: 
Study site: 
A corporation, governmental agency and sole proprietor conducting the study, excluding cases 
where only a part of the services related to storage of samples/information, statistical processing 
and other studies are entrusted. 
Investigators: 
Principal investigators and other parties involved in conduction of the study (including operations 
at institutions involved in collection/distribution of samples/information). Those involved only in 
providing existing samples/information outside the study sites and those engaged in part of the 
entrusted operations related to the study are excluded. 
Principal Investigator: 
An investigator who is engaged in implementation of the study and integrates the operations 
involved in this study at an affiliated study site. 
Chief executive of the study site: 
A representative of a corporation, head of a governmental agency, or a sole proprietor 
Study subject: 
A subject (including a dead subject) who meets any of the following:  
1. 
Subjects being studied (including those who have been asked to be studied)  
2. 
Subjects from whom existing samples/information to be used in the study have been 
obtained. 
 
PPD


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Table of Contents 
1.0 
STUDY ADMINISTRATIVE INFORMATION AND CLINICAL STUDY 
PRINCIPLES ........................................................................................................... 3 
1.1 
Clinical study principles .................................................................................... 3 
1.2 
Clinical study implementation system ............................................................... 3 
2.0 
STUDY SUMMARY ............................................................................................ 10 
3.0 
ABBREVIATION ................................................................................................. 17 
4.0 
INTRODUCTION ................................................................................................. 18 
4.1 
Background ...................................................................................................... 18 
4.2 
Rationale for the proposed study ..................................................................... 18 
5.0 
STUDY OBJECTIVES AND ENDPOINTS ........................................................ 20 
5.1 
Objectives ........................................................................................................ 20 
5.2 
Definition of endpoints .................................................................................... 20 
5.2.1 Primary endpoints ...................................................................................... 20 
5.2.2 Secondary endpoints .................................................................................. 20 
5.2.3 Other Endpoints ......................................................................................... 21 
6.0 
CLINICAL STUDY DESIGN............................................................................... 22 
6.1 
Clinical study design ....................................................................................... 22 
6.2 
Rationale for the clinical study design ............................................................ 24 
6.3 
Premature termination of entire clinical study or premature termination 
of clinical study at a study site ........................................................................ 24 
6.3.1 Premature termination criteria of entire clinical study .............................. 24 
6.3.2 Criteria for premature termination of study sites....................................... 25 
6.3.3 Procedures of clinical study suspension and premature termination of 
entire clinical study or clinical study at a study site .................................. 25 
6.4 
Procedures for protocol revision ..................................................................... 25 
7.0 
SELECTION AND WITHDRAWAL CRITERIA OF STUDY SUBJECTS ....... 26 
7.1 
Inclusion criteria .............................................................................................. 26 
7.2 
Exclusion criteria ............................................................................................. 26 
7.3 
Prohibited concomitant drugs and permitted concomitant drugs .................... 28 
7.4 
Study subject management .............................................................................. 28 


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7.5 
Criteria for discontinuation or withdrawal of a study subject ......................... 28 
7.6 
Procedures for discontinuation of individual study subjects ........................... 29 
8.0 
STUDY TREATMENT ......................................................................................... 31 
8.1 
Study drug and Comparative drug ................................................................... 31 
8.1.1 Study drug ................................................................................................. 31 
8.1.2 Comparative drug ...................................................................................... 31 
8.2 
Overdose of the study drug .............................................................................. 32 
8.3 
Medication other than the study drug and the comparative drug .................... 32 
8.4 
Allocation of the study drug and administration procedure ............................ 33 
8.5 
Preparation and storage of allocation list ........................................................ 33 
9.0 
CLINICAL STUDY PROTOCOL ........................................................................ 34 
9.1 
Clinical study procedures ................................................................................ 34 
9.1.1 Informed consent ....................................................................................... 34 
9.1.2 Demographic data and medical history ..................................................... 34 
9.1.3 Physical examination ................................................................................. 34 
9.1.4 Body weight, height, and BMI .................................................................. 34 
9.1.5 Concomitant drugs ..................................................................................... 34 
9.1.6 Comorbidities ............................................................................................ 35 
9.1.7 Laboratory tests ......................................................................................... 35 
9.1.8 The Basic Information on Study Subject (Your Basic Profile) ................. 36 
9.1.9 DTR-QOL Questionnaire .......................................................................... 36 
9.1.10 DTSQ ......................................................................................................... 37 
9.1.11 Treatment Compliance .............................................................................. 38 
9.1.12 Hospitalization for type 2 diabetes ............................................................ 38 
9.1.13 Contraception ............................................................................................ 38 
9.1.14 Pregnancy .................................................................................................. 38 
9.1.15 Record of study subjects who are withdrawn before randomization......... 39 
9.1.16 Record of randomization ........................................................................... 39 
9.2 
Implementation time point of the tests and observation .................................. 39 
9.2.1 Screening period (Week -4) ....................................................................... 39 
9.2.2 Treatment period (Week 0)........................................................................ 40 


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9.2.3 Treatment period (Week 4)........................................................................ 40 
9.2.4 Treatment period (Week 12) or discontinuation........................................ 41 
10.0 
ADVERSE EVENTS ............................................................................................ 42 
10.1 
Definitions ....................................................................................................... 42 
10.1.1 Adverse events ........................................................................................... 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 ......................................................................... 45 
10.1.6 Causality of adverse events ....................................................................... 45 
10.1.7 Relationship to study procedures ............................................................... 46 
10.1.8 Date of onset .............................................................................................. 46 
10.1.9 Date of resolution ...................................................................................... 46 
10.1.10Actions taken for the study drug or comparative drug .............................. 47 
10.1.11Outcome .................................................................................................... 47 
10.2 
Procedures ....................................................................................................... 48 
10.2.1 Collection and reporting of adverse events and its coverage .................... 48 
10.2.2 Collection and reporting of serious adverse events ................................... 49 
10.2.3 Reporting of additional information concerning adverse events ............... 50 
10.3 
Follow-up of serious adverse events ............................................................... 50 
10.3.1 Reporting of serious adverse events to Ethical Review Board, etc., 
and regulatory authorities .......................................................................... 50 
11.0 
COMMITTEES ESTABLISHED FOR THIS STUDY ........................................ 52 
11.1 
Clinical Study Steering Committee ................................................................. 52 
12.0 
DATA MANAGEMENT AND STORAGE OF RECORDS ............................... 53 
12.1 
Case report form .............................................................................................. 53 
12.2 
Timing of data entry into the EDC system ...................................................... 54 
12.3 
Storage of records ............................................................................................ 54 
13.0 
STATISTICAL ANALYSIS METHODS ............................................................. 55 
13.1 
Statistical and analytical plans ......................................................................... 55 
13.1.1 Analysis set ................................................................................................ 55 


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13.1.2 Analysis of demographic and other baseline characteristics ..................... 55 
13.1.3 Efficacy analysis ........................................................................................ 55 
13.1.4 Safety analysis ........................................................................................... 57 
13.2 
Criteria for interim analysis and premature discontinuation ........................... 57 
13.3 
Determination of the number of planned study subject ................................... 57 
14.0 
QUALITY CONTROL AND QUALITY ASSURANCE .................................... 59 
14.1 
Monitoring of the study site ............................................................................ 59 
14.2 
Deviation from the Ethical Guidelines for Medical and Health Research 
Involving Human Subjects and the study protocol .......................................... 59 
14.3 
Quality assurance audits and regulatory agency inspections........................... 59 
15.0 
ETHICAL CONDUCT OF CLINICAL STUDY .................................................. 61 
15.1 
Approval of the Ethical Review Board, etc. .................................................... 61 
15.2 
Conflict of interest ........................................................................................... 62 
15.3 
Informed consent form and information sheet, and the agreement of the 
study subjects ................................................................................................... 62 
15.4 
Personal information of the study subjects ...................................................... 63 
15.5 
Consultation windows for the study subjects or persons related to the 
study concerned ............................................................................................... 63 
15.6 
Financial burden or reward to the study subjects ............................................ 63 
15.7 
Benefits and inconveniences to the study subjects .......................................... 64 
15.7.1 Benefits to study subjects .......................................................................... 64 
15.7.2 Inconveniences to study subjects ............................................................... 64 
15.8 
Attribution of study results and access rights .................................................. 64 
15.8.1 Attribution of study results ........................................................................ 64 
15.8.2 Data access rights ...................................................................................... 64 
15.9 
Reporting of results, publication, disclosure, and clinical study 
registration policy ............................................................................................ 64 
15.9.1 Reporting of results, publication and disclosure ....................................... 64 
15.9.2 Clinical study registration .......................................................................... 65 
15.9.3 Clinical trial results disclosure .................................................................. 65 
15.10 Insurance and compensation for injury ........................................................... 65 
16.0 
REFERENCES ...................................................................................................... 66 


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LIST OF IN-TEXT TABLES 
Table 8.a  
Daily DPP-4 inhibitor ................................................................................ 32 
Table 9.a 
Laboratory tests ......................................................................................... 36 
Table 10.a 
Takeda Medically Significant AE List ...................................................... 45 
LIST OF IN-TEXT FIGURES 
Figure 6.a 
Outline of the clinical study design ........................................................... 24 
 


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2.0 
STUDY SUMMARY 
Sponsor: 
Takeda Pharmaceutical Company Limited 
Study drug: 
Trelagliptin  
Study title:  
Study of the QOL evaluation of Trelagliptin in patients with type 2 diabetes mellitus 
Protocol number: Trelagliptin-4002 
Clinical study design: 
This is a multi-center, randomized, open-label, parallel-group comparison study to assess the 
reduction in treatment burden during the administration of a DPP-4 inhibitor (trelagliptin or a daily 
DPP-4 inhibitor) for 12 weeks in patients with type 2 diabetes on diet and exercise therapy only. 
Subjects who are determined to be eligible based on the results of eligibility assessment after 
informed consent has been obtained will be randomized to either the study drug (trelagliptin) group 
or the comparative drug (daily DPP-4 inhibitor) group. Randomization was stratified by the total 
score (<80% (score 139.4), ≥80% (score 139.4)*)) for total score of the “Diabetes Therapy-Related 
QOL (DTR-QOL) Questionnaire” and “HbA1c (<8.0%, ≥8.0%)” at the start of the screening period. 
* A scale of 1 to 7 with 7 as the best was used for each QOL question item, and total score 
calculated by adding up scores of each question was expressed as a percentage of the maximum total 
score (i.e., the best score [203] = 100%; the worst score [29] = 0%.) 
Objectives: 
The objective is to assess the reduction in treatment burden during 12 weeks of trelagliptin 
administration in patients with type 2 diabetes on diet and exercise therapy only 
Subjects:  
Patients with type 2 diabetes on diet and exercise therapy alone 
Planned number of study subjects: 
As the number of randomized subjects: 
The study drug (Trelagliptin) group 120 subjects 
The comparative drug (daily DPP-4 inhibitor) group 
120 subjects 
Number of study sites: 
Approximately 15 
Dose and method of administration: 
The study drug (Trelagliptin) group: Trelagliptin 100 
mg is orally administered once weekly. Trelagliptin 
Route of administration: 
Oral 


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50 mg is orally administered once weekly in patients 
with moderate renal impairment. 
The comparative drug (Daily DPP-4 inhibitor) group: 
An inhibitor is orally administered at the dosage and 
administration in the package inserts for each drug. 
Duration of treatment: 
12 weeks 
Duration of evaluation: 
16 weeks 
(Screening period: 4 weeks; treatment 
period: 12 weeks) 
Inclusion criteria: 
Eligibility of study subjects shall be determined in accordance with the following criteria. 
1. 
Patients diagnosed as type 2 diabetes. 
2. 
Patients with a stable diet and exercise therapy only for at least 12 weeks prior to the start of the 
screening period. 
3. 
Patients who require a DPP-4 inhibitor treatment. 
4. 
Patients with HbA1c ≥6.5 % and <10.0 % at the start of the screening period. 
5. 
Patients who completed DTR-QOL questionnaire at the start of the screening period. 
6. 
Patients who have receive less than 2 types of medication for treatment of comorbidities (such 
as hypertension or dyslipidemia) at the start of the screening period (any number of daily 
doses). 
7. 
Patients who, in the opinion of the principal investigator or the investigator, are capable of 
understanding the content of the clinical study and complying with the study protocol 
requirements. 
8. 
Patients who can provide the written informed consent prior to the initiation of any study 
procedures. 
9. 
Patients aged ≥20 years at the time of informed consent. 
10. Outpatient. 
Exclusion criteria: 
Study subjects meeting any of the criteria below shall not be included in this study. 
1. 
Patients who are receiving any oral anti-diabetic medication for the treatment of type 2 diabetes 
at the start of the screening period. 
2. 
Patients diagnosed as type 1 diabetes. 


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3. 
Patients with severe renal impairment or renal failure (e.g., eGFR <30 mL/min/1.73 m2 or on 
dialysis). 
4. 
Patients with serious heart disease or cerebrovascular disorder, or serious pancreatic, blood, or 
other disease. 
5. 
Patients with a history of gastrointestinal resection. 
6. 
Patient with a proliferative diabetic retinopathy. 
7. 
Patient with malignancy. 
8. 
Patients with a history of hypersensitivity or allergy to DPP-4 inhibitors. 
9. 
Pregnant, lactating or postmenopausal women. 
10. Patients who may need to add or discontinue concomitant medication or change the dose during 
the study period. 
11. Patients who will require treatment with a prohibited concomitant medication during the study 
period. 
12. Patients participating in other clinical studies. 
13. Patients assessed ineligible in the study by the principal investigator or the investigator. 
ENDPOINTS: 
<Primary endpoint> 
Change from baseline (Week 0) in total score for all question items in the DTR-QOL Questionnaire 
at the end of the treatment period (Week 12). 
 
<Secondary endpoints> 
Efficacy assessment: 
• 
Changes in the total score for each factor provided through the DTR-QOL Questionnaire 
[Factor 1: Burden on social activities and daily activities (13 questions in all), Factor 2: Anxiety 
and dissatisfaction with treatment (8 questions in all), Factor 3: Hypoglycemia (4 questions in 
all) and Factor 4: Treatment satisfaction (4 questions in all)] at each assessment time point. 
• 
Change in the total score for all questions in the DTR-QOL Questionnaire at each assessment 
time point. 
• 
Change in the total score for all questions in the Diabetes Treatment Satisfaction Questionnaire 
(DTSQ) at each assessment time point. 
• 
Changes in the total scores for all questions in the DTR-QOL Questionnaire and DTSQ, 


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stratified by the following factors at the start of the treatment period (Week 0) within each 
treatment group. 
 
Use of medication for treatment of comorbidities 
 
Number of daily doses, including medication for treatment of comorbidities (<2 times or 
≥2 times) 
 
Total number of daily tablets, including medication for treatment of comorbidities (<2 
tablets or ≥2 tablets) 
 
Number of doses of the study drug or comparative drug (once weekly, once daily or twice 
daily) 
• 
Changes in the scores per question in the DTR-QOL Questionnaire at each assessment time 
point. 
• 
Changes in the scores per question in the DTSQ at each assessment time point. 
 
Safety assessment: 
• 
Adverse events 
• 
Incidence of hypoglycemia 
• 
Hospitalization for type 2 diabetes (duration and number, excluding educational hospitalization 
without worsening of diabetes) 
 
<Other Endpoints> 
• 
Laboratory tests [HbA1c, fasting blood glucose, fasting insulin, fasting glucagon, 
glycoalbumin, 1,5-AG, serum creatinine, urinary 8-OHdG (using a correction value of uric 
creatinine (8-OHdG/creatinine)) and urinary creatinine] 
• 
Treatment compliance 
• 
The Basic Information on Study Subject (Your Basic Profile) 
STATISTICAL ANALYSIS METHODS: 
<Analysis Sets> 
Two analysis sets comprising the “Full Analysis Set (FAS)” and the “Safety Population” will be 
established. The FAS used as the main efficacy analysis set is defined as “randomized subjects who 
receive at least one dose of trelagliptin or daily DPP-4 inhibitor.”  The safety population is defined 
as “subjects who receive at least 1 dose of trelagliptin or daily DPP-4 inhibitor.” 
 


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<Primary endpoint> 
• 
Change from baseline (Week 0) in total score for all question items in the DTR-QOL 
Questionnaire at the end of the treatment period (Week 12). 
(1) A comparison between the treatment groups will be carried out based on the ANCOVA 
model using a change in the total score by the end of treatment [the end of the treatment 
period (Week 12) - baseline (Week 0)] as a dependent variable; the total score at the 
baseline (Week 0), the total score of the DTR-QOL Questionnaire (<80% or ≥80%) at the 
start of the screening period and HbA1c (<8.0% or ≥8.0%) at the start of the screening 
period as covariates; and a treatment group as an independent variable. The level of 
significance will be 5% (two-sided). 
<Secondary endpoints> 
Efficacy endpoints: 
• 
Change in the total score for each factor provided through the DTR-QOL Questionnaire 
[“Factor 1: Burden on social activities and daily activities (13 questions in all)”, "Factor 2: 
Anxiety and dissatisfaction with treatment (8 questions in all)", “Factor 3: Hypoglycemia (4 
questions in all)”, and “Factor 4: Treatment satisfaction (4 questions in all)”] at each assessment 
time point. 
• 
Change in the total score for all questions in the DTR-QOL Questionnaire at each assessment 
time point. 
• 
Change in the total score for all questions in the DTSQ at each assessment time point. 
(1) Summary statistics [sample size, mean, standard deviation (SD), maximum, minimum and 
quantile] and the two-sided 95% confidence interval (CI) for means per treatment group at 
each assessment time point will be calculated to plot the changes in means and SDs. Point 
estimates and the two-sided 95% CI for differences between the treatment groups will also 
be calculated. 
(2) Changes from the baseline (Week 0) to each assessment time point will be calculated to be 
similarly analyzed to 1) above. 
(3) The analyses below carried out on the total score for each factor provided through the 
DTR-QOL Questionnaire, and on the total score for DTSQ: 
A comparison between the treatment groups will be carried out based on the ANCOVA 
model using a change in the total score by the end of treatment [the end of the treatment 
period (Week 12) - baseline (Week 0)] as a dependent variable; the total score at the 
baseline (Week 0), the total score of "the DTR-QOL Questionnaire (<80% or ≥80%)" at 
the baseline (Week 0) and "HbA1c (<8.0% or ≥8.0%)" at the baseline (Week 0) as 


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covariates; and a treatment group as an independent variable. The level of significance will 
be 5% (two-sided). Note that the total score for all questions in the DTR-QOL is out of the 
scope of the analysis. 
(4) To indicate the changes in the total scores for all questions in the DTR-QOL Questionnaire 
and DTSQ, the summary statistics and two-sided 95% CI for means per treatment group 
will be calculated, with stratification by the following factors at the start of the treatment 
period (Week 0): 
 
Use of medication for treatment of comorbidities 
 
Number of daily doses, including medication for treatment of comorbidities (<2 times 
or ≥2 times) 
 
Total number of daily tablets, including medication for treatment of comorbidities 
(<2 tablets or ≥2 tablets) 
 
Number of doses of the study drug or comparative drug (once weekly, once daily or 
twice daily) 
• 
Changes in the scores per question in the DTR-QOL Questionnaire at each assessment time 
point. 
• 
Changes in the scores for per question in the DTSQ at each assessment time point. 
(1) Summary statistics for measurements and the changes from the baseline (Week 0) will be 
calculated per treatment group. 
Safety endpoints: 
Frequency tables will be prepared for the incidences of adverse events, hypoglycemia, and 
hospitalization (duration and number) for type 2 diabetes after the first administration of the study 
drug or comparative drug in the “safety population” in each treatment group. 
 
<Other Endpoints> 
Summarizations below will be performed in the "full analysis set" (FAS). 
• 
Laboratory tests 
Summary statistics for measurements and the changes from the baseline (Week 0) will be 
calculated per treatment group to plot the changes in means and SDs. 
• 
Treatment compliance 
Treatment compliance of each study subject will be calculated and summary statistics of 
compliance per treatment group will be presented. 
• 
The Basic Information on Study Subject (Your Basic Profile) 


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Frequency of answers to each question at each visit will be analyzed per treatment group. 
Rationale for the number of planned study subjects: 
In this clinical study, to discuss the changes in the total score for all questions in the DTR-QOL 
Questionnaire from the baseline (Week 0) to the end of the treatment period, as the primary 
endpoint, mean changes in the daily DPP-4 inhibitor and trelagliptin groups were assumed as 14.4% 
and 19.0%, respectively. The mean change in the daily DPP-4 inhibitor group was assumed by 
reference to the data on a sodium glucose transporter 2 (SGLT2) inhibitor, from the previous 
research; and that in trelagliptin group was assumed by reference to the data from the validation trial 
of the DTR-QOL Questionnaire. The common SD was assumed as 12.1 % considering the former 
assumption. When 5% of significance level (two-sided) is based for the analysis of the primary 
endpoint, 110 subjects per group would be needed to ensure 80% power in comparisons between the 
trelagliptin group and daily DPP-4 inhibitor group. As this is a study on treatment for type 2 diabetes 
with DPP-4 inhibitors currently used in the medical setting, the number of randomized subjects was 
established as 120 subjects per group, for a total of 240 subjects, assuming a type 2 diabetes 
treatment discontinuation rate of 8%*. 
 
*Based on the results for Topic 2 of the “Strategic Studies on the Prevention of Diabetes” 
(JDOIT-2), the annual discontinuation rate for the “usual care group” without intervention is 
approximately 8%. 


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3.0 
ABBREVIATION 
AE 
adverse event 
COI 
conflict of interest 
CRO 
contract research organization 
DTSQ 
Diabetes Treatment Satisfaction Questionnaire 
DTR-QOL 
Diabetes Therapy-Related QOL 
FDA 
US Food and Drug Administration 
GCP 
Good Clinical Practice 
ICH 
International Conference on Harmonization of Technical 
Requirement for Registration on Pharmaceuticals for Human Use 
MHRA 
Medicines and Healthcare Products Regulatory Agency 
MedDRA 
Medical Dictionary for Regulatory Activities 
QOL 
Quality Of Life 
SAE 
serious adverse event 
SAP 
statistical analysis plan 


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4.0 
INTRODUCTION 
4.1 
Background 
 The aim of diabetes treatment is to maintain Quality of Life (QOL) similar to that of healthy people 
and continue the same QOL for life as that of healthy people 1). Well controlled blood glucose, lipid 
and blood pressure levels to prevent complications in the early stages and greatly influence the 
patients' QOL and prognoses. One of the characteristics of diabetes is a tendency of frequent 
treatment discontinuation because a patient tends to be unaware of his/her disease even after a 
diagnosis of diabetes due to limited subjective symptoms during the early stages without notable 
complications. However, in diabetes treatment, prevention of complications or slow disease 
progression cannot be expected unless the patient is committed to the treatment; therefore, the key 
point in diabetes treatment is to improve the patients' QOL to enable continued management of 
diabetes. On the other hand, discontinuation of diabetes treatment leads to progression of disease 
complications and poor QOL. Patients' understanding of the treatment and the relationship between 
patients and medical personnel are important 2). The research using an auto-recording system 
captured medication use reported that the level of compliance is decreased as dosing frequency 
increased 3). In this context, to minimize the dosing frequency (number of tablets) is expected to 
contribute to the improvement in the QOL and treatment satisfaction. 
Dipeptidyl peptidase 4 (DPP-4) inhibitors inhibit degradation of gastrointestinal hormones GIP and 
GLP-1, and thereby, enhance incretin effects glucose-level-dependently, and consequently decrease 
blood glucose. In Japan, the first DPP-4 inhibitor was approved in December 2009. Since then, many 
"daily-dosing" DPP-4 inhibitors have been approved one after another which required to be taken 
every day. In March 2015, trelagliptin was approved as the world's first "weekly-dosing" DPP-4 
inhibitor. In the use of trelagliptin, benefits of improving medication adherence are expected due to 
less frequent dosing compared with existing oral glucose-lowering medications, especially in 
patients who are starting oral glucose-lowering monotherapy. 
4.2 
Rationale for the proposed study 
QOL study in patients with type 2 diabetes starting treatment with oral glucose-lowering 
medications can be expected to provide useful rationales in choosing a therapeutic medication 
corresponding to various lifestyles of patients. DPP-4 inhibitors, including "daily-dosing" products, 
have presented limited evidence regarding effects on the QOL of diabetes patients. 
Accordingly, this study has been proposed to assess trends in the reduction of treatment burden using 
the Diabetes Treatment Satisfaction Questionnaire (DTSQ). Also, to assess changes and trends in the 
QOL at pre- and post-treatment of trelagliptin or a daily DPP-4 inhibitor in diabetes patients solely 


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controlled by diet/exercise therapy, comparing the "weekly-dosing" product with "daily-dosing" 
products, using the Diabetes Therapy-Related QOL (DTR-QOL) Questionnaire. 


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5.0 
STUDY OBJECTIVES AND ENDPOINTS 
5.1 
Objectives 
The objective is to assess the reduction in treatment burden during 12 weeks of trelagliptin 
administration in patients with type 2 diabetes on diet and exercise therapy only. 
5.2 
Definition of endpoints 
5.2.1 Primary endpoints 
Change from baseline (Week 0) in total score for all question items in the DTR-QOL Questionnaire 
at the end of the treatment period (Week 12) . 
5.2.2 Secondary endpoints 
5.2.2.1 Efficacy assessment: 
• 
Changes in the total score for each factor provided through the DTR-QOL Questionnaire 
[Factor 1: Burden on social activities and daily activities (13 questions in all), Factor 2: Anxiety 
and dissatisfaction with treatment (8 questions in all), Factor 3: Hypoglycemia (4 questions in 
all) and Factor 4: Treatment satisfaction (4 questions in all)] at each assessment time point. 
• 
Change in the total score for all questions in the DTR-QOL Questionnaire at each assessment 
time point. 
• 
Change in the total score for all questions in the Diabetes Treatment Satisfaction Questionnaire 
(DTSQ) at each assessment time point. 
• 
Changes in the total scores for all questions in the DTR-QOL Questionnaire and DTSQ, 
stratified by the following factors at the start of the treatment period (Week 0) within each 
treatment group. 
 Use of medication for treatment of comorbidities 
 Number of daily doses, including medication for treatment of comorbidities (<2 times or 
≥2 times) 
 Total number of daily tablets, including medications for treatment of comorbidities 
(<2tablets or ≥2 tablets) 
 
Number of doses of the study drug or comparative drug (once weekly, once daily or twice 
daily) 
• 
Changes in the score per question in the DTR-QOL Questionnaire at each assessment time 
point. 


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• 
Changes in the score per question in the DTSQ at each assessment time point. 
5.2.2.2 Safety endpoints 
• 
Adverse events 
• 
Incidence of hypoglycemia 
• 
Hospitalization for type 2 diabetes (duration and number, excluding educational 
hospitalization without worsening of diabetes) 
5.2.3 Other Endpoints 
• 
Laboratory tests [HbA1c, fasting blood glucose, fasting insulin, fasting glucagon, glycoalbumin, 
1,5-AG, serum creatinine, urinary 8-OHdG (using a correction value of uric creatinine 
(8-OHdG/creatinine)) and urinary creatinine] 
• 
Treatment compliance 
• 
The Basic Information on Study Subject (Your Basic Profile) 


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6.0 
CLINICAL STUDY DESIGN 
6.1 
Clinical study design 
<Clinical study design> 
This is a multi-center, randomized, open-label, parallel-group comparison study to assess the 
reduction in treatment burden during the administration of a DPP-4 inhibitor (trelagliptin or a daily 
DPP-4 inhibitor) for 12 weeks in patients with type 2 diabetes on diet and exercise therapy only. 
Eligible study subjects as a result of eligibility assessment after giving informed consent will be 
randomized to either of the study drug (trelagliptin) group or the comparative drug (daily DPP-4 
inhibitor) group as specified in Section 8.4. 
< Dosage and Administration> 
The study drug group: Trelagliptin 100 mg is orally administered once weekly. Trelagliptin 50 
mg is orally administered once weekly in patients with moderate renal 
impairment. 
The comparative drug group: An inhibitor is orally administered at the dosage and administration in 
the package inserts for each drug. 
<Evaluation period and visit frequency for study subjects> 
Evaluation period: 16 weeks (Screening period: 4 weeks; treatment period: 12 weeks) 
Number of visits: total 4 visits 
A study subject will visit to his/her study site at the start of the screening period (Visit 1; 
Week -4), at the start of the treatment period (Visit 2; Week 0 of the treatment period), 
during the treatment period (Visit 3; Week 4 of the treatment period) and at the end of 
the treatment period (Visit 4; Week 12 of the treatment period). 
<Planned number of study subjects> 
As the number of randomized subjects: 
The study drug (Trelagliptin) group 120 subjects 
The comparative drug (daily DPP-4 inhibitor) group 120 subjects 
<Number of study sites> 
Approximately 15 
Figure 6 (a) shows an outline of the clinical study design. Refer to Appendix A for schedule of 
examinations, observations, and evaluations. 


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Visit
Week
Time window
21 to 35
On diet and exercise therapy only
Informed consent procedure
Eligibility tests
Start of study
drug
administration
1
2
3
Daily DPP-4inhibitor
The comparative drug (Daily
DPP-4inhibitor) group
4
-4
0
4
12
70 to 97
Screening period
Treatment
　Trelaglipin 100 mgor50 mg/week
The study drug (Trelagliptin)
group
-29 to -1
0
DTR-QOL
DTR-QOL
DTR-QOL
DTR-QOL
DTSQ
DTSQ
DTSQ


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Figure 6.a 
Outline of the clinical study design 
<Outline of the clinical study> 
Duration of treatment: 12 weeks 
Number of visits: 4 visits 
6.2 
Rationale for the clinical study design 
(1) Rationale for the clinical study design 
The study was designed as an open-label, parallel-group comparative study, to assess impact 
of trelagliptin on QOL of type 2 diabetes compared with Daily DPP-4 inhibitors. In 
conducting this parallel-group comparative study, randomization with stratification will be 
performed, using "the total score for all factors (1-4) in the DTR-QOL Questionnaire (<80% 
or ≥80%)" and "HbA1c (<8.0% or ≥8.0%)" as stratification factors, for the purpose of 
adjusting effects on the reduction level of diabetes treatment burdens in patients controlled 
by diet/exercise therapy during Visit 1. 
(2) Rationale for the study period 
The treatment period was designed as 12 weeks, because switch to other treatment including 
combination therapy with other medications is recommended for a case fails to achieve the 
therapeutic target following three-month continuous administration, as the evaluation on 
responses to treatment with oral diabetic medications 1), and in a study which investigate 
changes in DTR-QOL score during treatment with sodium glucose transporter 2 (SGLT2) 
inhibitor, statistically significant increase in the score was observed at 12 weeks of treatment 
and scores at 12 weeks and 24 weeks was comparable. 
(3) Rationale for the number of planned study subjects 
See Section 13.3. 
6.3 
Premature termination of entire clinical study or premature termination of 
clinical study at a study site 
6.3.1 Premature termination criteria of entire clinical study 
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 study subject participation in the study. 


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 
When there is serious deviation from Ethical Guidelines or ICH-GCP for medical and health 
study involving human subjects. 
6.3.2 Criteria for premature termination of study sites 
Termination of involvement of a study site in the study may be requested prematurely at the 
discretion of the sponsor if the entity (e.g., principal investigator) is found to have significant 
violation of the ethical guidelines, protocol, or contractual agreement for medical and health study 
involving human subjects or becomes unable to ensure proper conduct of the study, or otherwise as 
specified in the contractual agreement. 
6.3.3 Procedures of clinical study suspension and premature termination of 
entire clinical study or clinical study at a study site 
In the event that the sponsor or a study site committee such as an Ethical Review Board decides to 
prematurely suspend or terminate the entire clinical study or clinical study at a study site, a 
study-specific procedure shall be provided by the sponsor. The procedure shall be followed by 
applicable study sites 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 study site shall be informed of the details of each protocol revision. 
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 study site shall submit the revised contents to 
committees such as the Ethical Review Board, 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 STUDY SUBJECTS 
The principal investigator or investigator shall check for all the inclusion/exclusion criteria including 
the test results prior to randomization. 
7.1 
Inclusion criteria 
Eligibility of study subjects shall be determined in accordance with the following criteria. 
1. 
Patients diagnosed as type 2 diabetes. 
2. 
Patients with a stable diet and exercise therapy only for at least 12 weeks prior to the start 
of the screening period. 
3. 
Patients who require a DPP-4 inhibitor treatment. 
4. 
Patients with HbA1c ≥6.5 % and <10.0 % at the start of the screening period. 
5. 
Patients who completed DTR-QOL questionnaire at the start of the screening period. 
6. 
Patients who have receive less than 2 types of medication for treatment of comorbidities 
(such as hypertension or dyslipidemia) at the start of the screening period (any number of 
daily doses). 
7. 
Patients who, in the opinion of the principal investigator or the investigator, are capable of 
understanding the content of the clinical study and complying with the study protocol 
requirements. 
8. 
Patients who can provide the written informed consent prior to the initiation of any study 
procedures. 
9. 
Patients aged ≥20 years at the time of informed consent. 
10. Outpatient. 
 [Rationale for the inclusion criteria] 
1-3: These were set to specify a study subject applicable to achieve objective of this  study. 
4: 
The lower and upper limits were set to include a study subject whom treatment with oral 
glucose-lowering medications is considered to require and who is suitable for 
glucose-lowering monotherapy. 
5: 
This was set because total score of DTR-QOL questionnaire at the start of the screening 
period is stratifying factor of randomization. 
6: 
This was set to minimize influences on drug taking behavior by medications for 
comorbidities in the QOL study. 
7-10: These were set as fundamentals for this study. 
7.2 
Exclusion criteria 
Study subjects meeting any of the criteria below shall not be included in this study. 


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1. Patients who are receiving any oral anti-diabetic medication for the treatment of type 2 
diabetes at the start of the screening period. 
2. Patients diagnosed as type 1 diabetes. 
3. Patients with severe renal impairment or renal failure (e.g., eGFR <30 mL/min/1.73 m2 or on 
dialysis). 
4. Patients with serious heart disease or cerebrovascular disorder, or serious pancreatic, blood, or 
other disease. 
5. Patients with a history of gastrointestinal resection. 
6. Patient with a proliferative diabetic retinopathy. 
7. Patient with malignancy. 
8. Patients with a history of hypersensitivity or allergy to DPP-4 inhibitors. 
9. Pregnant, lactating or postmenopausal women. 
10. Patients who may need to add or discontinue concomitant medication or change the dose 
during the study period. 
11. Patients who will require treatment with a prohibited concomitant medication during the study 
period. 
12. Patients participating in other clinical studies. 
13. Patients assessed ineligible in the study by the principal investigator or the investigator. 
 [Rationale for the exclusion criteria] 
1, 10: 
These were set to exclude influences on senses of burden against treatment using 
concomitant medications including diabetic medications other than the allocated oral 
glucose-lowering medication. 
2: 
This was set to exclude patients with type 1 diabetes, because the indications of 
trelagliptin and daily DPP-4 inhibitors are for "type 2 diabetes." 
3: 
This was set to exclude patients with severe renal dysfunction or renal failure, because 
trelagliptin is contraindicated in such patients. 
4-8, 11: These were set in consideration of patient safety. 
9: 
This was set because trelagliptin should not be administered in pregnant or possibly 
pregnant females unless potential therapeutic benefits outweigh risks, and because 
excretion of trelagliptin and alogliptin into milk was observed in the non-clinical studies. 
12, 13: These were set as fundamentals for this study. 


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7.3 
Prohibited concomitant drugs and permitted concomitant drugs 
The use of diabetic medications other than allocated oral glucose-lowering medication will 
be prohibited during from the start of the screening period (Week -4) until the end of the 
treatment period (Week 12). 
<Rationale of prohibited concomitant drugs> 
It was designed due to potential influences on the assessment of this clinical study. 
7.4 
Study 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. 
(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) 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. 
(4) On visit days for planned laboratory tests, give instructions for fasting ≥ 10 hours before visit. 
(5) 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. 
(6) 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. 
(7) 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 study subject 
The principal investigator or investigator shall record the main reason for discontinuation of protocol 
treatment on the case report form (CRF) according to the classification described below. Refer to 
Section 9.1.15 for study subjects who withdraw from the study before randomization. 
1. Adverse events 
When the study subject had an adverse event that requires withdrawal of the study subject from 
the study because continued participation in the study would impose an unacceptable risk to the 


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study subject’s health, or when the study subject is unwilling to continue study participation 
because of the adverse event. 
2. Major protocol deviation 
When it is discovered after randomization that a study subject does not meet the eligibility 
criteria or is not adhering to the protocol, and continued participation in the study would impose 
an unacceptable risk to the study subject’s health. 
3. Lost to follow-up 
When the study subject failed to make visits and could not be contacted despite the attempts to 
contact the study subject. 
4. Voluntary termination 
When the study subject wishes to withdraw from the study. The reason for discontinuation shall 
be obtained to the extent possible. 
5. Study termination 
When the sponsor or a committee such as the Ethical Review Board or regulatory authority has 
decided to terminate the study. Refer to Section 6.3.1 for details. 
6. Pregnancy 
When a female study subject was found to be pregnant. 
Note: The study subject must discontinue the study immediately after she was found to be 
pregnant. Refer to Section 9.1.13 for the procedures. 
7. Lack of efficacy  
When efficacy of the study drug is not evident and continuation of the study may pose an 
unacceptable risk to the study subjects in the opinion of the principal investigator or 
investigator. 
8. Others 
When the principal investigator or investigator determined to terminate the study for other 
reasons. 
The specific reasons should be recorded on the CRF. 
7.6 
Procedures for discontinuation of individual study subjects 
The principal investigator or investigator shall terminate a study subject’s study participation when 
the study subject meets the criteria described in Section 7.5. Individual study subjects may 
discontinue their study participation without giving a reason at any time during the study. Should a 


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study 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 
STUDY 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 
Study drug and Comparative drug 
8.1.1 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 
<Dose and administration method> 
Trelagliptin: Trelagliptin 100 mg is orally administered once weekly. Trelagliptin 50 mg is oraly 
administered once weekly in patients with moderate renal impairment. 
8.1.2 Comparative drug 
Daily DPP-4 inhibitor: Inhibitors shown in Table 8.a are orally administered at the dosage and 
administration instructed in the package inserts of each drug. 


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Table 8.a 
Daily DPP-4 inhibitor 
Inhibitors 
Dosage and Administration 
Sitagliptin:
Vildagliptin:
Alogliptin:
Linagliptin:
Teneligliptin:
Anagliptin:
Saxagliptin:
Take orally in accordance 
with the instructions in the 
package inserts. 
8.2 
Overdose of the study drug 
Overdose is defined as intentional or accidental administration of the study drug or comparative drug 
at a higher dose than that specified in the package inserts, either by a health professional or by the 
study 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 serious adverse events.” 
In the event of overdose, the principal investigator or investigator shall treat the subject as required 
based on symptoms. 
8.3 
Medication other than the study drug and the comparative drug 
Prohibited concomitant drugs (refer to Section 7.3.1) may not be used. Other treatments shall be 
conducted under normal medical practice. 
In principle, concomitant medications cannot be added or withdrawn, and the dosages of 
concomitant medications cannot be changed during this clinical study period (refer to the section 
7.2). However, the addition of concomitant medications will be allowed as long as the principal 
investigator or investigator considers its necessity due to reasons such as adverse events. The 
principal investigator or investigator shall provide directions to study subjects not to take any 
medications (including over-the-counter drugs) other than the medications instructed to use without 
prior consultation. 
CCI
CCI
CCI
CCI
CCI
CCI
CCI


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8.4 
Allocation of the study drug and administration procedure 
The principal investigator or the designee  shall access the Case Registration Web System to 
allocate the study subjects. The principal investigator or the designee shall notify the information 
required for allocation in addition to the study subject identification (ID) code. Then, drugs that 
should be administered to each study subject will be notified through the Case Registration Web 
System. The principal investigator or investigator shall prescribe the study drug or comparative drug 
according to the notification, and record the drug information (the name, dose per administration, 
number of daily administration and number of tablets per administration) into the CRF of each 
research subject. 
8.5 
Preparation and storage of allocation list 
The allocation responsible person (designated by the sponsor) shall create an allocation list. 
Study subjects will be allocated at the Case Registration Center through the Case Registration Web 
System, using "the total score for the DTR-QOL Questionnaire [<80% (<168.2 as a score) or ≥80% 
(≥168.2 as a score※)]" and "HbA1c (<8.0% or ≥8.0%)" at the start of the screening period as 
stratification factors. The Case Registration Center will use the allocation list for stratification 
prepared by the allocation responsible person in operating the treatment allocation. 
※ Refer to the section 9.1.9 for the calculation method of the total score for the DTR-QOL 
Questionnaire. 
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 
Clinical study procedures 
The principal investigator or investigator shall collect data in accordance with the procedure below. 
In principle, all the tests, observations, and evaluations of study subjects shall be performed by the 
same principal investigator or investigator with the exception of the specific 20-lipoprotein fraction. 
The study schedule is provided in Appendix A. 
9.1.1 Informed consent 
The procedures for obtaining informed consent are described in Section 15.3. 
Consent shall be obtained from the study subject before initiation of study procedures. 
A study subject ID code will be given to each study subject who provided informed consent, and 
then the study subject is to be de-identified. The study subject ID code shall be used throughout the 
study period and shall not be changed. 
9.1.2 Demographic data and medical history 
The following data will be collected as demographic data: 
- 
Date of birth, sex, smoking history, alcohol intake history, the time (month and year) of diabetes 
onset (or a diabetes diagnosis) 
As medical history, the information on clinically problematic diseases and symptoms 
resolved/recovered within a year before the start of the screening period will be collected. A 
continuous disease/symptom will be considered as a comorbidity. 
9.1.3 Physical examination 
The presence/absence of clinically significant abnormalities at subsequent physical examinations 
during the course of this study treatment will be determined compared with the baseline physical 
examination. 
9.1.4 Body weight, height, and BMI 
Body weight shall be measured to one decimal place in kilograms. 
Height shall be measured to the nearest whole number in centimeters. 
The sponsor will calculate BMI using the formula below, showing one decimal place. 
Body Mass Index: BMI=body weight (kg)/[height(m)]2 
9.1.5 Concomitant drugs 
Concomitant drugs are all drugs to be given in addition to the study drug or comparative drug. Drugs 
prescribed by physicians or the over-the-counter medicines purchased by the study subjects shall be 
included. At every visit of the study subject, any use of drugs (name, dosage/administration, route of 


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administration, duration of use, and intended use) shall be investigated and recorded on the CRF 
from the start of the screening period to the completion of the clinical study. In addition, the 
followings shall be recorded on the CRF; any use of therapeutic drugs for comorbidity *; number of 
daily doses of drugs including therapeutic drugs for comorbidities (<2 times or ≥2 times); and total 
number of daily tablets including of therapeutic drugs for comorbidity (<2 tablets or ≥2 tablets) from 
the start of the screening period to the completion of the clinical study. 
* For recording of any use of therapeutic drugs for comorbidity; number of daily doses of drugs 
including therapeutic drugs for comorbidity (<2 times or ≥2 times); and total number of daily tablets 
including of therapeutic drugs for comorbidity (<2 tablets or ≥2 tablets), drugs for as-needed use and 
topical use and supplements are not be included. For drugs for once-weekly use, the numbers shall 
be divided by 7 for recording. 
9.1.6 Comorbidities 
A comorbidity shall be defined as a disease or symptom present at the start of the screening period or 
observed from the start of the screening period until before the start of study drug or comparative 
drug administration. Clinically problematic laboratory tests and abnormal physical examination 
findings, etc. observed through the first tests and physical examination at the start of the screening 
period shall be considered as comorbidities at the discretion of the principal investigator or 
investigator. The details of comorbidities (diagnoses) shall be investigated. 
9.1.7 Laboratory tests 
The laboratories will perform the tests shown below in accordance with the Schedule for Study 
Procedures (Appendix A). The tests will be performed under the ≥10-hour fasting condition. The 
principal investigator or investigator will retain the reported results of laboratory tests along with 
evaluating them.. 


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Table 9.a 
Laboratory tests 
Serum chemistry  
・ HbA1c 
 
Glycoalbumin 
・ Fasting blood glucose  
・ 1,5-AG 
・ Fasting insulin  
・ serum creatinine 
・ Fasting glucagon  
 
Urinalysis  
・ urinary 8-OHdG 
 
Urinary creatinine 
The principal investigator shall keep laboratory test reference values, including the historical data. 
9.1.8 The Basic Information on Study Subject (Your Basic Profile) 
Study subjects will answer the ''Your Basic Profile'' regarding their diabetes therapy at each 
assessment time point during the screening period and treatment period. The principal investigator or 
investigator will provide directions to the study subjects to answer all questions truthfully, which 
will be recorded on the CRF. Of note, in the column "Other drugs than diabetic drugs (e.g., for 
hypertension)" in the ''Your Basic Profile'', drugs prescribed in a medical institution shall be 
recorded. (Supplements and medicines for as-needed use are not included, even though it was 
prescribed in a medical institution.) 
9.1.9 DTR-QOL Questionnaire 
Subjects will answer the DTR-QOL Questionnaire (all 29 questions) 5) regarding the diabetes 
therapy being conducted at each assessment time point during the screening period and treatment 
period. The investigator will instruct the subjects to answer all questions truthfully and record the 
scores of each question of the DTR-QOL Questionnaire (29 questions in total) on the CRF. 
[Calculation of the total score based on answers of the DTR-QOL Questionnaire] 
 
Calculation method of the total score of Factor 1: "burden on social activities and daily 
activities" (13 questions in all) 
Every score of the question number 1-13 will be simply added up, and the total figure will be 
subsequently converted to percentage [the best (91) and worst (13) scores will be equivalent to 
100% and 0%, respectively]. 
 
Calculation method of the total score of Factor 2: "anxiety and dissatisfaction with treatment" 
(8 questions in all) 


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Every score of the question number 14-21 will be simply added up, and the total figure will be 
subsequently converted to percentage [the best (56) and worst (8) scores will be equivalent to 
100% and 0%, respectively]. 
 
Calculation method of the total score of Factor 3: "hypoglycemia" (4 questions in all) 
Every score of the question number 22-25 will be simply added up, and the total figure will be 
subsequently converted to percentage [the best (28) and worst (4) scores will be equivalent to 
100% and 0%, respectively]. 
 
Calculation method of the total score of Factor 4: "treatment satisfaction" (4 questions in all) 
Each score of the question number 26-29 will be converted into reverse (i.e., 1 will be 
converted to 7, 7 will be converted to 1, and so on. The converted scores, where 7 is the best 
and 1 is the worst, have the opposite sequence of the original scores). Then, the converted 
scores will be simply added up, and the total figure will be subsequently converted to 
percentage [the best (28) and worst (4) scores will be equivalent to 100% and 0%, respectively]. 
 
Calculation method of the total score of all questions 
Each score of the question number 26-29 will be converted into reverse, as described above, 
and then these converted scores and original scores of the question number 1-25 will be simply 
added up. Subsequently, the total figure will be converted to percentage [the best (203) and 
worst (29) scores will be equivalent to 100% and 0%, respectively]. 
If some answers of a questionnaire are unavailable (i.e., missing data), the scores will be handled in 
the manner below: 
Factor 1-4: As for a factor associated with <50% missing data, the mean value calculated from 
available answers will be applied to cover the missing data. 
The total score for a factor with ≥50% missing data should not be calculated. 
The total score of whole questions should not be calculated as well, if a total score of any of the four 
factors is unavailable. 
9.1.10 DTSQ 
Subjects will answer the DTSQ (all 8 questions) 6), 7) regarding the diabetes therapy being conducted 
at each assessment time point during the treatment period. The investigator will instruct the subjects 
to answer all questions truthfully and record the scores of each question of the DTSQ (8 questions in 
total) on the CRF. 


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9.1.11 Treatment Compliance 
Throughout the study period, instructions for treatment will be given to subjects. If instructions were 
given for treatment incompliance, the details will be recorded on the source document. At each visit, 
the investigator will check with subjects the treatment compliance status with study drug or 
comparative drug. 
The investigator will instruct the subjects to record study drug or comparative drug usage on a 
“Diabetes Treatment Medication Record Card*.” The subjects will also be instructed to bring empty 
sheets allowing compliance and usage to be checked along with the “Diabetes Treatment Medication 
Record Card*” at each visit. The treatment compliance status with the study drug or comparative 
drug (administration time and quantity of the study drug or comparative drug prescribed and unused) 
will be recorded on the CRF throughout the study period. 
*: Diabetes Treatment Medication Record Card: The card contains an electronic circuit board, and 
the times that medication is taken are electronically recorded by pressing a button when medication 
is taken. 
9.1.12 Hospitalization for type 2 diabetes 
The investigator will check with study subjects any hospitalization for type 2 diabetes after the first 
administration of the study drug or comparative drug (excluding educational hospitalization without 
worsening of diabetes). The admission-discharge date will be recorded on CRF. 
9.1.13 Contraception 
Female subjects of childbearing potential (e.g., nonsterilized or premenopausal female subjects) 
must use adequate contraception from signing on the informed consent throughout the study period. 
At the time of acquisition of informed consent from an applicable study subject, signature on the 
informed consent should be acquired only after explanation is made about what is the adequate 
contraception and that the subject must avoid to be pregnant during the study period by use of the 
informed consent form until the subject thoroughly understands them. 
9.1.14 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. 


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9.1.15 Record of study subjects who are withdrawn before randomization 
A CRF shall be created for all study subjects who have signed the consent form and withdrawn 
before randomization. 
The following items are to be described on the CRF. 
• 
Date of consent obtainment 
• 
Date of birth 
• 
Gender 
• 
Eligibility 
• 
Reason for discontinuation 
The primary reason for withdrawal before randomization shall be recorded on the CRF according to 
the following classification: 
• 
Not satisfying at least one of the inclusion criteria or meeting any of the exclusion criteria 
• 
Major protocol deviation 
• 
Lost to follow-up 
• 
Voluntary discontinuation (specify the reason) 
• 
Study termination 
• 
Pregnancy 
• 
Others (specify the reason) 
Study subject ID codes assigned to study subjects withdrawn from the study before randomization 
shall not be reused. 
9.1.16 Record of randomization 
Study subjects to be randomized shall meet all of the inclusion criteria and shall not meet any of the 
exclusion criteria according to Section 8.4. The principal investigator or investigator shall specify 
the primary reason why the study subject cannot be randomized. 
9.2 
Implementation time point of the tests and observation 
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. 
9.2.1 Screening period (Week -4) 
After obtaining informed consent, the physical examination and tests will be performed for the 
determining eligibility for study enrollment. The eligibility of a patient will be determined based on 
the inclusion/exclusion criteria presented in the section 7.0. Refer to the section 9.1.16 for the 
preparation of records on a study subject withdrawn from the study before randomization. 


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Tests, observations and evaluations performed at the start of the screening period (Visit 1: Day -29 
to -1) are shown below. 
 
Informed consent 
 
Concomitant drugs＊ 
 
Inclusion/ exclusion criteria 
 
Comorbidity＊ 
 
Demographic data, medical history 
 
Laboratory tests (HbA1c only) ＊ 
 
Physical examination＊ 
 
DTR-QOL Questionnaire＊ 
 
Height, body weight and BMI 
 
The Basic Information on Study 
Subject (Your Basic Profile)＊ 
*: To be performed during from Day -29 until Day -14. 
9.2.2 Treatment period (Week 0) 
An eligible study subject in consequence of the tests, observations and evaluations before the start of 
the treatment period will be randomized in accordance with the section 8.4. 
Tests, observations and evaluations performed at the start of the screening period (Visit 2: Week 0) 
are shown below. 
 
Inclusion/ exclusion criteria 
 
DTR-QOL Questionnaire 
 
Physical examination 
 
DTSQ 
 
Concomitant drugs 
 
The Basic Information on Study 
Subject (Your Basic Profile) 
 
Comorbidity 
 
Adverse event# 
 
Laboratory tests (blood chemistry and 
urinalysis) 
 
Hospitalization for type 2 diabetes# 
 
Prescription of the study drug/ or 
comparative drug 
 
 
 
#: To be performed after the first administration (Day 1). 
9.2.3 Treatment period (Week 4) 
Tests, observations and evaluations performed during the treatment period (Visit 3: Week 4) are 
shown below. 
 
Physical examination 
 
DTR-QOL Questionnaire 
 
Concomitant drugs 
 
DTSQ 
 
Laboratory tests (blood chemistry and 
urinalysis) 
 
The Basic Information on Study 
Subject (Your Basic Profile) 
 
Prescription of the study drug/ or 
comparative drug 
 
Adverse event 


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 
Treatment Compliance 
 
Hospitalization for type 2 diabetes 
 
9.2.4 Treatment period (Week 12) or discontinuation 
Tests, observations and evaluations performed at the end of study treatment (Visit 4: Week 12) are 
shown below. 
 
Physical examination 
 
DTR-QOL Questionnaire 
 
body weight 
 
DTSQ 
 
Concomitant drugs 
 
The Basic Information on Study 
Subjects (Your Basic Profile) 
 
Laboratory tests (blood chemistry and 
urinalysis) 
 
Adverse event 
 
Treatment Compliance 
 
Hospitalization for type 2 diabetes 
 
Tests, observations and evaluations performed at the discontinuation are shown below. 
 
Physical examination 
 
DTR-QOL Questionnaire 
 
Concomitant drugs 
 
DTSQ 
 
Laboratory tests (blood chemistry and 
urinalysis) 
 
The Basic Information on Study 
Subject (Your Basic Profile) 
 
Treatment Compliance 
 
Adverse event evaluation 
 
 
 
Hospitalization for type 2 diabetes 
 
 
The reason for the discontinuation 
 


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10.0 
ADVERSE EVENTS 
10.1 
Definitions 
10.1.1 Adverse events 
An adverse event is defined as any untoward medical occurrence in a patient or a study subject 
receiving a pharmaceutical product (including the study drug or comparative drug). It does not 
necessarily have an apparent causal relationship with this pharmaceutical product (including study 
drug or comparative drug). 
An adverse event can therefore be any unfavorable and unintended sign (e.g., a clinically significant 
laboratory abnormality), symptom, or disease temporally associated with the use of a pharmaceutical 
product (including the study drug or comparative drug), regardless of whether it is considered related 
to the pharmaceutical product (including the study drug or comparative 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 comparative 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) 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: 
Abnormal laboratory values shall be recorded as adverse events when the principal investigator or 
the 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 study subject). Retest and/or continued 


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monitoring of an abnormality are not considered medical practice. 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 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 (a disease or symptom that is present at the start of the screening period or 
that is observed from the start of the screening period until before the start of study drug/or 
comparative drug administration): 
A disease or symptom that is present at the start of the screening period or that is observed from the 
start of the screening period until before the start of study drug/ or comparative drug administration 
are considered a comorbidity and not considered an adverse event. When a comorbidity 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 comorbidity 
(e.g., “aggravation of hypertension,” etc.). 
If a study 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 
study 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 the investigator shall ensure that the adverse event 
term to be reported represents the change in the condition from baseline (e.g. “worsening of…”).  
Worsening of adverse events: 
If a study subject experiences a worsening of the adverse event after a change of the study drug or 
comparative 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 the 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 study 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 treatment that were scheduled before the start of study drug or comparative 
drug administration 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 


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considered an adverse event. A complication that resulted from previously planned surgery shall be 
reported as an adverse event. 
Non-urgent surgery or treatment: 
Non-urgent surgery or treatment that does not induce a change in the condition of a study subject 
(cosmetic surgery, etc.) shall not be considered an adverse event; However, it shall be recorded in 
the source documents. Complications 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 the investigator shall make the distinction between worsening of 
a pre-existing condition and lack of therapeutic efficacy. 
Overdose of the study drug or comparative drug: 
Overdose of any medication without manifested symptoms shall not be recorded as an adverse event, 
but the overdose shall be recorded on the “Overdose” page of the CRF. Any manifested symptoms 
shall also be recorded as adverse events on the “Adverse events” of the CRF. 
10.1.3 Serious adverse event 
Of all the unfavorable medical events that develop with administration of a pharmaceutical product 
(including study drug/ or comparative 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. other medically significant condition: a medically important event that causes a risk to a 
study 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. In addition, 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 study 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 was 
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 or comparative 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. 
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 or comparative drug shall be 
classified and defined as shown below. 
Related 
An adverse event that follows a temporal sequence (including clinical course after 
discontinuation), or an adverse event in which there is at least a reasonable 


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probability that a causal relationship to the study drug or comparative drug cannot be 
ruled out, although other factors such as underlying disease, complications, or 
concomitant drugs/treatment are also suspected. 
Not 
related 
An adverse event that does not follow a temporal sequence from administration of 
the study drug or comparative drug. Very likely due to other factors such as 
underlying disease, complications, or concomitant drugs/treatment. 
10.1.7 Relationship to study procedures 
The relationship shall be recorded as “Yes” if the principal investigator or the 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 event shall be determined according to the following rules: 
Adverse events 
Date of onset 
Signs, symptoms, diseases 
(diagnoses) 
The date on which the first signs/symptoms were noted by the 
study 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 complications 
The date on which the first worsening of diseases/symptoms was 
noted by the study subject and/or the principal investigator or 
investigator. 
Onset of a test abnormality 
after the start of study drug 
administration or comparative 
drug administration 
The date on which a clinically significant laboratory abnormality 
was detected. 
Worsening of a baseline test 
abnormality after the start of 
study drug administration or 
comparative drug 
administration  
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 study subject recovered 
(including resolution with sequelae). If a study subject died due to the adverse event concerned, it 


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shall be the date of death. The adverse event shall be recorded as “ongoing” if the study subject has 
not yet recovered by the end of the study. 
10.1.10 Actions taken for the study drug or comparative drug 
Actions taken for the study drug or comparative drug shall be classified or defined as shown below. 
Drug withdrawn 
The study drug or comparative drug is discontinued because of an adverse 
event (including withdrawal by the study subject at his/her own discretion). 
When the study is discontinued but administration of the study drug or 
comparative drug is still continued, the classification should be “Dose not 
changed.” 
Dose not 
changed 
The dose was not changed after the onset of the adverse event. 
The study drug or comparative drug was discontinued, reduced, or increased 
because of another adverse event. 
The study drug was discontinued or reduced for a reason other than the 
adverse event, e.g., inadvertence of the study subject. 
Unknown 
It has not been possible to determine what action has been taken because the 
study subject is lost to follow-up. 
Not Applicable 
The administration of the study drug or comparative drug had already been 
completed or discontinued before the onset of the adverse event. 
Dose reduced 
The dose of the study drug or comparative drug is reduced because of an adverse 
event (including dose reduction by the study subject at his/her own discretion). 
Dose increased 
The dose of the study drug or comparative drug was increased because of the 
adverse event (including dose increase by the study subject at his/her own 
discretion). 
Washout 
If administration of the study drug or comparative drug is suspended (i.e., 
interrupted) (including suspension/interruption by the study subject at his/her own 
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 study subject died from a cause other than the concerned adverse event 
while the condition was resolving (recording of the date of death unnecessary) 


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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 study 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 
Death 
- Direct relationship between death and the concerned adverse event, etc. 
“Direct relationship” means that the concerned adverse event, etc. was the 
cause of death, or the concerned adverse event, etc. 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 study subject is not considered as 
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 and its coverage 
10.2.1.1 Adverse event collection period 
Adverse events shall be collected from the start of administration with the study drug/ or 
comparative drug (day1) until completion of the treatment period (or discontinuation). 
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 study subjects experiencing an adverse 
event irrespective of the causal relationship with the study drug or comparative drug, until the 
symptom resolve, or any clinically significant abnormal laboratory values have returned to baseline 
or there is a satisfactory explanation for the change (permanent and irreversible adverse events, etc.). 
All adverse events shall be recorded in the CRF. For the adverse event, the name, date of onset, date 
of resolution, category, severity, causal relationship with the study procedures (the procedure 
possibly having causal relationship, if applicable), causal relationship with the study drug or 
comparative drug (i.e. "Not related" or "Related"), action taken for the study drug or comparative 
drug, outcome, and seriousness shall be recorded. 


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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 
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 
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 after notification of the onset by the study subject, 
the principal investigator shall report the serious adverse event to the chief executive of the study site 
immediately, and the sponsor or the contract research organization (CRO) to whom the sponsor has 
entrusted responsibility shall notify the principal investigator of the study site. 


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The principal investigator shall then report the serious adverse event to the sponsor (for the contact 
information, refer to the attachment) within 1 working day after notification of the onset. Further, the 
investigator shall submit a formal report within 10 calendar days to the sponsor. 
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 
• 
Study subject ID code 
• 
Name of principal investigator or the investigator 
• 
Name of the study drug or comparative 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 Electronic Data Capture (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, principal 
investigator or the 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 study site (e.g., ECG charts, laboratory test values, discharge summary, 
postmortem results) shall be sent to the sponsor or the committee such as the Ethical Review Board 
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 Ethical Review Board, etc., and 
regulatory authorities 
When the chief executive of study site receives a report of a serious adverse event from the principal 
investigator, the chief executive of study site shall consult the Ethical Review Board, etc., and notify 


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the study sites that are conducting the clinical study through the sponsor or the CRO consigned by 
the sponsor. 
When the principal investigator reported a serious adverse event for which a causal relationship to 
the study (study drug or comparative drug) cannot be ruled out and is unexpected, the chief 
executive of the study site 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 study sites 
conducting the clinical study. (The chief executive of the study site may report it to the Minister of 
Health, Labour and Welfare via the sponsor, and notify it to other clinical study sites via the 
sponsor.) 
• 
Actions taken for serious adverse events 
(discontinuation of new enrollment, revision of informed consent form, re-consents to other 
study subjects, etc.) 
• 
Date of review, summery of review, result, necessary action, etc., related to Ethical Review 
Board, etc. 
• 
Notification to other collaborative study sites 
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 the chief executive of study site. 
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 risk-benefit of the study drug or comparative drug, continuation of administration of the study 
drug or comparative drug, or continuation of clinical study. The study site shall submit copies of 
emergency report documents to the Ethical Review Board, etc. 


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11.0 
COMMITTEES ESTABLISHED FOR THIS STUDY 
11.1 
Clinical Study Steering Committee 
The Clinical Study Steering Committee is composed of the chair and the sponsor. The 
Clinical Study Steering Committee supervise implementation and reporting of the 
clinical study, secure medical guidance of a high degree of professionalism and a 
high-level scientific quality, and revise the study protocol appropriately. The 
responsibilities of the committee shall be prescribed in the procedures of the Clinical 
Study Steering Committee. 
 


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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 comorbidities shall be coded using the MedDRA. Drugs shall 
be coded using the World Health Organization (WHO) Drug Dictionary. 
12.1 
Case report form 
The principal investigator or investigator shall complete a CRF for each study subject who has 
signed the informed consent form. 
The sponsor or the designee shall provide access rights to the EDC system to the study site. Before 
use of the EDC 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. CRF must be completed 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 CRF. 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 (unless recorded in the source document). 
• 
Eligibility, completion status, reason for discontinuation, seriousness of adverse events, 
severity of adverse events and causal relationship between adverse events and the study 
drug or comparative drug or the study procedures, and outcome 
The following data shall not be recorded directly into the CRF. 
• 
Laboratory test values 
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; DCF) 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. 
The sponsor or the designee shall confirm that the CRFs are completed appropriately according to 
the procedures set by study. The sponsor or the designee shall have access to the medical records of 


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the study 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 the 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 EDC system 
The sponsor or the designee shall request the principal investigator and investigator to promptly 
enter data into the EDC following enrolment of the study subject, each visit during treatment with 
the study drug or comparative drug, completion/discontinuation of the study, and follow-up period. 
12.3 
Storage of records 
The principal investigator or the chief executive of the study site shall store the following materials, 
including those specified in Section 12.1, and study-specific documents to be investigated or audited 
by the regulatory authority and the sponsor or the designee. The documents include the list of study 
subject ID code, medical records, clinical study worksheets (if used), original signed and dated 
informed consent forms, the record (copy) of modification or correction on the CRF, and electric 
copies of EDC including audit trail. The principal investigator and the chief executive of the study 
site shall appropriately retain the material/information related to this study for at least 5 years from 
the date of reporting the end of the study 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 study site shall discuss the period and 
methods of storage with the sponsor. 


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13.0 
STATISTICAL ANALYSIS METHODS 
The person in charge of analysis and the designee [analysis personnel, who belongs to CRO 
independent from the sponsor] shall perform the statistical analysis. The sponsor will not be 
involved in the statistical analysis. 
13.1 
Statistical and analytical plans 
The analysis personnel shall prepare a statistical analysis plan (SAP) before the acquisition of the 
informed consent of the earliest study subject, and issue the first edition. Detailed definition of 
endpoints and analytical methods should be specified in the SAP to deal with all the purposes of the 
study. 
13.1.1 Analysis set 
Two analysis sets comprising the “Full Analysis Set (FAS)” and the “Safety Population” will be 
established. The FAS used as the main efficacy analysis set is defined as “randomized subjects who 
receive at least one dose of trelagliptin or daily DPP-4 inhibitor.”  The safety population is defined 
as “subjects who receive at least 1 dose of trelagliptin or daily DPP-4 inhibitor.” 
13.1.2 Analysis of demographic and other baseline characteristics 
From “SAS” primary study subject background items will be tabulated. 
13.1.3 Efficacy analysis 
From FAS the following shall be analyzed. 
<Primary endpoint> 
Change from baseline (Week 0) in total score for all question items in the DTR-QOL 
Questionnaire at the end of the treatment period (Week 12). 
1) 
A comparison between the treatment groups will be carried out based on the ANCOVA model 
using "the change in the total score by the end of treatment [the end of the treatment period - 
baseline (Week 0)]" as a dependent variable; "the total score at the baseline, the total score of 
the DTR-QOL Questionnaire (<80% or ≥80%) at the start of the screening period and HbA1c 
(<8.0% or ≥8.0%) at the start of the screening period as covariates; and "a treatment group" as 
an independent variable. The level of significance will be 5% (two-sided). 
<Secondary endpoints> 
Efficacy endpoints: 


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• 
Changes in the total score for each factor provided through the DTR-QOL Questionnaire 
[“Factor 1: Burden on social activities and daily activities (13 questions in all)”, Factor 2: 
Anxiety and dissatisfaction with treatment (8 questions in all), “Factor 3; Hypoglycemia (4 
questions in all)”, and “Factor 4: Treatment satisfaction (4 questions in all)”] at each assessment 
time point. 
• 
Change in the total score for all questions in the DTR-QOL Questionnaire at each assessment 
time point. 
• 
Change in the total score for all questions in the DTSQ at each assessment time point. 
1) 
Summary statistics [sample size, mean, standard deviation (SD), maximum, minimum and 
quantile] and the two-sided 95% confidence interval (CI) for means per treatment group at 
each assessment time point will be calculated to plot the changes in means and SDs. Point 
estimates and the two-sided 95% CI for differences between the treatment groups will also 
be calculated. 
2) 
Changes from the baseline (Week 0) to each assessment time point will be calculated to be 
similarly analyzed to 1) above.  
3) 
The analyses below carried out on the total score for each factor provided through the 
DTR-QOL Questionnaire, and on the total score for DTSQ: 
A comparison between the treatment groups will be carried out based on the ANCOVA 
model using "the change in the total score by the end of treatment [the end of the treatment 
period (Week 12) - baseline (Week 0)]" as a dependent variable; the total score at the 
baseline (Week 0), the total score of "the DTR-QOL Questionnaire (<80% or ≥80%)" at 
the baseline (Week 0) and "HbA1c (<8.0% or ≥8.0%)" at the baseline (Week 0) as 
covariates; and "a treatment group" as an independent variable. The level of significance 
will be 5% (two-sided). Note that the total score for all questions in the DTR-QOL is out 
of the scope of the analysis. 
4) 
To indicate the changes in the total scores for all questions in the DTR-QOL Questionnaire 
and DTSQ, the summary statistics and two-sided 95% CI for means per treatment group 
will be calculated, with stratification by the following factors at the start of the treatment 
period (Week 0): 
 
Use of medication for treatment of comorbidities 
 
Number of daily doses, including medication for treatment of comorbidities (<2 times 
or ≥2 times) 


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 
Total number of daily tablets, including medication for treatment of comorbidities 
(<2 tablets or ≥2 tablets) 
 
Number of doses of the study drug or comparative drug (once weekly, once daily or 
twice daily) 
• 
Changes in the scores per question in the DTR-QOL Questionnaire at each assessment time 
point. 
• 
Changes in the scores for per question in the DTSQ at each assessment time point. 
1) 
Summary statistics for measurements and the changes from the baseline (Week 0) will be 
calculated per treatment group. 
<Other endpoints> 
Summarizations below will be performed in the "full analysis set" (FAS). 
• 
Laboratory tests 
Treatment compliance of each study subject will be calculated and summary statistics of 
compliance per treatment group will be presented. 
• 
Treatment compliance 
Treatment compliance of each study subject will be calculated and summary statistics of 
compliance per treatment group will be presented. 
• 
The Basic Information on Study Subject（Your Basic Profile） 
Frequency of answers to each question at each visit will be analyzed per treatment group. 
13.1.4 Safety analysis 
Frequency tables will be prepared for the incidences of adverse events, hypoglycemia, and 
hospitalization for type 2 diabetes (number and duration of hospitalization) after the first 
administration of the study drug or comparative drug administration in the “safety population” in 
each treatment group. 
13.2 
Criteria for interim analysis and premature discontinuation 
No interim analysis is planned. 
13.3 
Determination of the number of planned study subject  
In this clinical study, to discuss changes in the total score for all questions in the DTR-QOL 
Questionnaire from the baseline (Week 0) to the end of the treatment period, as the primary endpoint, 
mean changes in the daily DPP-4 inhibitor and trelagliptin groups were assumed as 14.4% and 


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19.0%, respectively. The mean change in the daily DPP-4 inhibitor group was assumed by reference 
to the data on SGLT2 inhibitor, from the previous research 4); and that in trelagliptin group was 
assumed by reference to the data from the validation trial of the DTR-QOL Questionnaire 6). The 
common SD was assumed as 12.1 % considering the former assumption. When 5% of significance 
level (two-sided) is based for the analysis of the primary endpoint, 110 subjects per group would be 
needed to ensure 80% power in comparisons between the trelagliptin group and daily DPP-4 
inhibitor group. As this is a study on treatment for type 2 diabetes with DPP-4 inhibitors currently 
used in the medical setting, the number of randomized subjects was established as 120 subjects per 
group, for a total of 240 subjects, assuming a type 2 diabetes treatment discontinuation rate of 8%*.  
*Based on the results for Topic 2 of the “Strategic Studies on the Prevention of Diabetes” (JDOIT-2), 
the annual discontinuation rate for the “usual care group” without intervention is approximately 8% 
2). 


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14.0 
QUALITY CONTROL AND QUALITY ASSURANCE 
14.1 
Monitoring of the study site 
The sponsor or the designee shall perform periodic monitoring of the study site during the study to 
confirm that the study is conducted in accordance with all specifications in the study protocol. In the 
monitoring, 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 study site shall ensure that the sponsor or the designee and 
the Ethical Review Board, etc., have access to the source documents. 
The sponsor or the designee shall access the records, including the list of study subject ID codes, 
medical records of the study subjects, and signed and dated original consent forms to confirm that 
the study is appropriately conducted in compliance with the study protocol. Also, confirm the 
consistency between CRF and the related source documents. The principal investigator, investigator, 
and other personnel involved in the study shall spare sufficient time to facilitate monitoring 
procedures during visits to the study site. 
Detailed procedures for monitoring shall be described separately in the written procedures. 
14.2 
Deviation from the Ethical Guidelines for Medical and Health Research 
Involving Human Subjects and the study protocol 
The principal investigator or investigator shall record all deviations from Ethical Guidelines for 
Medical and Health Research Involving Human Subjects, and study protocol. 
If any deviation is found, the principal investigator shall promptly notify the chief executive of the 
study site for the clinical study 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 study site for approval of the 
committee such as the Ethical Review Board. 
14.3 
Quality assurance audits and regulatory agency inspections 
The sponsor or the designee shall perform audit at the study site as necessary. In such a case, the 
auditor designated by the sponsor shall contact the study site 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 study. In addition, this study 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 study 
site is contacted for an inspection by a regulatory body, the sponsor should be notified promptly. The 


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principal investigator and the chief executive of the study site shall ensure that the auditor has access 
to all the study-related source documents. 


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15.0 
ETHICAL CONDUCT OF CLINICAL STUDY 
This clinical study shall be conducted with the highest respect for the individual participants (i.e., 
study subjects) according to the study protocol, the ethical principles that have their origin in the 
Declaration of Helsinki, and “Ethical Guidelines for Medical and Health Research Involving Human 
Subjects.” Each principal investigator will conduct the study according to regulatory requirements 
and in accordance with “Responsibilities of the Principal 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 the designee should obtain the document listing the name and title of each committee 
member. When a committee member directly participates in this clinical study, the document 
describing that he/she is not participating in deliberation or voting for the study will be obtained. 
The sponsor or the designee shall supply relevant documents for submission to study site committee 
such as the Ethical Review Board for the protocol’s review and approval. In addition to the study 
protocol, a copy of the informed consent form and information sheet, written materials related to 
study subject recruitment, advertisement, and other documents required by regulations, when 
necessary, shall be submitted to the central committee or a study site committee such as the Ethical 
Review Board to obtain approval. The sponsor or the designee must obtain written approval of the 
protocol and the informed consent form and information sheet from the study site committee such as 
the Ethical Review Board before commencement of the study. The study site committee such as the 
Ethical Review Board’s approval must refer to the study by exact protocol title, number and version 
date; identify versions of other documents (e.g., informed consent form and information sheet) 
reviewed; and state the approval date. The sponsor shall notify the study site, the principal 
investigator, and investigator after confirming the validity of the regulatory documents of the study 
site. Protocol procedures such as obtainment of consent shall not be started until the study site, the 
principal investigator, and investigator receive notification. 
The study site shall observe all requirements that the Ethical Review Board, etc. prescribe. The 
requirements may include notifications to committees such as the Ethical Review Board, for 
example, revision of the protocol, revision of the informed consent form and information sheet, 
revision of materials related to study subject recruitment, reports on safety in accordance with the 
regulatory requirements, reports on status of implementation of the study at intervals determined by 
a study site committee such as the Ethical Review Board, and submission of the study completion 
report. The sponsor or the designee shall obtain written approval from the Ethical Review Board, etc. 
related to the above mentioned items and all related materials. 


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15.2 
Conflict of interest 
This clinical study shall be conducted with the support of the sponsor. 
Prior to the conduction of this clinical study, the principal investigators involved in this clinical 
study shall ensure appropriate management of any conflicts of interest (COI) in the conduct of the 
study in accordance with the rules of the study site.9)-13) 
The study site shall observe all requirements that the Ethical Review Board, etc. prescribe. This will 
include self-declaration of COI, clinical study protocol, informed consent form and information 
sheet. 
15.3 
Informed consent form and information sheet, and the agreement of the 
study subjects 
The informed consent 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 study subjects in this clinical study (both in and 
outside Japan: supply to a third party), and disclosure. The informed consent form will explain in 
detail the nature of the clinical study, its objectives, and potential risks and benefits. The informed 
consent form will detail the requirements of the participant and the fact that study subject is free to 
withdraw at any time without giving a reason and without any negative effect on 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 Ethical Review Board. The 
informed consent form and information sheet must be approved by the committee such as the Ethical 
Review Board prior to use. 
The informed consent form shall be written in language that can be easily understood by the 
potential study subjects. The principal investigator or investigator shall be responsible for providing 
detailed explanation of the informed consent form to the potential study subjects. Information should 
be given in both oral and written form whenever possible and in manner deemed appropriate by the 
committee such as the Ethical Review Board. 
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 study 
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 study subject. 
The principal investigator or investigator shall follow the same procedure as for obtaining the initial 
consent when newly obtaining re-consent from the concerned study subject when the informed 


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consent form and information sheet is revised. The date of obtaining new consent shall be recorded 
in the study subject’s medical record, and a copy of the revised consent form shall be provided to the 
study subject. 
15.4 
Personal information of the study subjects 
The sponsor or the designee shall affirm the principle of the protection of study subjects' 
private/personal information. Throughout this study, study subject ID codes shall be used to link the 
subject's source data to the sponsor's study database and study-related documents. Limited 
information on study subjects such as gender, age, and date of birth may be used within the scope of 
all applicable laws and regulations for identification of study subjects and confirmation of accuracy 
of study subject ID code. 
For verification of the conduct of the study 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 study sponsor’s designee, representatives of regulatory 
authorities, designated auditors, and committees such as the Ethical Review Board direct access to 
study subjects’ original medical records (source data or documents), including laboratory test results, 
admission and discharge records during a subject’s study participation, and autopsy reports. The 
principal investigator or investigator shall obtain specific authorization of the study subject as part of 
the informed consent process for access to study subject's original medical records by study 
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 study 
subject, other personal information not recorded on the CRF of the study subject). 
15.5 
Consultation windows for the study subjects or persons related to the study 
concerned 
The principal investigator shall establish a contact service to respond to inquiries concerning this 
clinical study from study subjects or concerned people. Details of the contacts for inquiries will be 
described in the informed consent form and information sheet. 
15.6 
Financial burden or reward to the study subjects 
Of the expenses for this clinical study, the sponsor shall offer compensation for medical treatment 
not covered by health insurance as study expenses. The study 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 study to the study subjects at each visit from the research funds. Details 


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of the financial burden on the study subjects and rewards shall be described in the informed consent 
form and information sheet. 
15.7 
Benefits and inconveniences to the study subjects 
15.7.1 Benefits to study subjects 
Study subjects can deeply learn their own conditions of type 2 diabetes including such as the change 
in the QOL associated with the change in treatment approaches and the level of treatment 
satisfaction, through the study participation 
15.7.2 Inconveniences to study subjects 
Burdens of study subjects may be increased due to requirements of providing answers to the Basic 
Information on Study Subject, DTR-QOL Questionnaire and DTSQ, through the study participation. 
15.8 
Attribution of study results and access rights 
15.8.1 Attribution of study results 
The study results and data obtained from this study shall belong to the sponsor. In addition, 
secondary use (meta-analysis, etc.) of the data obtained in this clinical study 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. 
15.9 
Reporting of results, publication, disclosure, and clinical study registration 
policy 
15.9.1 Reporting of results, publication and disclosure 
The principal investigator shall report a written summary of results of the study to the chief 
executive of the study site and provide the sponsor with all the results and data obtained from the 
study. Only the sponsor may disclose the study information to other principal investigators, 
investigators or regulatory authorities during the study period, except when required by laws and 
regulations. The sponsor shall be responsible for publication of the study protocol and study-related 
results (including the public web site) except for other cases permitted in the study contract. 
During the study period and after the end of study, the sponsor or the designee should promptly 
summarize the results and present it to medical journals and academic conferences, etc. The sponsor 


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may publish any data or information obtained from the study (including data and information 
provided by the principal investigator) without obtaining agreement 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 study at an academic conference, etc. 
15.9.2 Clinical study registration 
To ensure that information on clinical study 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 study 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), before initiation of the clinical study. On 
such websites, the study location (city, country), study 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 study 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 
In case of injuries, each study subject in the clinical study must be insured in accordance with the 
regulations applicable to the study site where the subject is participating. The sponsor or the 
designee shall buy an insurance policy to compensate for health injury in study subjects. 
Healthy injury in a study 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 the designee. 


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16.0 
REFERENCES 
1. 
Treatment Guide for Diabetes 2016-2017. Edited by Japan Diabetes Society. BUNKODO 
Corp. 2016 
2. 
Izumi K, Noda M. In order to reduce the interruption of diabetes treatment. Diabetes Frontier. 
2014;25:709-718. 
3. 
Paes AH, Bakker A, Soe-Agnie CJ. Impact of dosage frequency on patient compliance. 
Diabetes Care. 1997;20:1512-1517. 
4. 
Yamazaki M, Higo N, Kaneko T, et.al. SGLT2 Inhibitors As the Trigger for Diabetes Care: 
Reconfirmed Importance of Behavior Modification After Drug Administration. J.Japan 
Dab.Soc.2015;58:745-752. 
5. 
Ishii H. Development and psychometric validation of the Diabetes Therapy-Related QOL 
(DTR-QOL) questionnaire. J Med Econ. 2012;15:556-563. 
6. 
Bradley C: Diabetes treatment satisfaction questionnair (DTSQ). In: Handbook of 
psychology and diabetes (ed. by Bradley C.). Harwood Academic Pubi., Chur, 1994 
7. 
Ishii H, Bradley C, Riazi A, et al. The Japanese Version of the Diabetes Treatment 
Satisfaction Questionnaire (DTSQ): translation and clinical evaluation. Journal of Clinical 
and Experimental Medicine. 2000;192:809-14. (A Japanese Journal published in Japanese) 
8. 
Sadamoto K, Takamori H, Sadamoto T, et al. Impact of push-through-packages with 
electronic devices for accurate drug taking. Journal of Scientific and Innovative Research. 
2014;3:288-294. 
9. 
Report of the Working Group on Conflict of Interest (Ministry of Education, Culture, Sports, 
Science and Technology dated November 1, 2002) 
10. Guidelines for determining the conflict of interest polity for clinical research (Review group 
for ethical aspects of clinical study and conflict of interest, March 2006) 
11. Guidelines on the Management of COI in Health and Labor Sciences Research (No. 0331001, 
science, issued on March 31, 2008, and approved by the Chief of the Health Sciences 
Division) 
12. Guidelines for management of COI in medical research (COI Committee of Japan 
Association of Medical Sciences, February 2011) 
13. Common guidelines for conflict of interest (COI) in clinical research (Japanese Society of 
Internal Medicine, Japan Society of Hepatology, 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, Japan Geriatrics Society, Aug 2011) 

SAP_001.pdf: 
 
 
Title: Study of the QOL evaluation of Trelagliptin in patient with type 2 Diabetes 
mellitus (TRENDS) 
 
NCT Number: NCT03014479 
Statistical analysis plan Approve Date: 28-Dec-2017 
 
Certain information within this statistical analysis plan has been redacted (ie, specific 
content is masked irreversibly from view with a black/blue bar) to protect either 
personally identifiable information or company confidential information. 
 
This may include, but is not limited to, redaction of the following: 
 
Named persons or organizations associated with the study. 
 
Patient identifiers within the text, tables, or figures or in by-patient data listings. 
 
Proprietary information, such as scales or coding systems, which are considered 
confidential information under prior agreements with license holder. 
 
Other information as needed to protect confidentiality of Takeda or partners, 
personal information, or to otherwise protect the integrity of the clinical study. 
 
If needed, certain appendices that contain a large volume of personally identifiable 
information or company confidential information may be removed in their entirety if it 
is considered that they do not add substantially to the interpretation of the data (eg, 
appendix of investigator’s curriculum vitae). 
 
Note; This document was translated into English as the language on original version 
was Japanese. This file is Statistical Analysis Plan Version 2.0 as the latest version and 
the initial version of SAP is not included in this file because the amendment was 
occurred for just only minor updates to correct expression/ misspellings. 
 


Protocol number: Trelagliptin-4002 
 
 
Statistical Analysis Plan 
 
 
Study Name 
Study of the QOL evaluation of Trelagliptin in 
patient with type 2 diabetes mellitus 
  
Protocol number 
Trelagliptin-4002 
 
Sponsor 
Takeda Pharmaceutical Company Limited 
 
 
 
 
 
 
 
 
 
 
Authorizer:   
 
Takeda Pharmaceutical Company Limited 
 
 
 
Biostatistics Manager:  
 
 
Version.2.0:  28 Dec 2017
PPD
PPD
PPD
PPD


Protocol number: Trelagliptin-4002 
 
0 
Contents 
DEFINITIONS of TERMS ................................................................................................................... 2 
ANALYSIS SET ................................................................................................................................... 2 
TIME WINDOW .................................................................................................................................. 2 
OTHER DATA HANDLING ............................................................................................................... 3 
Display digit .......................................................................................................................................... 5 
AE related to Hypoglycaemia ............................................................................................................... 5 
1 SUBJECTS, DEMOGRAPHIC and OTHER BASELINE CHARACTERISTICS ........................... 6 
1.1 Subject Disposition ......................................................................................................................... 6 
1.1.1 Study Information .................................................................................................................... 6 
1.1.2 Eligibility of Subjects .............................................................................................................. 6 
1.1.3 Disposition of Subjects ............................................................................................................ 6 
1.1.4 Protocol Deviations .................................................................................................................. 7 
1.1.5 Datasets Analyzed .................................................................................................................... 7 
1.2 Demographics and Other Baseline Characteristics ......................................................................... 7 
1.2.1 Distribution of Demographics Items ........................................................................................ 7 
1.2.2.Medical History and Concurrent Disease ................................................................................ 9 
1.2.3 Concomitant Medications ........................................................................................................ 9 
1.2.4 Dosing conditions of Study drug ............................................................................................. 9 
2 EFFICACY EVALUATIONS ......................................................................................................... 11 
2.1 Primary Endpoint and the Analytical Methods ............................................................................. 11 
2.2 Secondary Endpoints and the Analytical Methods ....................................................................... 11 
2.3 Other Analysis .............................................................................................................................. 12 
2.4 CONSIDERATIONS on STATISTICAL ANALYSIS ................................................................ 15 
 Adjustments for Covariates ........................................................................................................ 15 
2.4.1
 Handling of Dropouts or Missing Data ...................................................................................... 15 
2.4.2
 Interim Analysis and Early Discontinuation .............................................................................. 15 
2.4.3
 Multicenter Studies .................................................................................................................... 15 
2.4.4
 Multiple Comparisons/Multiplicity ............................................................................................ 15 
2.4.5
 Use of an Efficacy Subset of Subjects ....................................................................................... 15 
2.4.6
 Active-Control Studies Intended to Show Equivalence ............................................................. 15 
2.4.7
 Subgroup Analysis ..................................................................................................................... 15 
2.4.8
3 SAFETY EVALUATION ............................................................................................................... 16 
3.1 Treatment -Emergent Adverse Event ............................................................................................ 16 
 Brief Summary of Adverse Events ............................................................................................ 16 
3.1.1
 Display of TEAE........................................................................................................................ 17 
3.1.2
3.2 Frequency of Hypoglycemia ......................................................................................................... 18 


Protocol number: Trelagliptin-4002 
 
1 
3.3 Hospitalization related to type 2 diabetes mellitus ....................................................................... 18 
4 LISTINGS ........................................................................................................................................ 18 
Significance level, Confidence coefficient ......................................................................................... 21 
REVISION HISTORY........................................................................................................................ 22 
 
 


Protocol number: Trelagliptin-4002 
 
2 
DEFINITIONS of TERMS 
・ Treatment -emergent adverse event (TEAE) : The AE which occurs after taking the first dose of 
trial medication. 
・ Summary Statistics:  Number of subjects, mean, SDs, maximum values, minimum values, and 
quartiles 
・ BMI: Body Mass Index 
・ MedDRA: Medical Dictionary for Regulatory Activities 
・ QOL: Quality Of Life 
・ WHO: World Health Organization 
・ DTSQ: Diabetes Treatment Satisfaction Questionnaire 
・ DTR -QOL: Diabetes Therapy -Related QOL 
・ Subject with hypoglycemia: The subject with AE related to hypoglycemia 
・ Non Serious TEAE: Non -Serious TEAE is defined as Non -Serious TEAEs of at least 5% in 
any treatment group by SOC and PT. (if no event exceeds the 5% frequency, cutoff is 
lowered to 2%). 
 
ANALYSIS SET 
・ Full Analysis Set 
The subjects who were randomized and received at least one dose of the Trelagliptin or Daily 
DPP-4 inhibitor 
・ Safety Analysis Set 
The subjects who received at least one dose of the Trelagliptin or Daily DPP-4 inhibitor 
 
TIME WINDOW 
For each assessment, observation and evaluation item, evaluable data is selected according to 
the following table. When there are multiple data exist within a time window, the one with the 
closest date to the reference date is adopted, and if the differences from the reference date are 
the same for multiple data, the later one is adopted. 
 
1) DTR -QOL Questionnaire, The Basic Information on Study Subject, Laboratory Test (HbA1c)  
Analysis Visit 
Reference Date 
Time Allowance 
 (Number of Study Days)  
Week -4 
 -30 
 -30～-15 
Week 0 
 -1 
 -14～-1 
Week 4 
28 
21～35 
Week 12 
84 
70～97 


Protocol number: Trelagliptin-4002 
 
3 
Analysis Visit 
Reference Date 
Time Allowance 
 (Number of Study Days)  
End of Study 
The latest date in treatment period 
21～97 
 
2) DTSQ, Laboratory Test (except HbA1c)  
Analysis Visit 
Reference Day 
Time Allowance 
 (Number of Study Days)  
Week -4 
 -30 
 -30～-2 
Week 0 
 -1 
 -1 
Week 4 
28 
21～35 
Week 12 
84 
70～97 
End of Study 
The latest date in treatment period 
21～97 
 
OTHER DATA HANDLING 
Items 
Method 
Conditions 
DTR -QOL Questionnaire 
Factor1: Burden on Social 
Activities and Daily 
Activities 
The sum total of questions number 1 
-13 was converted into a 0 -100 
score [the best (91) = 100 and worst 
(13) = 0]. 
For a factor with <50% missing 
data, the mean value (round off 2 
digits) calculated from available 
answers is applied to cover the 
missing data. 
DTR -QOL Questionnaire 
Factor 2: Anxiety and 
Dissatisfaction with 
Treatment 
The sum total of questions number 
14 and 19 -25 is converted into a 0 
-100 score [the best (56) = 100 and 
worst (8) = 0]. 
For a factor with <50% missing 
data, the mean value (round off 2 
digits) calculated from available 
answers is applied to cover the 
missing data. 
DTR -QOL Questionnaire 
Factor 3: Hypoglycemia 
The sum total of questions number 
15 -18, and is converted into a 0 -100 
score [the best (28) = 100 and worst 
(4) = 0]. 
For a factor with <50% missing 
data, the mean value (round off 2 
digits) calculated from available 
answers is applied to cover the 
missing data. 
DTR -QOL Questionnaire 
Factor 4: Treatment 
Satisfaction 
Each score of question number 26 
-29 is reversed (i.e., 1 converted to 7, 
7 converted to 1, and so on; the 
converted scores, where 7 is the best 
For a factor with <50% missing 
data, the mean value calculated 
from available answers is applied to 
cover the missing data. 


Protocol number: Trelagliptin-4002 
 
4 
Items 
Method 
Conditions 
and 1 is the worst, had the opposite 
sequence of the original scores). The 
converted scores are then added up, 
and the total is converted into a 0 
-100 score [the best (28) = 100 and 
worst (4) = 0]. 
 
DTR -QOL Questionnaire 
Total Score of all 
Questions 
1) Each score of question number 26 
-29 was reversed.( (i.e., 1 converted 
to 7, 7 converted to 1, and so on;). 
Factor1 – Factor 4 are calculated as 
described above.(Not converted) 
2) Factor 1 - Factor 4, which 
calculated by the method described 
above, are subsequently added up, 
and converted into a 0 -100 score 
[the best (203) = 100 and worst (29) 
= 0]. 
The total score of whole questions 
is not calculated if a total score of 
any of the four factors was 
unavailable.  
 
DTSQ Total Score 
 
Item 1, 4, 5, 6, 7, 8 scores are  
added up, 
All data must not be missing. 
Planned Number of 
Dosage of Trelagliptin 
(tablets)  
(The last administration date - the 
first administration date) / 7) +1. 
* Cut off to the whole number 
All data must not be missing. 
Planned Number of 
Dosage of Daily DPP -4 
Inhibitor (tablets)  
 (The last administration date - the 
first administration date) ) ×number 
of daily dose×number of tablets at 
the first administration date 
All data must not be missing. 
 
 
Study Medication 
Compliance (%)  
Actual number of dosage / Planned 
number of dosage ×100 (tablets) 
All data must not be missing. 
Days after Administration 
(Days)  
Examination/observation/evaluation 
date - the first administration date +1 
All data must not be missing. 


Protocol number: Trelagliptin-4002 
 
5 
Items 
Method 
Conditions 
Duration of Diabetes 
(year) 
{ (The first administration date 
(year) ×12+The first administration 
date (month) )  - (Onset Date of 
Diabetes (year) ×12 + Onset Date of 
Diabetes (month) ) } / 12 (rounded 
off two decimal places) 
All data must not be missing. 
If only the month of the onset of 
diabetes is unknown, the month of 
the onset of diabetes is regarded as 
“January”. 
 
8 -OHdG/Creatinine  
(ng/mg CRE）  
8 -OHdG (ng/mL) / Urine creatinine 
(mg/dL) ×100 
All data must not be missing. 
 
 
Display digit 
Item 
Defitintion 
Mean, Confidence 
interval, Quartiles 
Round statistics down to the 1 digits lower than significant digits of the data. 
Standard Deviation 
Round 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 to the one decimal place. 
P-value 
Round down to four decimal places. If p-value is less than 0.0001, display 
“p<0.0001” 
 
AE related to Hypoglycaemia 
AE related to Hypoglycaemia is defined as below. 
PT Code 
PT Name (Japanese) 
PT Name (English)  
10020993 
低血糖 
Hypoglycaemia 
10040576 
低血糖ショック 
Shock hypoglycaemic 
10065981 
低血糖性意識消失 
Hypoglycaemic unconsciousness 
10048803 
低血糖性痙攣 
Hypoglycaemic seizure 
10021002 
低血糖性脳症 
Hypoglycaemic encephalopathy 
10021000 
低血糖昏睡 
Hypoglycaemic coma 
10020997 
無自覚性低血糖 
Hypoglycaemia unawareness 
10054998 
神経低糖症 
Neuroglycopenia 


Protocol number: Trelagliptin-4002 
 
6 
1 SUBJECTS, DEMOGRAPHIC and OTHER BASELINE CHARACTERISTICS 
1.1 Subject Disposition 
1.1.1 Study Information 
Analysis Set:  
All subjects who are obtained informed consent 
Items:  
Date of First Subject Signed Informed Consent Form 
 
Date of Last Subject's Last Dose/Last Observation/Last Examination 
 
MedDRA Version 
 
SAS Version 
Method : 
For the above analysis items, the following analysis will be performed. 
 
 (1)  Display the above items 
 
1.1.2 Eligibility of Subjects 
Analysis Set:  
All subjects who are obtained informed consent 
Items:  
Randomization into the Treatment 
Period of the Study 
[Yes, No] 
 
Reason for Not randomized 
[Major Protocol Deviation, Lost to 
Follow-Up, Voluntary Withdrawal, 
Study Termination, Pregnancy, Did 
not meet entrance criteria, Other] 
Method : 
For the above analysis items, the following analysis will be performed. 
The denominator for the reasons is the number of subjects of Not 
randomized. 
 
 (1)  Frequency distribution 
 
1.1.3 Disposition of Subjects 
Analysis Set:  
All Randomized subjects 
Items:  
Status at the End of Study 
 
[Completed, Not Completed] 
 
Reason for Not Completed 
[Adverse Event, Major Protocol 
Deviation, Lost to Follow-Up, 
Voluntary Withdrawal, Study 
Termination, Pregnancy, Lack of 
Efficacy, Other] 
Method : 
For the above analysis items, the following analysis will be performed for 
each treatment group and total. 
The denominator for the reasons is the number of subjects of Not 
completed. 


Protocol number: Trelagliptin-4002 
 
7 
 
 (1)  Frequency distribution 
1.1.4 Protocol Deviations 
Analysis Set:  
All Randomized subjects 
Items:  
Protocol Deviations 
[Major GCP Violation, Deviations of 
Protocol Entry Criteria, Deviations Related to 
Treatment Procedure or Dose, Deviations 
Concerning Excluded Medication or 
Therapy,Deviation to Avoid Emergency 
Risk , Other] 
Method: 
For the above analysis items, the following analysis will be performed for 
each treatment group and total. Summarize the number of subjects who 
have deviated from the protocol, classify the deviations into the above 
category, and show the breakdown of deviations. Subjects applicable for 
multiple categories will be counted once in each category. 
 
 (1)  Frequency distribution 
 
1.1.5 Datasets Analyzed 
Analysis Set:  All Randomized subjects 
Items:  
Subjects Included/Excluded from 
Analysis Sets 
Full Analysis Set 
Safety Analysis Set 
 
 
[Inclusion ] 
[Inclusion] 
Method: 
For the above analysis items, the following analysis will be performed. 
 
 (1) Frequency distribution 
 
1.2 Demographics and Other Baseline Characteristics 
1.2.1 Distribution of Demographics Items 
Analysis Set:  Full Analysis Set 
Items:  
Age (years) 
[Min<=  - <65, 65<=  - <75,  
75<=  - <=Max]  
 
Gender 
[Male, Female] 
 
Height (cm)  
[Min<=  - <150, 150<=  - <160, 
160<=  - <170, 170<=  - <=Max] 
 
Weight (kg) 
[Min<=  - <50.0, 50.0<=  - <60.0, 
60.0<=  - <70.0, 70.0<=  - <80.0, 
80.0<=  - <=Max] 
 
BMI (kg/m2) 
[Min<=  - <18.5, 18.5<=  - <25.0, 


Protocol number: Trelagliptin-4002 
 
8 
25.0<=  - <=Max] 
 
Smoking Classification 
 
[Never smoked, Current smoker, 
Ex-smoker] 
 
Drink Alcohol Almost Every Day? 
[Yes, No] 
 
Duration of type 2 Diabetes Mellitus  
(years) 
[Min<=  - < 5, 5<=  - <10, 10<=  - 
<=Max] 
 
Any Medication for Concurrent 
Condition?(Week 0) 
[Yes, No] 
 
Number of Daily Doses of Drugs 
(Concurrent Condition Medicine.) 
[Less than 2 Times, 2 Times or More] 
 
Total Number of Daily Tablets 
(Concurrent Condition Medicine.) 
[Less than 2 Tablets, 2 Tablets or 
More] 
 
Number of Doses of Drugs 
(Study drug.) 
[Once a Week, Once daily, Twice 
daily] 
 
HbA1c (Week -4)     
[Less than 8.0%, 8.0% or more] 
 
DTR -QOL Total Score (Week -4)    [Less than 80, 80 or more] 
 
DTR -QOL Total Score (Week 0)   
 
 
DTR -QOL Total Score of 
"Factor 1: Burden on Social 
Activities and Daily Activities” 
(Week 0)  
 
 
DTR -QOL Total Score of 
"Factor 2: Anxiety and 
Dissatisfaction with Treatment” 
(Week 0)  
 
 
DTR -QOL Total Score of 
"Factor 3: Hypoglycemia” (Week 0)  
 
 
DTR -QOL Total Score of "Factor 4: 
Satisfaction with Treatment” (Week 
0)  
 
 
DTSQ Total Score (Week 0)  
 
Method:  
For the above analysis items, the following analysis will be performed for 
each treatment group and total.  
 (1) Summary of frequency distribution for discrete variables and summary 
statistics for continuous variables. 
 


Protocol number: Trelagliptin-4002 
 
9 
1.2.2.Medical History and Concurrent Disease 
Analysis Set:  Full Analysis Set 
Items:  
Medical History 
 
Concurrent Medical Conditions 
Method:  
 
For the above analysis items, the following analysis will be performed for 
each treatment group and total.  
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) Medical history: Summary of frequency distribution by SOC/PT 
(2) Concurrent medical conditions: Summary of frequency distribution by 
SOC/PT 
The method of accounting for the frequency is as follows. 
[Number of subjects] 
For 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. 
 
1.2.3 Concomitant Medications 
Analysis Set:  Full Analysis Set 
Items:  
Concomitant Medication 
Method:  
 
For the above analysis items, the following analysis will be performed for 
each treatment group and total. 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 distribution 
 
1.2.4 Dosing conditions of Study drug 
Analysis Set:  Full Analysis Set 
Items:  
Trelagliptin (mg/week) 
[50, 100, Other] 
Control Drugs 
[Sitagliptin, Vildagliptin, Alogliptin, 
Linagliptin, Teneligliptin, Anagliptin, 
Saxagliptin] 
Control Drug(mg/day)   
 
 
 
Sitagliptin 
[25, 50, 100, Other] 
 
 
Vildagliptin 
[50, 100, Other] 


Protocol number: Trelagliptin-4002 
 
10 
 
 
Alogliptin 
[25, Other] 
 
 
Linagliptin 
[5, Other] 
 
 
Teneligliptin 
[20, 40, Other] 
 
 
Anagliptin 
[200, 400, Other] 
 
 
Saxagliptin 
[2.5, 5, Other] 
Method:  
 (1) Frequency distribution at Week 0. 
 
 


Protocol number: Trelagliptin-4002 
 
11 
2 EFFICACY EVALUATIONS 
2.1 Primary Endpoint and the Analytical Methods 
Analysis Set:  Full Analysis Set 
Items:  
Change from Baseline in DTR-QOL Total Score at End of Study  
 (Week 12) 
Method:  
Analysis of covariance (ANCOVA) is conducted to compare between the 
treatment groups using "Change from baseline in DTR-QOL total score by 
the end of treatment [the End of Study (Week 12) - baseline (Week 0)]" as a 
dependent variable; DTR-QOL Total Score at the start of the screening 
period(<80 or ≥80) and HbA1c (<8.0% or ≥8.0%) at the start of the 
screening period as covariates; and "treatment group" as an independent 
variable. The level of significance is defined as 5% (two-sided). 
 
 
2.2 Secondary Endpoints and the Analytical Methods 
Analysis Set:  Full Analysis Set 
Items:  
1) DTR -QOL Total Score 
 
2) DTR -QOL Total Score of Factor1 to Factor 4 
"Factor 1: Burden on Social Activities and Daily Activities” (13 questions) 
"Factor 2: Anxiety and Dissatisfaction with Treatment” (8 questions) 
"Factor 3: Hypoglycemia” (4 questions) 
"Factor 4: Satisfaction with Treatment” (4 questions)  
 
3) DTSQ Total Score 
 
4) DTR -QOL Total Score of Each Items  
 
5) DTSQ Total Score of Each Items 
Analysis 
Visit:  
Week 0, Week 4, Week 12, End of Study 


Protocol number: Trelagliptin-4002 
 
12 
Method:  
(1) The following analysis will be performed for the Items 1 to 3 described 
above. 
Summary statistics of observed value and 95% confidence interval for the 
mean will be calculated by treatment groups and Analysis Visit. In addition, 
Mean (+/-SD) plots will be made by treatment group and Analysis Visit. 
Adjusted mean differences and the 95% confidence interval (two-sided) 
will also be provided. The same analyses described above will be 
performed on change from baseline at each analysis visit. 
(2) The following analysis will be performed for the Items 2 to 3 described 
above. 
Analysis of covariance (ANCOVA) will be conducted to compare between 
the treatment groups using "the change from baseline in the total score by 
the end of treatment [the End of Study(Week 12) - baseline (Week 0)]" as a 
dependent variable; the total score of "the DTR-QOL Total score (<80 or 
≥80)" at the baseline (Week 0) and "HbA1c (<8.0% or ≥8.0%)" at the 
baseline (Week 0) as covariates; and "a treatment group" as an independent 
variable.  
 (3) The following analysis will be performed for the Items 1, 3 described 
above. 
The summary statistics and two-sided 95% CI for means of change from 
baseline by treatment group will be calculated, with stratification by the 
following factors at the start of the treatment period (Week 0):  
 Use of medication for treatment of comorbidities; 
 Number of daily doses of medication for treatment of comorbidities 
(<2 times or ≥2 times); 
 total number of daily tablets of medication for treatment of 
comorbidities (<2 tablets or ≥2 tablets); 
 Number of doses of the study drug or comparative drug (once 
weekly, once daily or twice daily). 
 (4) The following analysis will be performed for the Items 4 -5 described 
above. 
Summary statistics for measurements and the change from baseline (Week 
0) will be calculated by treatment group per question at each analysis visit. 
 
2.3 Other Analysis 
Analysis Set:  
Full Analysis Set 
Items:  
1) Laboratory Tests 


Protocol number: Trelagliptin-4002 
 
13 
 
Serum Chemistry:  
 
HbA1c 
 
Fasting Blood Glucose 
 
Fasting Insulin 
 
Fasting Glucagon 
 
Fasting Glycoalbumin 
 
1.5 -AG 
 
Serum creatinine 
 
Urinalysis:  
 
Urinary 8-OHdG (using a correction value of uric creatinine ) 
 
Urinary creatinine 
 
2) Treatment Compliance 
 
3) The Basic Information on Study Subject 
 
How was Blood Glucose level in 
the previous a month? 
[1: Well-Controlled, 2, 3: Not Sure, 4, 
5: Poorly-Controlled] 
 
Which diabetes Med do you like 
to use? If efficacy, side effect, 
cost are equivalent 
[3 Times Daily, Twice Daily, Once 
Daily, Once a Week, Any Will be 
OK] 
 
Have you experienced 
hypoglycemia in the previous a 
month? 
[Yes, No] 
 
How many times have you 
experienced hypoglycemia in the 
previous a month? 
[0, 1, 2, 3, 4, 5<= - <=Max] 
 
When do you take other medicine 
(ex. hyperpiesia) in the previous a 
month? 
[multiple answers are allowed]  
[Breakfast, Lunch, Dinner, Bedtime, 
No Rules, Not Taking] 
 
How often do you forget to take 
other medicine (ex. hyperpiesia) 
in the previous a month? 
[Never, Rarely, 1-3 Times per Month, 
Once a Week, A Few Times a Week, 
>4 Times a Week, Not Taking] 
 
What kind Job are you with? 
[Full Time Job, Part Time Job, No 
Job, Other] 
 
How many Days Go to Work or 
go outside from Morning? 
 
[Rarely, 1-2 Days per Week, 3-4 Days 
per Week, 5-6 Days per Week, 7 Days 
per Week] 


Protocol number: Trelagliptin-4002 
 
14 
 
Hours taken from wake up to 
leave Home 
[Less than 1 hr, More than 1 hr Less 
than 2 hr, More than 2 hr Less than 3 
hr, More than 3 hr] 
 
How often do you have to take 
medicine during busy hours in the 
previous one month ?  
 
[Always, Sometimes, Occasionally, 
Rarely, Never] 
 
When do you take diabetes 
medicine?  [multiple]  
[Breakfast, Lunch, Dinner, Bedtime,  
No Rules, Not Taking] 
 
How Often do you forget to take 
diabetes medicine in the previous 
one month ?  
 
 
[Never, Rarely,  
1-3 Times per Month, Once a Week, 
A Few Times a Week,  
>4 Times a Week, Not Taking,] 
 
Felt guilty when forgot to take 
DM medicine 
[Exactly, Somewhat, Not Sure,  
Not Exactly, Never] 
 
Burdensome to take diabetes 
medicine outside 
[Exactly, Somewhat, Not Sure,  
Not Exactly, Never] 
Analysis Visit:  Item 1: Week 0, Week 4, Week 12, End of Study 
 
Item 3: Week 0, Week 4, Week 12, End of Study  
Method:  
(1) The following analysis will be performed for the Items 1 described 
above. 
Summary statistics of observed value and change from baseline (week 
0) will be calculated by treatment groups. Mean differences and the 
95% confidence interval (two-sided) will also be provided. In addition, 
Mean (+/-SD) plots will be made by treatment group.  
 
(2) The following analysis will be performed for the Items 2 described 
above. 
Treatment compliance of each subject will be calculated and summary 
statistics of compliance by treatment group will also be provided. 
 
(3)  The following analysis will be performed for the Items 3described 
above. 
Frequency distribution to each question will be analyzed byper 
treatment group. 
 
 


Protocol number: Trelagliptin-4002 
 
15 
2.4 CONSIDERATIONS on STATISTICAL ANALYSIS 
 Adjustments for Covariates 
2.4.1
ANCOVA will be performed on primary and secondary endpoints using treatment group as 
independent variables. Details are described in 2.1 and 2.2 
 
 
 Handling of Dropouts or Missing Data 
2.4.2
Data which are not adopted as a result of data missing of each analysis item or data handling 
in accordance with this statistical analysis plan item will be excluded from the analysis target 
for the statistical test or estimation of the evaluation. 
 
 Interim Analysis and Early Discontinuation 
2.4.3
Interim analysis will not be performed. 
 
 Multicenter Studies 
2.4.4
Analyses for consideration of centers will not be performed. 
 
 Multiple Comparisons/Multiplicity 
2.4.5
It does not adjust multiplicity. 
 
 Use of an Efficacy Subset of Subjects 
2.4.6
Not applicable in this study. 
 
 Active-Control Studies Intended to Show Equivalence 
2.4.7
This is not an active-control study intended to show equivalence.  
 
 Subgroup Analysis 
2.4.8
Subgroup analysis will be performed in 2.2. 
 
 
 


Protocol number: Trelagliptin-4002 
 
16 
3 SAFETY EVALUATION 
3.1 Treatment -Emergent Adverse Event 
 Brief Summary of Adverse Events 
3.1.1
Analysis Set:  
Safety Analysis Set 
Items:  
TEAE 
Classification:  
Causal relationship with 
treatment/control drug 
[Related, Not related] 
 
Severity  
[Mild, Moderate, Severe] 
Method:  
For the above analysis items, the following analyses of frequency 
distribution will be performed 
 
(1) Brief Summary of TEAE (events, subject, percent) 
 
1) All TEAEs 
 
2) TEAEs by causality 
 
3) All TEAEs by severity 
 
4) TEAEs leading to discontinuation 
 
5) Serious TEAEs 
 
6) Serious TEAEs by causality 
 
7) Serious TEAEs leading to study drug discontinuation 
 
8) TEAEs leading to death 
 
Incidence rates will be calculated as following on each analysis 
 [Number of Subjects] 
• Frequency by Causality 
In case of the analysis by causality, subjects with one or more adverse 
events within a level of MedDRA term is counted only once as related 
AE. 
• Frequency by Severity 
Subjects with one or more adverse events within a level of MedDRA 
term will be counted only once in that level using the most severe 
incident.  
• Others 
Subjects with one or more adverse events within a level of MedDRA 
term will be 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. 
[Number of Events] 
Number of events will be allowed multiple counts for the subject with 
one or more adverse events within a level of MedDRA term. 


Protocol number: Trelagliptin-4002 
 
17 
 
 Display of TEAE 
3.1.2
Analysis Set:  
Safety Analysis Set 
Items:  
TEAE 
Classification:   Severity  
[Mild, Moderate, Severe] 
Method:  
For the above analysis items, the following analysis will be 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 TEAEs by SOC and PT  
 
 (2) All TEAEs by SOC 
 
 (3) All TEAEs by PT 
 
(4) Drug-related TEAEs by SOC and PT 
 
(5) All TEAEs by severity by SOC and PT 
 
 (6) Drug-related TEAEs by severity by SOC and PT 
 
 (7) TEAEs leading to discontinuation by SOC and PT 
 
 (8) Serious TEAEs by SOC and PT 
 
 (9) Non-serious TEAEs of by SOC and PT 
 
Incidence rates will be calculated as following on each analysis. 
 [Number of Subjects] 
• Frequency distribution (by SOC/PT, 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. 
 
 


Protocol number: Trelagliptin-4002 
 
18 
3.2 Frequency of Hypoglycemia 
Analysis Set:  Safety Analysis Set 
Items:  
Hypoglycemia During Study 
[Yes, No] 
 
Incidence of Hypoglycemia (times) 
[0, 1, 2, 3, 4, 5<=  - <=Max] 
Method:  
Incidence rates will be calculated as following on each analysis. 
 (1) Frequency distribution 
 
3.3 Hospitalization related to type 2 diabetes mellitus 
Analysis Set:  Safety Analysis Set 
Items:  
Hospitalization Related to Type 2 
Diabetes Mellitus 
[Yes, No] 
 
Period (Days)  
[Min<=  - <7, 7<=  - < 14, 14<=  
- <=Max] 
 
Frequency (Times)  
[1, 2, 3, 4, 5<=  - <=Max] 
Method:  
Incidence rates will be calculated as following on each analysis. 
 (1) Frequency distribution 
For subjects who hospitalized for type 2 diabetes, duration and number of 
times will be counted. For subjects who remain hospitalized at the end of this 
study, duration will be calculated by using the last examination date. 
 
4 LISTINGS 
Analysis Set:  All Randomized subjects 
Items:  
Demographics 
[Subject No., Site Name, Treatment group, 
Medication name(control drug), Informed consent 
date, Age (years) , Sex, Height (cm) , Weight (kg) , 
BMI (kg / m2) , Smoking Classification, Drink 
alcohol , Date of DM onset, Medical history(YN), 
Concurrent Medical Conditions (YN)] 
 
Protocol Deviation 
[Subject No., Site Name, Treatment group, 
Age(years) , Sex, Contents of Protocol Deviation] 
 
Excluded from 
Efficacy 
[Subject No., Treatment group, Age(years) , Sex, 
Reason for exclusion] 
 
Medical History 
[Subject No., Site Name, Treatment group, 
Age(years) , Sex, Medical history(YN), Reported 
term for the medical history, SOC name, PT Name] 


Protocol number: Trelagliptin-4002 
 
19 
 
Concurrent Medical 
Conditions 
[Subject No., Site Name, Treatment group, 
Age(years) , Sex, Concurrent Medical Conditions 
(YN), Reported term for the concurrent medical 
conditions, SOC name, PT name] 
 
Medication for 
Concurrent 
Condition 
[Subject No., Site Name, Treatment group, 
Age(years) , Sex, Medication for concurrent 
Condition (YN), Number of daily doses of drugs, 
Total number of daily tablets] 
 
Concomitant 
Medications 
[Subject No., Site Name, Treatment group, 
Age(years) , Sex, Concomitant medication during 
study(YN), Trade name or Generic medication name, 
Drug code, Drug code(label), Preferred name, Total 
daily dose, Dose unit, Total daily dose (as needed), 
Route, Medication start date, Medication end date, 
Medication given to treat PTE/AE, Adverse event, 
Indication] 
 
Basic Information 
Questionnaire 
[Subject No., Site Name, Treatment group, 
Age(years) , Sex, Analysis visit, Result(No.1-14)] 
 
DTR -QOL 
Questionnaire 
[Subject No., Site Name, Treatment group, 
Age(years) , Sex, Analysis Visit, Total score (Factor 
1-Factor 4), DTR-QOL total score, Each score] 
 
DTSQ 
[Subject No., Site Name, Treatment group, 
Age(years) , Sex, Analysis Visit, DTSQ total score，
Each score] 
 
Withdrawal 
[Subject No., Site Name, Treatment group, 
Age(years) , Sex, Reason, Details of reason, Date of 
last dose , Experience an overdose(YN), PTE/AE 
During Study(YN), Concomitant Medication(YN)] 
 
Treatment drug / 
Control drug 
[Subject No., Site Name, Treatment group, 
Age(years) , Sex, Dose date, Dose time (first) , Dose 
time (second) ] 
 
Laboratory Test 
[Subject No., Site Name, Treatment group, 
Age(years) , Sex, Analysis Visit, Sample date, Item, 
Result, Normal/Abnormal, Specimen abnormal] 


Protocol number: Trelagliptin-4002 
 
20 
 
Hospitalization 
Related to Type 2 
Diabetes Mellitus 
[Subject No., Site Name, Treatment group, 
Age(years) , Sex, Date of hospitalization, Date of 
discharge] 
 
TEAE 
[Subject No., Treatment group, Age(years) , Sex, 
Adverse event (Verbatim) , SOC name, PT name , AE 
start date, AE end date, Intensity, Relationship to 
study drug , Action Concerning Study Drug, Date 
Dose Stopped, Date Dose Restarted, Outcome, Date 
of Death, Seriousness] 
 
Serious TEAE 
[Subject No., Site Name, Treatment group, 
Age(years), Sex, Adverse event (Verbatim) , SOC 
name, PT name , AE start date, AE end date, 
Intensity, Relationship to study drug , Action 
Concerning Study Drug, Date Dose Stopped, Date 
Dose Restarted, Outcome, Date of Death,] 
 
Dose Dispensed 
[Subject No., Site Name, Treatment group, 
Age(years) , Sex, Date of dispensed, Quantity of 
dispensed, Drug unused confirmed date, Quantity of 
unused] 
 
Investigational Drug 
Overdose 
[Subject No., Site Name, Treatment group, 
Age(years) , Sex, overdose start date, overdose end 
date, maximum daily amount taken, related to study 
proc./product packaging, nature of overdose, details 
of overdose, any untoward occurrences?, concomitant 
medication, procedure, prescribed dose amended, 
unknown, Other] 
Method:  
Lists described above will be created for randomized subjects 


Protocol number: Trelagliptin-4002 
 
21 
 Significance level, Confidence coefficient 
・ Significance level of 5% (2-sided) will be used for analysis.  
・ Confidence coefficient of 95% (2-sided) will be used for all confidence intervals. 
 


Protocol number: Trelagliptin-4002 
 
22 
REVISION HISTORY 
Version 
Date 
Author 
Revised Content 
1.0 
2017.1.10 
First Edition 
2.0 
2017.12.28 
Revision base on revised protocol Ver.1. 
 
PPD
PPD