Clinical trial NCT03231709
Conditions: Type 2 Diabetes Mellitus
Sponsor: Takeda
Start date: 2017-08-18; Completion date: 2018-02-09
Enrollment: 60 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The purpose of this study is to examine the participant's preference for treatment with once-weekly dosing of DPP-4 inhibitor trelagliptin versus once-daily dosing of DPP-4 inhibitor alogliptin among the participants with type 2 diabetes mellitus who are being treated with once-daily dosing of DPP-4 inhibitor.

Detailed description:
The drugs being tested in this study are called Trelagliptin and Alogliptin. This study will look at the participant's preference for treatment with Trelagliptin versus Alogliptin.

The study enrolled 60 patients. Participants will be randomly assigned (by chance, like flipping a coin) to one of the two treatment groups:

* Trelagliptin 100 mg, followed by Alogliptin 25 mg
* Alogliptin 25 mg, followed by Trelagliptin 100 mg All participants will be asked to take one tablet of trelagliptin orally once a week or one tablet of alogliptin orally once a day throughout the study period.

This multi-center trial will be conducted in Japan. The overall time to participate in this study is 16 weeks. Participants will make 3 visits to the clinic.

Arms: arm 1: Trelagliptin preceding group (T-A group): Trelagliptin 100 mg, tablets, orally, once a week for 8 weeks, followed by alogliptin, 25 mg, tablets, orally, once a day for 8 weeks. arm 2: Alogliptin preceding group (A-T group): Alogliptin, 25 mg, tablets, orally, once a day for 8 weeks, followed by trelagliptin, 100 mg, tablets, orally, once a week for 8 weeks.
Interventions: intervention 1: Trelagliptin intervention 2: Alogliptin
Intervention descriptions: intervention 1: Trelagliptin tablets intervention 2: Alogliptin tablets

Protocol documents:
Prot_000.pdf: 
 
 
Title: Treatment preference for weekly DPP-4 inhibitors versus daily DPP-4 inhibitors 
in patients with type 2 diabetes mellitus < TRINITY > 
 
NCT Number: NCT03231709 
Protocol Approve Date: 6-Jun-2017 
 
Certain information within this protocol has been redacted (ie, specific content is 
masked irreversibly from view with a black/blue bar) to protect either personally 
identifiable information or company confidential information. 
 
This may include, but is not limited to, redaction of the following: 
 
Named persons or organizations associated with the study. 
 
Patient identifiers within the text, tables, or figures or in by-patient data listings. 
 
Proprietary information, such as scales or coding systems, which are considered 
confidential information under prior agreements with license holder. 
 
Other information as needed to protect confidentiality of Takeda or partners, 
personal information, or to otherwise protect the integrity of the clinical study. 
 
If needed, certain appendices that contain a large volume of personally identifiable 
information or company confidential information may be removed in their entirety if it 
is considered that they do not add substantially to the interpretation of the data (eg, 
appendix of investigator’s curriculum vitae). 
 
Note; This document was translated into English as the language on original version 
was Japanese. 


Trelagliptin-4003 
Page 1 of 61
Version 1   
June 6, 2017
 
CONFIDENTIAL 
PROTOCOL 
 
 
 
 
 
 
 
Treatment preference for weekly DPP-4 inhibitors versus daily DPP-4 inhibitors in patients 
with type 2 diabetes mellitus 
(TRINITY) 
 
 
Sponsor 
Takeda Pharmaceutical Company Limited 
12-10, Nihonbashi 2-chome, Chuo-ku, Tokyo 
Protocol number 
Trelagliptin-4003 
Version Number 
Version 1 
Study drug: 
Trelagliptin and alogliptin 
Creation date 
June 6, 2017 
 
 
 
 


Trelagliptin-4003 
Page 2 of 61
Version 1   
June 6, 2017
 
CONFIDENTIAL 
CONFIDENTIAL PROPERTY OF TAKEDA 
This document is a confidential communication of Takeda. Acceptance of this document constitutes the 
agreement by the 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 
persons to whom the drug may be administered. Furthermore, the information is only meant for review 
and compliance by the recipient, his or her staff, and applicable institutional review committee and 
regulatory agencies to enable conduct of the study. 


Trelagliptin-4003 
Page 3 of 61
Version 1   
June 6, 2017
 
CONFIDENTIAL 
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 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). 
• 
International Conference on Harmonisation E6 Good Clinical Practice: Consolidated Guideline. 
• 
All applicable laws and regulations, including, without limitation, data privacy laws and conflict 
of interest guidelines. 
 
1.2 
Clinical Study Implementation 
This study will be conducted in accordance with the requirements of this protocol designed and 
prepared by the sponsor and also in accordance with the following. Other study administrative 
structures are shown in the annexes. 
 
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 study. Methods of supervision of the 
contractor entrusted with the services related to this study will be described in the procedure to be 
prepared separately. 
Expenses* required for the operation of this 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 study. Expenses agreed by the study site 
shall be paid to the site based on the “Research Expense Standard.” 
 
PPD


Trelagliptin-4003 
Page 4 of 61
Version 1   
June 6, 2017
 
CONFIDENTIAL 
 
 
 
 
PPD


Trelagliptin-4003 
Page 5 of 61
Version 1   
June 6, 2017
 
CONFIDENTIAL 
SIGNATURES 
The signature of MACS program head, Medical Director of Japan Medical Affairs and the 
responsible statistician can be found on the signature page. 
 
 
 
PPD
PPD


Trelagliptin-4003 
Page 6 of 61
Version 1   
June 6, 2017
 
CONFIDENTIAL 
TABLE OF CONTENTS 
1.0 
STUDY ADMINISTRATIVE INFORMATION AND CLINICAL STUDY PRINCIPLES ............... 3 
1.1 
Clinical Study Principles ................................................................................................................ 3 
1.2 
Clinical Study Implementation ....................................................................................................... 3 
2.0 
STUDY SUMMARY .......................................................................................................................... 11 
3.0 
LIST OF ABBERVIATIONS ............................................................................................................. 15 
4.0 
INTRODUCTION............................................................................................................................... 17 
 
Background ................................................................................................................................... 17 
4.1
 
Rationale for the Proposed Study ................................................................................................. 18 
4.2
5.0 
STUDY OBJECTIVES AND ENDPOINTS ...................................................................................... 19 
 
Objectives ..................................................................................................................................... 19 
5.1
5.1.1 
Primary Objectives ........................................................................................................... 19 
5.1.2 
Secondary Objectives........................................................................................................ 19 
 
Endpoints ...................................................................................................................................... 19 
5.2
5.2.1 
Primary Endpoint .............................................................................................................. 19 
5.2.2 
Secondary Endpoints ........................................................................................................ 19 
5.2.3 
Additional Endpoints ........................................................................................................ 19 
6.0 
STUDY DESIGN AND DESCRIPTION ........................................................................................... 20 
 
Study Design ................................................................................................................................. 20 
6.1
 
Justification for Study Design ...................................................................................................... 21 
6.2
 
Premature Termination of Study or Study Site ............................................................................. 22 
6.3
6.3.1 
Criteria for Premature Termination of the Study .............................................................. 22 
6.3.2 
Criteria for Premature Termination of Study Sites ........................................................... 22 
6.3.3 
Procedures for Premature Termination or Suspension of the Study or the 
Participation of Study Sites ............................................................................................... 22 
 
Procedures for Protocol Revision ................................................................................................. 22 
6.4
7.0 
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS ................................. 24 
 
Inclusion Criteria .......................................................................................................................... 24 
7.1
7.1.1 
Justification for Inclusion Criteria .................................................................................... 24 
 
Exclusion Criteria ......................................................................................................................... 25 
7.2
7.2.1 
Justification for Exclusion Criteria ................................................................................... 25 


Trelagliptin-4003 
Page 7 of 61
Version 1   
June 6, 2017
 
CONFIDENTIAL 
 
Excluded Medications .................................................................................................................. 26 
7.3
 
Subject Management .................................................................................................................... 26 
7.4
 
Criteria for Discontinuation or Withdrawal of a Subject .............................................................. 26 
7.5
 
Procedures for Discontinuation or Withdrawal of a Subjects ....................................................... 27 
7.6
8.0 
STUDY TREATMENT ...................................................................................................................... 28 
 
Study Drug .................................................................................................................................... 28 
8.1
8.1.1 
Dose and Regimen ............................................................................................................ 28 
8.1.2 
Overdose ........................................................................................................................... 28 
 
Allocation of the Study Drug and Administration Procedure ....................................................... 29 
8.2
 
Preparation and Storage of Allocation List ................................................................................... 29 
8.3
9.0 
STUDY PLAN .................................................................................................................................... 30 
 
Clinical study procedure ............................................................................................................... 30 
9.1
9.1.1 
Informed Consent Procedure ............................................................................................ 30 
9.1.2 
Demographics and Medication History Collection Procedure .......................................... 30 
9.1.3 
Physical Examination Procedure ...................................................................................... 30 
9.1.4 
Weight, Height, and Body Mass Index (BMI) .................................................................. 30 
9.1.5 
Documentation of Concomitant Medications ................................................................... 31 
9.1.6 
Documentation of Concurrent Medical Conditions .......................................................... 31 
9.1.7 
Questionnaire for Patient Preference for Treatment ......................................................... 31 
9.1.8 
DTSQ ................................................................................................................................ 31 
9.1.9 
Procedure for Clinical Laboratory Samples ...................................................................... 31 
9.1.10 
Pregnancy.......................................................................................................................... 32 
9.1.11 
Record of Subjects Who are Withdrawn Before Start of Administration ......................... 32 
 
Monitoring Subject Treatment Compliance.................................................................................. 32 
9.2
 
Schedule of Observations and Procedures .................................................................................... 33 
9.3
9.3.1 
Start of Administration（VISIT 1: Week 0） .................................................................. 33 
9.3.2 
Switch of Study drug（VISIT2: Week 8） ...................................................................... 33 
9.3.3 
End of Study (VISIT3: Week 16) ..................................................................................... 34 
9.3.4 
Discontinuation ................................................................................................................. 34 
10.0 ADVERSE EVENTS .......................................................................................................................... 35 
 Definitions .................................................................................................................................... 35 
10.1


Trelagliptin-4003 
Page 8 of 61
Version 1   
June 6, 2017
 
CONFIDENTIAL 
10.1.1 
AEs ................................................................................................................................... 35 
10.1.2 
Additional Points to Consider for AEs ............................................................................. 35 
10.1.3 
SAEs ................................................................................................................................. 37 
10.1.4 
Intensity of AEs ................................................................................................................ 38 
10.1.5 
Causality of AEs ............................................................................................................... 38 
10.1.6 
Relationship to Study Procedures ..................................................................................... 38 
10.1.7 
Study Date......................................................................................................................... 38 
10.1.8 
Stop Date .......................................................................................................................... 39 
10.1.9 
Action Concerning Study Drug ........................................................................................ 39 
10.1.10 Outcome ............................................................................................................................ 39 
 Procedures .................................................................................................................................... 40 
10.2
10.2.1 
Collection and Reporting of AEs ...................................................................................... 40 
10.2.2 
Collection and Reporting of SAEs .................................................................................... 42 
10.2.3 
Reporting of Additional Information Concerning AEs ..................................................... 42 
 Follow-up of SAEs ....................................................................................................................... 42 
10.3
10.3.1 
Reporting of SAEs, etc., to IECs, etc., and Regulatory Authorities ................................. 43 
11.0 STUDY-SPECIFIC COMMITTEES .................................................................................................. 44 
 Steering Committee ...................................................................................................................... 44 
11.1
12.0 DATA HANDLING AND RECORDKEEPING ................................................................................ 45 
 Case Report Forms (CRFs) ........................................................................................................... 45 
12.1
 Timing of Data Entry into the EDC System ................................................................................. 46 
12.2
 Storage and Disposal of Specimens and Documents, etc. ............................................................ 46 
12.3
13.0 STATISTICAL METHODS ............................................................................................................... 47 
 Statistical and Analytical Plans..................................................................................................... 47 
13.1
13.1.1 
Analysis Sets ..................................................................................................................... 47 
13.1.2 
Analysis of Demographics and Other Baseline Characteristics ........................................ 47 
13.1.3 
Efficacy Analysis .............................................................................................................. 47 
13.1.4 
Safety Analysis ................................................................................................................. 48 
13.1.5 
Other Analyses .................................................................................................................. 48 
 Interim Analysis and Criteria for Early Termination .................................................................... 48 
13.2
 Determination of Sample Size ...................................................................................................... 48 
13.3


Trelagliptin-4003 
Page 9 of 61
Version 1   
June 6, 2017
 
CONFIDENTIAL 
14.0 QUALITY CONTROL AND QUALLITY ASSURANCE ................................................................ 50 
 Study-Site Monitoring Visits ........................................................................................................ 50 
14.1
 Deviation from the Ethical Guideline for Clinical Research and the Protocol ............................. 50 
14.2
 Quality Assurance Audits and Regulatory Agency Inspections ................................................... 50 
14.3
15.0 ETHICAL ASPECT OF THE STUDY ............................................................................................... 51 
 IEC Approval ................................................................................................................................ 51 
15.1
 Conflict of Interests ...................................................................................................................... 51 
15.2
 Informed Consent and Information Sheet, and the Agreement of the Subjects ............................ 52 
15.3
 Personal Information of Subjects .................................................................................................. 53 
15.4
 Consultation for Subjects or Persons Related to the Study ........................................................... 53 
15.5
 Financial Burden or Reward to Subjects ...................................................................................... 53 
15.6
 Benefits and Inconveniences to Subjects ...................................................................................... 54 
15.7
15.7.1 
Benefits to Subjects .......................................................................................................... 54 
15.7.2 
Inconveniences to Subjects ............................................................................................... 54 
 Attribution of Study Results and Access Rights ........................................................................... 54 
15.8
15.8.1 
Attribution of Study Results ............................................................................................. 54 
15.8.2 
Data Access Rights ........................................................................................................... 54 
 Reporting of Results, Publication, Disclosure, and Clinical Study Registration Policy ............... 54 
15.9
15.9.1 
Reporting of Results, Publication and Disclosure............................................................. 54 
15.9.2 
Clinical Study Registration ............................................................................................... 55 
15.9.3 
Clinical Study Results Disclosure ..................................................................................... 55 
 Insurance and Compensation for Injury ........................................................................................ 55 
15.10
16.0 REFERENCES .................................................................................................................................... 56 
 
LIST OF IN-TEXT FIGURES 
Table 8.a. 
Dose and regimen ................................................................................................................... 28 
Table 9.a 
Laboratory tests ...................................................................................................................... 31 
Table 10.a Takeda Medically Significant Adverse Event List....................................................................... 37 
 


Trelagliptin-4003 
Page 10 of 61
Version 1   
June 6, 2017
CONFIDENTIAL 
LIST OF IN-TEXT FIGURES 
Figure 6.a  
Outline of Clinical Research Design ...................................................................................... 21 
LIST OF APPENDICES 
Appendix A Clinical Research Schedule .................................................................................................... 58 


Trelagliptin-4003 
Page 11 of 61
Version 1   
June 6, 2017
 
CONFIDENTIAL 
2.0 
STUDY SUMMARY 
Name of Sponsor: 
Takeda Pharmaceutical Co., Ltd. 
Compounds: 
Trelagliptin and alogliptin 
Title of Protocol: 
Treatment preference for weekly DPP-4 inhibitors versus daily DPP-4 inhibitors in patients with type 
2 diabetes mellitus 
Study Number: Trelagliptin-4003 
Clinical Research Design: 
This is a randomized, open-label, two-way crossover study which aims to examine the patient 
preference for treatment with once-weekly dosing of DPP-4 inhibitor trelagliptin versus once-daily 
dosing of DPP-4 inhibitor alogliptin among the patients with type 2 diabetes mellitus who are being 
treated with once-daily dosing of DPP-4 inhibitor. 
After obtaining the consent, the subjects who are judged eligible as a result of eligibility check will be 
randomized either to trelagliptin preceding group (T-A group) or alogliptin preceding group (A-T 
group). 
The outline of the clinical research design is shown in Figure 1. See the appendix for schedules of 
tests, observations, and assessments. 
 
Fig. 1 Outline of Clinical Research Design 
Primary Objectives:  
To examine the patient preference for treatment with once-weekly dosing of DPP-4 inhibitor 
trelagliptin versus once-daily dosing of DPP-4 inhibitor alogliptin among the patients with type 2 
diabetes mellitus. 
Secondary Objective: 
Trelagliptin
A-T group
Alogliptin
Trelagliptin
Alogliptin
Informed consent procedure
Eligibility check
Randomization
Start of study drug
Administration
Switch of study drug
Questionnaire for patient
preference
Visit
1
2
3
Week
0
8
16
T-A group


Trelagliptin-4003 
Page 12 of 61
Version 1   
June 6, 2017
 
CONFIDENTIAL 
To investigate subjects' background which affect the patient preference for treatment. 
Subject Population: 
Patients with type 2 diabetes mellitus 
Number of Subjects: 
60 patients as randomized subjects 
(T-A group: 30 subjects, A-T group: 30 subjects) 
Number of Sites: 
2 medical institutions 
Dosage Levels: 
Trelagliptin, 100 mg, once weekly. 
Alogliptin, 25 mg, once daily. 
Route of Administration: 
Oral 
Duration of administration: 
16 weeks 
Period of Evaluation: 
16 weeks 
Criteria for Inclusion: 
Subject eligibility is determined according to the following criteria prior to entry into the study.  
1. 
Subjects who have been diagnosed with type 2 diabetes mellitus 
2. 
Subjects who are being treated with any of the following DPP-4 inhibitors for at least 8 weeks 
prior to the start of treatment period (Week 0). 
 
Sitagliptin : 50 mg once daily 
 
Alogliptin : 25 mg once daily 
 
Linagliptin : 5 mg once daily 
 
Teneligliptin : 20 mg once daily 
 
Saxagliptin : 5 mg once daily 
3. 
Subjects who were judged by the investigators possible to change the treatment from once-daily 
dosing of DPP-4 inhibitor shown in Inclusion Criteria 2 to study drug trelagliptin 100 mg or 
alogliptin 25 mg 
4. 
Subjects whose HbA1c value measured within 8 weeks prior to the start of treatment period 
(Week 0) is below 10.0% 
5. 
Subjects who responded to DTSQ (Diabetes Treatment Satisfaction Questionnaire) at the start of 
treatment period (Week 0) 
6. 
Subjects who were judged by the investigators capable to understand the contents of this clinical 
research and comply with them 
7. 
Subjects who are able to sign and date the Informed Consent Form before any clinical research 
procedure begins 
8. 
Subjects who are at least 20 years old at the time of giving the consent 
9. 
Subjects who are classified as outpatients 


Trelagliptin-4003 
Page 13 of 61
Version 1   
June 6, 2017
 
CONFIDENTIAL 
Criteria for Exclusion: 
Subjects who correspond to any of the following criteria will not be subjects of this clinical research. 
1. 
Subjects who have a history of taking once-weekly dosing of DPP-4 inhibitor (trelagliptin or 
omarigliptin) 
2. 
Subjects who are being treated with drugs other than those for once-daily oral dosing for the 
purpose of treatment of chronic complication (for example, “BENET® Tablets 75 mg”, a 
therapeutic agent for osteoporosis which is administered once monthly) 
3. 
Subjects who are being treated with twice-daily dosing of DPP-4 inhibitor (vildagliptin or 
anagliptin) 
4. 
Subjects who are being treated with anti-diabetic fixed-dose combination pill contained a DPP-4 
inhibitor.  
5. 
Subjects with moderate or severe renal impairment (for example, patients whose eGFR is below 
60 mL/min/1.73m2) 
6. 
Subjects for whom blood sugar control by insulin preparations is desired (for example, patients 
with severe ketosis, diabetic coma or precoma, type 1 diabetes mellitus, severe infection, or 
serious trauma before or after surgery) 
7. 
Subjects who have a history of hypersensitivity or allergy to DPP-4 inhibitor 
8. 
Subjects with serious heart disease, cerebrovascular disorder, or patients with serious disease in 
the pancreas, blood, etc. 
9. 
Subjects with unstable proliferative diabetic retinopathy 
10. Subjects with malignant tumor 
11. Subjects who are pregnant, breast-feeding, possibly pregnant, or planning to become pregnant. 
12. Subjects participating in other clinical studies. 
13. Subjects who have been determined as inappropriate subjects by the investigator. 
Criteria for Evaluation and Analyses: 
The primary endpoint for this study is patient preference for treatment interviewed from the subjects 
using the standardized questions* at the end of treatment period (treatment selection rate) 
*: Questions 
Regarding the drug therapy after the end of this research, which treatment do you select from 
the following choices from 1 to 4? 
1. Either once-weekly DPP-4 inhibitor or daily DPP-4 inhibitor 
2. Once-weekly DPP-4 inhibitor 
3. Daily DPP-4 inhibitor 
4. Neither once-weekly DPP-4 inhibitor nor daily DPP-4 inhibitor 
The secondary endpoints: 
• 
Preference for treatment (treatment selection rate) by drug (trelagliptin or alogliptin) selected by 
subjects at the end of treatment period and by background factor 


Trelagliptin-4003 
Page 14 of 61
Version 1   
June 6, 2017
 
CONFIDENTIAL 
Additional endpoints:  
• 
Change in DTSQ treatment satisfaction* at each evaluation point 
*: Evaluated with the total points of questions 1, 4, 5, 6, 7, and 8 
• 
Efficacy endpoint: HbA1c 
• 
Safety endpoint: Adverse events 
Statistical Consideration: 
<Primary endpoint> 
Patient preference for treatment interviewed from the subjects using the standardized questions at the 
end of treatment period (treatment selection rate) 
Among the subjects who were randomized and treated with the study drugs, the treatment selection 
rate will be calculated by merging the subjects from whom preference for treatment was interviewed 
by treatment group with the treatment groups. Also, the treatment selection rates for once-weekly 
DPP-4 inhibitor and daily DPP-4 inhibitor are compared by applying the Mainland-Gart test. 
Sample Size Justification: 
By referring to the results of the questionnaire for treatment selection rate after dosing of once-weekly 
DPP-4 inhibitor, the treatment selection rate of once-weekly DPP-4 inhibitor is assumed to be 60%, 
treatment selection rate of daily DPP-4 inhibitor 20%, and rate of subjects who do not show any 
preference for treatment (either is fine/prefer neither) 20%, respectively. 
In doing so, a total of 54 patients will be necessary in order to secure 90% power in the binomial test 
with two-sided significance level at 5%.  With the estimated rate of discontinuation at 10%, the 
number of randomized subjects was set to be 30 subjects per group or 60 subjects in total. 
 
 
 


Trelagliptin-4003 
Page 15 of 61
Version 1   
June 6, 2017
 
CONFIDENTIAL 
3.0 
LIST OF ABBERVIATIONS  
AE 
adverse event 
COI 
conflict of interest 
CRO 
contract research organization 
DTSQ 
Diabetes Treatment Satisfaction Questionnaire 
eGFR 
estimated Glomerular Filtration Rate 
EDC 
electronic data capture 
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 
MedDRA 
Medical Dictionary for Regulatory Activities 
MHRA 
Medicines and Healthcare Products Regulatory Agency 
SAE 
serious adverse event 
 
 
 


Trelagliptin-4003 
Page 16 of 61
Version 1   
June 6, 2017
 
CONFIDENTIAL 
The terms used in this protocol are defined as follows: 
Study site: 
A corporation, a governmental agency, or a sole proprietor who is conducting the study, excluding 
the 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 conduct 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 investigators: 
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 
Subject: 
A 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. 


Trelagliptin-4003 
Page 17 of 61
Version 1   
June 6, 2017
 
CONFIDENTIAL 
4.0 
INTRODUCTION 
 
Background 
4.1
A relationship has been reported between blood glucose control and medication adherence in 
patients who received oral antidiabetic drugs for type 2 diabetes1). Blood glucose control is crucial in 
preventing complication of diabetes. Poor adherence, due to miss of a dose for instance, sometimes 
results in poor control of blood glucose2), thereby increasing the risk of the complications. Hence, it 
is important to maintain good treatment adherence in the treatment for diabetes. 
Taking many drugs every day is a burden for patients and is regarded as a reason for reduced 
medication adherence3). A majority of patients with type 2 diabetes receive two drugs or more 
concomitantly once or more times daily. Many of those wish to reduce the dose frequency and/or the 
numbers of drugs that they are taking at a time. In particular, those who continue to work while 
being treated for type 2 diabetes find it difficult to take the drugs as prescribed, due to their 
occasional business trips or relatively irregular eating patterns4). Thus, reducing dose frequency may 
improve medication adherence for them. Indeed, switch to weekly bisphosphonates has been 
reported to improve the adherence in patients with osteoporosis who had received once daily 
bisphosphonates5). 
Trelagliptin is the first once-weekly oral dipeptidyl peptidase 4 (DPP-4) inhibitor. DPP-4 
inhibitors increase incretin levels (GLP-1 and GIP) by blocking DPP-4-dependent their proteolytic 
degradation, thereby stimulating insulin secretion in a glucose-dependent manner. DPP-4 inhibitors 
are widely used as oral antidiabetic drugs for type 2 diabetes. Most of the DPP-4 inhibitors require 
once or twice daily dosing. Thus, weekly DPP-4 inhibitors may offer a novel therapeutic option for 
the patients who receive daily DPP-4 inhibitors. They are also expected to improve the medication 
adherence and prevent treatment discontinuation by relieving the burden associated with frequent 
dosing of the patients. 
There have been several studies that compare weekly DPP-4 inhibitors with daily DPP-4 
inhibitors with regard to treatment preference. Suzuki et al. reported based on the questionnaire 
survey that 55.3% of 170 patients taking daily DPP-4 inhibitors would like to change their daily 
DPP-4 inhibitors to weekly ones6). Higuchi et al. reported that 61% of all the patients with type 2 
diabetes treated in their clinic (364 patients) answered that weekly drugs were preferable7). Uchida 
reported that 36 out of 38 patients showed their preference for once weekly DPP-4 inhibitors after 
treatment with the once-weekly DPP-4 inhibitors (trelagliptin or omarigliptin) for three or four 
months8). Moreover, Nakamura et al. reported that 63% of 201 patients chose weekly inhibitors as a 
preferential treatment a few months after the treatment had been switched from their once-daily 
DPP-4 inhibitors to the once-weekly DPP-4 inhibitor trelagliptin9). All the above reports suggest 
patients' interests in once-weekly DPP-4 inhibitors as well as preference for them before and after 


Trelagliptin-4003 
Page 18 of 61
Version 1   
June 6, 2017
 
CONFIDENTIAL 
the prescription. However, these studies cannot rule out the possible influence of the proximate 
medication or accustomed drug-taking behavior on preference for the subsequent treatment.  
The present study is a randomized, open-label, two-way crossover study which aims to examine 
the patient preference for treatment with once-weekly DPP-4 inhibitor trelagliptin versus once-daily 
DPP-4 inhibitor alogliptin among the patients with type 2 diabetes mellitus who are being treated 
with once-daily DPP-4 inhibitor. Two-way crossover design enables us to reduce the possible 
influence of the proximate medication or drug-taking behavior on the preference. The study also 
includes a background research on the patients to explore the factors that influence the treatment 
preference. This study may bring us more information on the future antidiabetic treatment aimed at 
improved medication adherence as well as treatment of choice for a range of patients with 
individually different life-styles.    
 
 
Rationale for the Proposed Study 
4.2
Once-weekly DPP-4 inhibitors are expected to contribute to reducing patient burden caused by 
multiple dosing and thereby improve medication adherence. Several questionnaire surveys suggest 
preference of the patients for once-weekly DPP-4 inhibitors over daily inhibitors. However, no 
treatment preference study, which takes timing effects into account, has been reported for DPP-4 
inhibitors. The present study is designed to examine the patient preference for once-weekly DPP-4 
inhibitors versus once-daily DPP-4 inhibitors among the patients with type 2 diabetes mellitus, who 
receive once-daily dosing of alogliptin for 8 weeks and then once-weekly dosing of trelagliptin for 
another 8 weeks, or the reverse sequence. 


Trelagliptin-4003 
Page 19 of 61
Version 1   
June 6, 2017
 
CONFIDENTIAL 
5.0 
STUDY OBJECTIVES AND ENDPOINTS 
 
Objectives 
5.1
5.1.1 
Primary Objectives 
To examine the patient preference for treatment with once-weekly dosing of DPP-4 inhibitor 
trelagliptin versus daily dosing of DPP-4 inhibitor alogliptin among the patients with type 2 
diabetes mellitus. 
5.1.2 
Secondary Objectives 
To investigate subjects' background which affect the patient preference for treatment. 
 
Endpoints 
5.2
5.2.1 
Primary Endpoint 
Patient preference for treatment interviewed from the subjects using the standardized questions* at 
the end of treatment period (treatment selection rate).  
*: Questions 
Regarding the drug therapy after the end of this research, which treatment do you select from 
the following choices from 1 to 4? 
1. Either once-weekly DPP-4 inhibitor or daily DPP-4 inhibitor 
2. Once-weekly DPP-4 inhibitor 
3. Daily DPP-4 inhibitor 
4. Neither once-weekly DPP-4 inhibitor nor daily DPP-4 inhibitor 
5.2.2 
Secondary Endpoints 
• 
Preference for treatment (treatment selection rate) by drug (trelagliptin or alogliptin) selected by 
subjects at the end of treatment period and by background factor 
5.2.3 
Additional Endpoints 
• 
Change in DTSQ10), 11) treatment satisfaction* at each evaluation point 
*: Evaluated with the total points of questions 1, 4, 5, 6, 7, and 8 
• 
Efficacy endpoint: HbA1c 
• 
Safety endpoint: Adverse events 


Trelagliptin-4003 
Page 20 of 61
Version 1   
June 6, 2017
 
CONFIDENTIAL 
6.0 
STUDY DESIGN AND DESCRIPTION 
 
Study Design 
6.1
<Study design> 
This is a randomized, open-label, two-way crossover study which aims to examine the patient 
preference for treatment with once-weekly dosing of DPP-4 inhibitor trelagliptin versus daily dosing 
of DPP-4 inhibitor alogliptin among the patients with type 2 diabetes mellitus who are being treated 
with daily dosing of DPP-4 inhibitor. 
After obtaining the consent, the subjects who are judged eligible as a result of eligibility check will 
be randomized either to trelagliptin preceding group (T-A group) or alogliptin preceding group (A-T 
group). 
 
Planned number of subjects is 60 in total.  
 
<Duration> 
The study period is 16 weeks. The number of visits is 3. 
VISIT 1: Start of administration (week 0) 
VISIT 2: Switch of study drug (week 8) 
VISIT 3: End of study (week 16) 
 
<Treatment> 
Trelagliptin preceding group (T-A group): 
The subjects receive 100 mg of trelagliptin once a week for 8 weeks and then 25 mg of alogliptin 
once a day for 8 weeks. 
Alogliptin preceding group (A-T group) 
The subjects receive 25 mg of alogliptin once a day for 8 weeks and then 100 mg of trelagliptin once 
a week for 8 weeks. 
 
The outline of the clinical research design is shown in Figure 6.a.   
See the appendix for schedules of tests, observations, and assessments. 
 


Trelagliptin-4003 
Page 21 of 61
Version 1   
June 6, 2017
 
CONFIDENTIAL 
 
Figure 6.a  Outline of Clinical Research Design 
 
 
Justification for Study Design 
6.2
1) 
Justification for study design 
The primary objective of this randomized, open-label study is to evaluate treatment preference of 
patients with type 2 diabetes mellitus for once weekly DPP-4 inhibitors. After obtaining informed 
consent, the eligible subjects receive both once weekly trelagliptin and once daily alogliptin for 8 
weeks each sequentially and they are then asked about their treatment preference. The study is also 
designed as a two-way crossover study in order to mitigate potential effects of drug sequence on 
treatment preference.  
2) 
Justification for dose of the drugs 
Significant change in blood glucose control during the study can affect the outcomes (treatment 
preference of the subjects) and should be avoided. The efficacy of trelagliptin at 100 mg in lowering 
blood glucose level is considered equivalent to that of alogliptin at 25 mg12).  
3) 
Justification for dosing period 
There is a study reporting that the time it took people to form habit of doing relatively simple things 
in everyday life need more than 2 months13). In addition, a majority of patients with type 2 diabetes 
mellitus visit clinics once a month or once every 2 months. Therefore, 8-week is set as the dosing 
period.  
4) 
Justification for the number of subjects 
Refer to 13.3 
 
Trelagliptin
A-T group
Alogliptin
Trelagliptin
Alogliptin
Informed consent procedure
Eligibility check
Randomization
Start of study drug
Administration
Switch of study drug
Questionnaire for patient
preference
Visit
1
2
3
Week
0
8
16
T-A group


Trelagliptin-4003 
Page 22 of 61
Version 1   
June 6, 2017
 
CONFIDENTIAL 
 
Premature Termination of Study or Study Site 
6.3
6.3.1 
Criteria for Premature Termination of the Study 
The sponsor should immediately discontinue the study when at least one of the following criteria is 
applicable: 
 
New information or other evaluation regarding the safety or efficacy of the study drug that 
indicates a change in the known risk/benefit profile for the product, such that the risk/benefit is 
no longer acceptable for subjects participating in the study. 
 
Significant violation of Good Clinical Practice (GCP) that compromises subject safety.  
6.3.2 
Criteria for Premature Termination of Study Sites 
A study site may be terminated prematurely if the site (including the principal investigator) is found 
in significant violation of the Ethical Guideline for Clinical Research, protocol, or contractual 
agreement, is unable to ensure adequate performance of the study or as otherwise permitted by the 
contractual agreement. 
6.3.3 
Procedures for Premature Termination or Suspension of the Study or the 
Participation of Study Sites 
In the event that the sponsor or a study site committee such as an independent ethics committee 
(IEC) elects to terminate or suspend the study or the participation of a study site, a study-specific 
procedure for early termination or suspension will be provided by the sponsor; the procedure will be 
followed by applicable study sites during the course of termination or study suspension.  
 
Procedures for Protocol Revision 
6.4
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. 
Investigators shall confirm the content of the revision of the protocol and submit an agreement form 
to the sponsor as evidence of agreement with the protocol revision. 
 [Protocol revision is required in the following cases:] 
1. Change or addition of objectives 
2. Change in or addition of efficacy or safety evaluation methods 
3. More frequent or additional laboratory tests for which subjects incur additional expenses or 
changes in laboratory test methods 


Trelagliptin-4003 
Page 23 of 61
Version 1   
June 6, 2017
 
CONFIDENTIAL 
4. Change in dose 
5. Significant change in or addition of inclusion and/or exclusion criteria 
6. Change in the planned number of subjects 
7. Change in plans or in description of the protocol due to serious adverse events or other reasons 
8. Change which is considered as a significant change, as a result of discussion between the 
sponsor and the chair of the Steering Committee 
 
Upon notification, the principal investigator at each study site shall submit the revised contents to the 
relevant committees (such as an institutional ethics review committee), for review and approval as 
necessary according to institutional regulations. 


Trelagliptin-4003 
Page 24 of 61
Version 1   
June 6, 2017
 
CONFIDENTIAL 
7.0 
SELECTION AND DISCONTINUATION/WITHDRAWAL OF 
SUBJECTS 
The investigators shall confirm all the inclusion/exclusion criteria prior to enrollment. 
 
Inclusion Criteria 
7.1
Subject eligibility is determined according to the following criteria prior to entry into the study.  
1. 
Subjects who have been diagnosed with type 2 diabetes mellitus 
2. 
Subjects who are being treated with any of the following DPP-4 inhibitors for at least 8 weeks 
prior to the start of treatment period (Week 0). 
 
Sitagliptin : 50 mg once daily 
 
Alogliptin : 25 mg once daily 
 
Linagliptin : 5 mg once daily 
 
Teneligliptin : 20 mg once daily 
 
Saxagliptin : 5 mg once daily 
3. 
Subjects who were judged by the investigators possible to change the treatment from daily 
dosing of DPP-4 inhibitor shown in Inclusion Criteria 2 to study drug trelagliptin 100 mg or 
alogliptin 25 mg 
4. 
Subjects whose HbA1c value measured within 8 weeks prior to the start of treatment period 
(Week 0) is below 10.0% 
5. 
Subjects who responded to DTSQ (Diabetes Treatment Satisfaction Questionnaire) at the start 
of treatment period (Week 0) 
6. 
Subjects who were judged by the investigators capable to understand the contents of this 
clinical research and comply with them 
7. 
Subjects who are able to sign and date the Informed Consent Form before any clinical research 
procedure begins 
8. 
Subjects who are at least 20 years old at the time of giving the consent 
9. 
Subjects who are classified as outpatients 
 
7.1.1 Justification for Inclusion Criteria 
1, 4, and 5 
These were set to evaluate the efficacy of the drugs in patients with type 2 diabetes 
mellitus. 
2 and 3 
These were set to include the subjects who would not have a significant change in their 
blood glucose control, which may affect the outcomes (treatment preference) 
6 to 9 
These were set as fundamental items for the study. 
 


Trelagliptin-4003 
Page 25 of 61
Version 1   
June 6, 2017
 
CONFIDENTIAL 
 
Exclusion Criteria 
7.2
Subjects who correspond to any of the following criteria will not be subjects of this clinical research. 
1. 
Subjects who have a history of taking once-weekly dosing of DPP-4 inhibitor (trelagliptin or 
omarigliptin). 
2. 
Subjects who are being treated with drugs other than those for daily oral dosing for the purpose 
of treatment of chronic complication (for example, “BENET® Tablets 75 mg”, a therapeutic 
agent for osteoporosis which is administered once monthly). 
3. 
Subjects who are being treated with twice-daily dosing of DPP-4 inhibitor (vildagliptin or 
anagliptin). 
4. 
Subjects who are being treated with anti-diabetic fixed-dose combination pill contained a 
DPP-4 inhibitor.  
5. 
Subjects with moderate or severe renal impairment (for example, subjects whose eGFR is 
below 60 mL/min/1.73m2). 
6. 
Subjects for whom blood sugar control by insulin preparations is desired (for example, subjects 
with severe ketosis, diabetic coma or precoma, type 1 diabetes mellitus, severe infection, or 
serious trauma before or after surgery). 
7. 
Subjects who have a history of hypersensitivity or allergy to DPP-4 inhibitor 
8. 
Subjects with serious heart disease, cerebrovascular disorder, or subjects with serious disease in 
the pancreas, blood, etc. 
9. 
Subjects with unstable proliferative diabetic retinopathy 
10. Subjects with malignant tumor 
11. Subjects who are pregnant, breast-feeding, possibly pregnant, or planning to become pregnant. 
12. Subjects participating in other clinical studies. 
13. Subjects who have been determined as inappropriate subjects by the investigator. 
 
7.2.1 Justification for Exclusion Criteria 
1 
This was set to exclude possible effects of previous experience of taking weekly DPP-4 
inhibitors on the treatment preference. 
2 
This was set to exclude possible effects of previous experience of taking non-daily 
orally available drugs on the treatment preference. 
3 
This was set to limit the dose frequencies as explanation factor to once daily and once 
weekly, since vildagliptin or anagliptin is a twice daily DPP-4 inhibitor. 
4 
This was set to rule out the possibility that the drug change from combination tablet to 
DPP-4 inhibitor only affects the subjects' blood glucose levels or the possibility that 
increase of the tablets affects their treatment preference. 


Trelagliptin-4003 
Page 26 of 61
Version 1   
June 6, 2017
 
CONFIDENTIAL 
5 to 11 
These were set in consideration of safety of the subjects. 
12, 13 
These were set as fundamental items for the study. 
 
 
Excluded Medications 
7.3
Addition of drugs or changes in dose/regimen of drugs for treatment of type 2 diabetes mellitus 
or concurrent medical conditions such as hypertension are not allowed. However, the drugs to 
treat adverse events are permitted to be used.  
 
[Justification for excluded medications] 
These were set because they would affect evaluation of primary endpoint. 
 
Subject Management 
7.4
The investigators shall instruct subjects to adhere to the following throughout the study period:  
1. Adhere to the instructions or restrictions prescribed in the study period. 
2. Take glucose or sucrose (sugar) if hypoglycemia symptom (hunger abnormal, feeling of 
weakness, trembling of hands and fingers, cold sweat, palpitations, etc.) is observed, and if 
symptoms continue, visit the study site promptly.  
3. 
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. 
4. 
Adhere to instructed prohibited concomitant drugs. When drugs are taken other than the 
drugs prescribed by the investigators, have the research subject report its content. 
5. 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. 
 
Criteria for Discontinuation or Withdrawal of a Subject 
7.5
The primary reason for discontinuation or withdrawal of the subject from the study or study drug 
should be recorded in the case report form (CRF) using the following categories. For subjects who 
withdraw from the study before administration, refer to Section 9.1.11.  
1. Adverse event 
The subject has experienced an adverse event (AE) that requires early termination because 
continued participation imposes an unacceptable risk to the subject’s health or the subject is 
unwilling to continue because of the AE. 


Trelagliptin-4003 
Page 27 of 61
Version 1   
June 6, 2017
 
CONFIDENTIAL 
2. Significant protocol deviation  
The discovery after the first dose of study drug that the subject failed to meet protocol entry 
criteria or did not adhere to protocol requirements, and continued participation poses an 
unacceptable risk to the subject’s health.  
3. Lost to follow-up 
The subject did not return to the clinic and attempts to contact the subject were unsuccessful. 
Attempts to contact the subject must be documented in the subject’s source documents 
4. Voluntary withdrawal 
The subject (or subject’s legally acceptable representative) wishes to withdraw from the study. 
The reason for withdrawal, if provided, should be recorded in the CRF. 
Note: All attempts should be made to determine the underlying reason for the withdrawal and, 
where possible, the primary underlying reason should be recorded (ie, withdrawal due to an AE 
should not be recorded in the “voluntary withdrawal” category). 
5. Study termination  
The sponsor, IEC or regulatory authority terminates the study. Refer to Section 6.3.1 for details. 
6. Pregnancy 
The subject is found to be pregnant. 
Note: If the subject is found to be pregnant, the subject must be withdrawn immediately. The 
procedure is described in Section 9.1.10. 
7. Lack of efficacy 
The investigator has determined that the subject is not benefiting from study treatment; and, 
continued participation would pose an unacceptable risk to the subject. 
8. Others 
The investigator determined to terminate the study for other reasons.  
Note: The specific reasons should be recorded on the CRF. 
 
Procedures for Discontinuation or Withdrawal of a Subjects 
7.6
The investigator may discontinue a subject’s study participation at any time during the study when 
the subject meets the study termination criteria described in Section 7.5. In addition, a subject may 
discontinue his or her participation without giving a reason at any time during the study. Should a 
subject’s participation be discontinued, the primary criterion for termination must be recorded by the 
investigator. In addition, efforts should be made to perform all procedures scheduled for the Early 
Termination Visit.  


Trelagliptin-4003 
Page 28 of 61
Version 1   
June 6, 2017
 
CONFIDENTIAL 
8.0 
STUDY TREATMENT 
This section indicates the treatment regimen of this study. See the latest package insert for details 
and handling of the drug. 
 
Study Drug 
8.1
Generic name: trelagliptin succinate 
Chemical name: 
2-({6-[(3R)-3-Aminopiperidin-1-yl]-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl}
methyl)-4-fluorobenzonitrile monosuccinate 
 
Generic name: alogliptin benzoate 
Chemical name: 
2-({6[-(3R)-3-Aminopiperidin-1-yl]-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl}m
ethyl)benzonitrile monobenzoate 
8.1.1 
Dose and Regimen 
The investigators shall administer the study drugs as shown in figure 8.a. 
For trelagliptin preceding group (T-A group), trelagliptin 100 mg is orally administered once weekly 
for 8 weeks and then alogliptin 25 mg once daily for 8 weeks. For alogliptin preceding group (A-T 
group), alogliptin 25 mg is orally administered once daily for 8 weeks and then trelagliptin one 
weekly for 8 weeks.  
Table 8.a. Dose and regimen 
Treatment period 
Drug 
Dose 
Regimen 
Trelagliptin 
100 mg 
Once weekly, Orally 
Alogliptin 
25 mg 
Once daily, Orally 
8.1.2 
Overdose 
An overdose is defined as a known deliberate or accidental administration of study drug, to or by a 
study subject, at a dose above that which is assigned to that individual subject according to the 
protocol. 
All cases of overdose (with or without associated AEs) will be documented on an Overdose page of 
the CRF, in order to capture this important safety information consistently in the database. Cases of 


Trelagliptin-4003 
Page 29 of 61
Version 1   
June 6, 2017
 
CONFIDENTIAL 
overdose without manifested signs or symptoms are not considered AEs. AEs associated with an 
overdose will be documented on AE CRF according to Section 10.0. 
Serious AEs (SAEs) associated with overdose should be reported according to the procedure 
outlined in Section 10.2.2 
In the event of overdose, the subject should be treated symptomatically.  
 
Allocation of the Study Drug and Administration Procedure 
8.2
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 
investigators 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.  
 
Preparation and Storage of Allocation List 
8.3
The allocation responsible person (designated by the sponsor) shall create an allocation list. 
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. 


Trelagliptin-4003 
Page 30 of 61
Version 1   
June 6, 2017
 
CONFIDENTIAL 
9.0 
STUDY PLAN 
 
Clinical study procedure 
9.1
The investigators 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 investigators. The 
study schedule is provided in Appendix A.  
9.1.1 
Informed Consent Procedure 
The procedures for obtaining informed consent are described in Section 15.3. 
Consent shall be obtained from the study subject before initiation of study. 
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 
Demographics and Medication History Collection Procedure 
The following data will be collected as demographic data: 
- 
Date of birth, gender, the time (month and year) of diabetes onset (or a diabetes diagnosis), work 
status, alcohol intake history, smoking history, experience in educational hospitalization on 
diabetes, presence of cohabiter, compliance with DPP-4 inhibitors for the last 4 weeks before the 
start of the treatment period, the number of oral drugs per day, complication of metabolic 
syndrome*. 
*: to be confirmed according to the following criteria:  
waist size ≥ 85 cm (for male), ≥ 90 cm (for female) 
serum triglyceride ≥ 150 mg/dl and/or HDL < 40 mg/dl 
systolic blood pressure ≥ 130 mmHg and/or diastolic blood pressure ≥ 85 mmHg 
9.1.3 
Physical Examination Procedure 
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 
Weight, Height, and Body Mass Index (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 


Trelagliptin-4003 
Page 31 of 61
Version 1   
June 6, 2017
 
CONFIDENTIAL 
9.1.5 
Documentation of Concomitant Medications 
Concomitant medication is any drug given in addition to the study drug. These may be prescribed by 
a physician or obtained by the subject over the counter. At each study visit, subjects will be asked 
the status of use (drug name, route of administration, treatment period, and treatment purpose) of any 
medication other than the study drug (including vitamin compound, over-the-counter medication, 
and Chinese medicine) used from signing of informed consent through the end of the study. 
9.1.6 
Documentation of Concurrent Medical Conditions 
Concurrent medical conditions are those significant ongoing conditions or diseases that are present 
prior to first dose. This includes clinically significant laboratory or physical examination 
abnormalities noted at baseline examination, according the judgment of the investigator. The 
condition (ie, diagnosis) should be described.  
9.1.7 
Questionnaire for Patient Preference for Treatment  
Patient preference for treatment interviewed from the subjects using the standardized questions* at 
the end of treatment period (treatment selection rate) 
*: Questions 
Regarding the drug therapy after the end of this research, which treatment do you select from 
the following choices from 1 to 4? 
1. Either once-weekly DPP-4 inhibitor or daily DPP-4 inhibitor 
2. Once-weekly DPP-4 inhibitor 
3. Daily DPP-4 inhibitor 
4. Neither once-weekly DPP-4 inhibitor nor daily DPP-4 inhibitor 
9.1.8 
DTSQ 
Subjects will answer the DTSQ (all 8 questions) 10), 11) 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. 
9.1.9 
Procedure for Clinical Laboratory Samples 
All samples will be collected in accordance with acceptable laboratory procedures. Clinical 
laboratory tests are listed in Table 9.a.  
Table 9.a 
Laboratory tests 
Serum chemistry  
 
HbA1c 


Trelagliptin-4003 
Page 32 of 61
Version 1   
June 6, 2017
 
CONFIDENTIAL 
The local laboratory will perform laboratory tests. The results of laboratory tests will be returned to 
the investigator, who is responsible for reviewing and filing these results. 
9.1.10 
Pregnancy 
When a subject or a partner of subject was found to be pregnant during the study period, the 
investigator should notify the monitoring staff of the sponsor. The investigator should provide 
detailed information using the Follow-up Form for Pregnancy separately wherever possible. 
9.1.11 
Record of Subjects Who are Withdrawn Before Start of Administration 
A CRF shall be created for all subjects who sign the consent form and are then withdrawn before 
start of administration.  
The following items are to be recorded on the CRF: 
• 
Date of informed consent signature 
• 
Date of birth (or the age at the time of informed consent) 
• 
Gender 
• 
Eligibility 
• 
Reason for withdrawal 
The primary reason for withdrawal before start of administration shall be recorded on the CRF 
according to the following classification:  
• 
Did not meet inclusion criteria or did meet exclusion criteria 
• 
Significant protocol deviation 
• 
Lost to follow-up 
• 
Voluntary withdrawal <specify reason> 
• 
Study termination 
• 
Pregnancy 
• 
Others <specify the reason> 
Subject identification numbers assigned to subjects withdrawn from the study before start of 
administration should not be reused.  
 
Monitoring Subject Treatment Compliance 
9.2
The investigator will confirm treatment compliance of study drug at every visit. 


Trelagliptin-4003 
Page 33 of 61
Version 1   
June 6, 2017
 
CONFIDENTIAL 
Treatment compliance will be classified into 4 categories, as follows: “took the drug properly 
(≥ 90%),” “usually took the drug (≥ 70%),” “took the drug more than half of the time of dosing 
(≥ 50%),” and “took the drug less than half of the time of dosing (< 50%).” 
 
Schedule of Observations and Procedures 
9.3
The schedule for all study-related procedures for all evaluations is shown in Appendix A. 
Assessments should be completed at the designated visit/time points. 
9.3.1 
Start of Administration（VISIT 1: Week 0） 
After acquisition of informed consent, a physical examination and tests for screening will be 
performed. Eligibility of subjects will be determined in accordance with the inclusion and exclusion 
criteria as described in Section 7.0. 
An eligible study subject will be randomized in accordance with section 8.2 and starts to be 
administered trelagliptin or alogliptin. 
Tests, observations and evaluations performed at the start of the screening period (Visit 1: Week 0) 
are shown below. 
 
Informed consent* 
 
Demographics, medication history 
 
Inclusion/exclusion criteria 
 
Height / weight / BMI 
 
Physical examination 
 
Concurrent medical conditions 
 
Concomitant medication (a) 
 
Prescription of study drug 
 
HbA1c 
 
DTSQ 
*Informed consent shall be obtained prior to any other tests, observations and evaluations. 
(a) Record all concomitant medications 
9.3.2 
Switch of Study drug（VISIT2: Week 8） 
As described in Section 8.4, the preceding drug is switched with the following drug. The study 
subjects then stats to be administered with the following drug. 
Tests, observations and evaluations performed during the treatment period (Visit 2: Week 8) are 
shown below. 
 
Physical examination 
 
Concomitant medication (a) 
 
HbA1c 
 
Prescription of study drug 
 
Treatment compliance 
 
DTSQ 


Trelagliptin-4003 
Page 34 of 61
Version 1   
June 6, 2017
 
CONFIDENTIAL 
9.3.3 
End of Study (VISIT3: Week 16) 
The study subjects choose either trelagliptin or alogliptin, or neither of them. If the subjects cannot 
choose either of them, then the investigators choose the drug for consequent treatment upon 
adequate explanation.  
Tests, observations and evaluations performed at the start of the screening period (Visit 3: Week 16) 
are shown below. 
9.3.4 
Discontinuation 
Tests, observations and evaluations performed at the discontinuation are shown below. 
 
 
Physical examination 
 
Concomitant medication (a) 
 
HbA1c 
 
Treatment compliance 
 
DTSQ 
 
Questionnaire for patient preference for 
treatment 
 
Physical examination 
 
Concomitant medication (a) 
 
HbA1c 
 
Treatment compliance 
 
DTSQ 
 
Questionnaire for patient preference for 
treatment 


Trelagliptin-4003 
Page 35 of 61
Version 1   
June 6, 2017
 
CONFIDENTIAL 
10.0 
ADVERSE EVENTS 
 
Definitions 
10.1
10.1.1 
AEs 
An AE is defined as any untoward medical occurrence in a subject administered a pharmaceutical 
product (including the study drug). It does not necessarily have to have a causal relationship with 
this pharmaceutical product (including the study drug).  
An AE can therefore be any unfavorable and unintended sign (e.g., a clinically significant abnormal 
laboratory value), symptom, or disease temporally associated with the use of a pharmaceutical 
product (including the study drug) whether or not it is considered related to the pharmaceutical 
product (including the study drug). 
10.1.2 
Additional Points to Consider for AEs 
An untoward finding generally may: 
• 
Indicate a new diagnosis or unexpected worsening of a pre-existing condition. (Intermittent 
events for pre-existing conditions or underlying disease should not be considered AEs.). 
• 
Necessitate therapeutic intervention. 
• 
Require an invasive diagnostic procedure. 
• 
Require discontinuation or a change in the dose of the study drug, or concomitant 
medication. 
• 
Be considered unfavorable by the investigator for any reason. 
Diagnosis vs signs and symptoms: 
Each event should be recorded to represent a single diagnosis. Accompanying signs (including 
abnormal laboratory values or ECG findings) or symptoms should NOT be recorded as additional 
AEs. If a diagnosis is unknown, sign(s) or symptom(s) should be recorded appropriately as an AE(s). 
Laboratory values and ECG findings: 
Changes in laboratory values or ECG findings are only considered to be PTEs or AEs if they are 
judged to be clinically significant (ie, if some action or intervention is required or if the investigator 
judges the change to be beyond the range of normal physiologic fluctuation). A laboratory or ECG 
re-test and/or continued monitoring of an abnormal value or findings are not considered an 
intervention. In addition, repeated or additional noninvasive testing for verification, evaluation or 
monitoring of an abnormality is not considered an intervention. 


Trelagliptin-4003 
Page 36 of 61
Version 1   
June 6, 2017
 
CONFIDENTIAL 
If abnormal laboratory values or ECG findings are the result of pathology for which there is an 
overall diagnosis (eg, increased creatinine in renal failure), the diagnosis only should be reported 
appropriately as an AE. 
Pre-existing conditions (a disease or symptom that is present at the start of study drug 
administration): 
Pre-existing conditions are considered concurrent medical conditions and should NOT be recorded 
as AEs. However, if the subject experiences a worsening or complication of such a concurrent 
medical condition, the worsening or complication should be recorded appropriately as an AE 
(worsening or complication occurs after start of study drug). Investigators should ensure that the 
event term recorded captures the change in the condition (eg, “worsening of…”). 
If a subject has a pre-existing episodic concurrent medical condition (eg, asthma, epilepsy) any 
occurrence of an episode should only be captured as an AE if the condition becomes more frequent, 
serious or severe in nature. Investigators should ensure that the AE term recorded captures the 
change in the condition from baseline (eg “worsening of…”). 
Worsening of AEs: 
If the subject experiences a worsening or complication of an AE after any change in study drug, the 
worsening or complication should be recorded as a new AE. Investigators should ensure that the AE 
term recorded captures the change in the condition (eg, "worsening of…”). 
Changes in intensity of AEs: 
If the subject experiences changes in intensity of an AE, the event should be captured once with the 
maximum intensity recorded. 
Preplanned procedures (surgery or interventions): 
Preplanned procedures (surgeries or therapies) that were scheduled prior to signing of informed 
consent are not considered AEs. However, if a preplanned procedure is performed early (eg, as an 
emergency) due to a worsening of the pre-existing condition, the worsening of the condition should 
be recorded as an AE. Complications resulting from any planned surgery should be reported as AEs. 
Elective surgeries or procedures: 
Elective procedures performed where there is no change in the subject’s medical condition should 
not be recorded as AEs, but should be documented in the subject’s source documents. Complications 
resulting from an elective surgery should be reported as AEs. 
Insufficient clinical response (lack of efficacy):  
Insufficient clinical response, efficacy, or pharmacologic action, should NOT be recorded as an AE. 
The investigator must make the distinction between exacerbation of pre-existing illness and lack of 
therapeutic efficacy. 
Overdose: 
Cases of overdose with any medication without manifested side effects are NOT considered AEs, 


Trelagliptin-4003 
Page 37 of 61
Version 1   
June 6, 2017
 
CONFIDENTIAL 
but instead will be documented on an Overdose page of the CRF. Any manifested side effects will be 
considered AEs and will be recorded on the AE page of the CRF. 
10.1.3 
SAEs 
An SAE is defined as any untoward medical occurrence that at any dose: 
● Results in death, 
● Is life threatening*, 
● Requires inpatient hospitalization or prolongation of existing hospitalization, 
● Results in persistent or significant disability/incapacity, 
● Leads to a congenital anomaly/birth defect, 
● Is an important medical event that may expose the subject to danger even though the event is not 
immediately life-threatening or fatal does not result in hospitalization, or requires intervention to 
prevent items 1 through 5 above. In addition, event or synonym described in the Takeda 
Medically Significant Adverse Event List (Table 10.a) is included in this section. 
* The term “life threatening” refers to an event in which the subject was at risk of death at the time 
of the event; it does not refer to an event that hypothetically might have caused death if it were more 
severe. 
Table 10.a Takeda Medically Significant Adverse Event 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 


Trelagliptin-4003 
Page 38 of 61
Version 1   
June 6, 2017
 
CONFIDENTIAL 
10.1.4 
Intensity of AEs 
The different categories of intensity (severity) are characterized as follows. 
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. 
10.1.5 
Causality of AEs 
The relationship of each AE to the study drug will be assessed using the following categories. 
Related 
An AE that follows a temporal sequence (including clinical course after discontinuation), 
or an AE in which there is at least a reasonable probability that a causal relationship to 
the study drug cannot be ruled out, although other factors such as underlying disease, 
complications, or concomitant drugs/treatment are also suspected. 
Not 
related 
An AE 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. 
10.1.6 
Relationship to Study Procedures 
The relationship should be assessed as Related if the investigator considers that there is reasonable 
possibility that an event is due to a study procedure. Otherwise, the relationship should be assessed 
as Not Related. 
10.1.7 
Study Date 
The start date of AEs will be determined using the following criteria. 
AE 
Start date 
Signs, symptoms, diseases 
(diagnoses) 
The date on which the first signs/symptoms were noted by the 
subject and/or the 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 comorbidities 
The date on which the first worsening of diseases/symptoms was 
noted by the subject and/or the investigator. 


Trelagliptin-4003 
Page 39 of 61
Version 1   
June 6, 2017
 
CONFIDENTIAL 
Onset of a test abnormality after 
the start of study 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 
The date on which a clear increase/decrease in a laboratory 
parameter was clinically confirmed based on the time profile of the 
parameter. 
10.1.8 
Stop Date 
The stop date of the AE is the date at which the subject recovered, the event resolved but with 
sequelae or the subject died. The AE will be recorded as “ongoing” if the subject has not yet 
recovered by the end of the study. 
10.1.9 
Action Concerning Study Drug 
Action concerning study drug will be classified or defined as shown below. 
Drug withdrawn 
The study drug is discontinued because of an AE (including withdrawal by the 
subject at his/her discretion). 
If the study drug is continued after the study termination, the action should be 
“Dose not changed”. 
Dose not changed 
The dose was not changed after the onset of the AE. 
The study drug was discontinued, reduced, or increased because of another AE. 
The study drug was discontinued or reduced for a reason other than the AE, e.g., 
inadvertence of the subject. 
Unknown 
It has not been possible to determine what action has been taken because the 
subject is lost to follow-up. 
Not Applicable 
The administration of the study drug had already been completed or discontinued 
before the onset of the AE. 
Dose reduced 
The dose of the study drug was reduced because of the AE (including dose 
reduction by the subject at his/her discretion). 
Dose Increased 
The dose was increased due to the particular AE (including dose reduction by the 
subject at his/her discretion). 
Washout 
The study drug was suspended (i.e., interrupted) because of the AE (including 
suspension/interruption by the subject at his/her discretion), but resumed later. 
10.1.10 
Outcome 
Outcome of AEs is classified as follows: 
Category 
Criteria 
Recovered 
Disappearance or recovery of symptoms and findings 


Trelagliptin-4003 
Page 40 of 61
Version 1   
June 6, 2017
 
CONFIDENTIAL 
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 subject died from a cause other than the concerned AE while the condition was 
resolving (recording of the date of death unnecessary) 
Not recovered 
No change in symptoms, findings, or laboratory data 
The symptoms, findings, or laboratory data on the final day of observable period 
were aggravated compared with the date of onset 
Irreversible congenital anomaly 
The subject died from another cause before resolution of the concerned AE 
(recording of the date of death unnecessary) 
Recovered 
with sequelae 
Disability that disturbs daily life 
Death 
Direct relationship between death and the concerned AE 
“Direct relationship” means that the concerned AE was the cause of death, or the 
concerned AE was clearly responsible for death. 
Outcome of an AE which was not determined (judged, presumed) a direct cause of 
death observed in the same 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. 
 
Procedures 
10.2
10.2.1 
Collection and Reporting of AEs 
10.2.1.1 
AE collection Period 
Collection of AEs will commence from the time that the subject is first administered study drug 
(VISIT 1). Routine collection of AEs will continue until VISIT 3. 
10.2.1.2 
AE Reporting 
At each study visit, the investigator will assess whether any subjective AEs have occurred. A neutral 
question, such as “How have you been feeling since your last visit?”. Subjects may report AEs 
occurring at any other time during the study. 
All subjects experiencing AEs, whether considered associated with the use of the study drug or not, 
must be monitored until the symptoms subside and any clinically relevant changes in laboratory 
values have returned to baseline or until there is a satisfactory explanation for the changes observed. 
All AEs will be documented in the AE page of the CRF, whether or not the investigator concludes 


Trelagliptin-4003 
Page 41 of 61
Version 1   
June 6, 2017
 
CONFIDENTIAL 
that the event is related to the drug treatment. The following information will be documented for 
each event:  
1. Event term. 
2. Start and stop date. 
3. Frequency. 
4. Intensity. 
5. Investigator's opinion of the causal relationship between the event and administration of the 
study drug (related or not related),  
6. Investigator's opinion of the causal relationship to study procedures, including the detail of the 
suspected procedure. 
7. Action concerning study drug. 
8. Outcome of event. 
9. Seriousness.  
10.2.1.3 
Reporting of adverse events of special interest (specific adverse events) 
If AE of Special interest (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 investigators. AESI Form should be completed and signed (or signed and sealed) by 
the principal investigator and reported to the sponsor within 10 business days. 
The criteria for AESIs (hypoglycemia-related AEs, intestinal obstruction-related AEs, acute 
pancreatitis-related AEs, and QT/QTc interval prolongation-related AEs) are as shown below. If any 
other AEs potentially related to the study drug occur, it will be considered whether to include them 
in the AESIs. 
[Hypoglycemia-related AEs] 
AEs related to hypoglycemia 
[Intestinal obstruction-related AEs] 
Intestinal obstruction, ileus, subileus, obstruction of the digestive tract, gastrointestinal motility 
disorder, impaired gastric emptying, and AEs related to these conditions 
[Acute pancreatitis-related AEs] 
AEs related to pancreatitis or acute pancreatitis 
[QT/QTc interval prolongation-related AEs] 
Torsade de pointes, sudden death, ventricular tachycardia, ventricular fibrillation, ventricular flutter, 
consciousness disturbed, convulsion, ECG QT prolonged, and AEs related to these conditions 
[Liver dysfunction or jaundice-related AEs] 


Trelagliptin-4003 
Page 42 of 61
Version 1   
June 6, 2017
 
CONFIDENTIAL 
AEs corresponding to 'Liver dysfunction related to drug - comprehensive search' in MedDRA 
standard search formula. 
The AESIs have to be recorded as AEs in the CRF. A report along with all other required 
documentation must be submitted to the sponsor. 
10.2.2 
Collection and Reporting of SAEs 
When a SAE occurs through the AE collection period it should be reported according to the 
following procedure: 
At the time of onset of a SAE or notification of the onset by the subject, the principal investigator 
shall report the SAE to the chief executive of the study site immediately, and the sponsor or the 
contract study organization (CRO) to whom the sponsor has entrusted responsibility shall notify the 
principal investigator of the study site. 
A SAE should be reported by the investigator to the sponsor within 1 business day of the SAE 
occurrence. The investigator should submit the detailed SAE Form to the sponsor (for contact 
information, refer  )  within 10 calendar days. .  
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. 
• 
A short description of the event and the reason for why the event is categorized as serious. 
• 
Study title. 
• 
Subject identification number. 
• 
Study site's name. 
• 
Investigator's name. 
• 
Name of the study drug. 
• 
Causality assessment. 
The investigator shall report spontaneously reported SAEs that are collected even after the AE 
collection period to the sponsor. 
10.2.3 
Reporting of Additional Information Concerning AEs 
If the sponsor requests provision of additional information concerning AEs for reporting to 
regulatory authorities, the investigators 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.  
 
Follow-up of SAEs 
10.3
If information not available at the time of the first report becomes available at a later date, the 
investigator should complete a follow-up SAE form (copy) or provide other written documentation 


Trelagliptin-4003 
Page 43 of 61
Version 1   
June 6, 2017
 
CONFIDENTIAL 
and submit it to the sponsor (for contact information, refer ) within 1 working day. 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 ethics review committee upon 
request. 
All SAEs should be followed up until resolution or permanent outcome of the event.  
10.3.1 Reporting of SAEs, etc., to IECs, etc., and Regulatory Authorities 
When the chief executive of study site receives a report of a SAE from the principal investigator, the 
chief executive of study site shall consult the Ethical Review Board, etc., and notify the study sites 
that are conducting the study through the sponsor or the CRO consigned by the sponsor. 
When the principal investigator reported a SAE 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 SAE 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 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 study sites via the sponsor.) 
• 
Actions taken for SAEs 
(discontinuation of new enrollment, revision of informed consent form, re-consents from 
other subjects, etc.) 
• 
Date of review, summery of review, result, necessary action, etc., related to Ethics Review 
Committee, etc. 
• 
Notification to other study sites 
The sponsor shall report, in accordance with regulations, unexpected serious adverse drug reactions 
and other SAEs that are subject to emergency reporting to regulatory authorities, the investigators, 
and chief executive s of study sites. 
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 risks/benefits of the study drug, continuation of study drug administration, or continuation of 
study. The study site shall submit copies of emergency report documents to the Ethics Review 
Committee, etc. 
 


Trelagliptin-4003 
Page 44 of 61
Version 1   
June 6, 2017
 
CONFIDENTIAL 
11.0 
STUDY-SPECIFIC COMMITTEES 
 
Steering Committee 
11.1
The Steering Committee will comprise of the chair and the sponsor. The Steering Committee will 
supervise implementation and reporting of the study, secure medical guidance of a high degree of 
professionalism and a high-level scientific quality, and revise the protocol appropriately. The 
responsibilities of the committee will be described in the procedures of the Steering Committee.  


Trelagliptin-4003 
Page 45 of 61
Version 1   
June 6, 2017
 
CONFIDENTIAL 
12.0 
DATA HANDLING AND RECORDKEEPING 
Data Management department of the sponsor shall be in charge of implementing data management 
operation according to the standard operating procedures, independently from Medical Affairs 
department. AEs, and concurrent conditions shall be coded using MedDRA. Drugs shall be 
translated using the World Health Organization (WHO) Drug Dictionary.  
 
Case Report Forms (CRFs) 
12.1
Completed CRFs are required for each subject who signs informed consent.  
The sponsor or its designee will provide study sites with access authorization to the EDC system. 
Before use of the EDC system, the sponsor shall provide training to the investigators, and study 
collaborators. The CRF shall be used to report the information collected during the study period to 
the sponsor. The CRF shall be prepared 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 or its designee shall ensure the accuracy and completeness of the CRF, 
and provide an electronic signature on the relevant page of the CRF. The principal investigator bear 
full responsibility for the accuracy and reliability of all the data entered on the CRF. 
The following data shall be recorded on the CRF directly, except for those recorded in the source 
documents: 
• 
Eligibility, completion status, reason for discontinuation, seriousness of adverse events, 
severity of adverse events, and causal relationship between adverse events and the study 
drugs or the study procedures, and outcome 
When the investigators make a change or correction in the data entered on the CRF after fixation of 
clinical data base, a record (Data Clarification Form) of change or correction on the CRF provided 
by the sponsor shall be used. The principal investigator shall confirm that the record of change or 
correction on the CRF is accurate and complete, and sign or write name/ affix a seal, and date it. 
The sponsor or the designee shall confirm that the CRF has been made appropriately in conformity 
with the procedure defined for each study. The sponsor or its designee shall have access to the 
medical records of the subjects and in-house records to ensure the accuracy of the CRF as necessary. 
The completed CRF shall be the property of the sponsor, and the investigator shall not disclose the 
information to a third party without written permission from the sponsor.  


Trelagliptin-4003 
Page 46 of 61
Version 1   
June 6, 2017
 
CONFIDENTIAL 
 
Timing of Data Entry into the EDC System 
12.2
The sponsor or its designee shall request the investigators to promptly enter data into the EDC 
system following enrollment of the subject, each visit during study treatment, and 
completion/discontinuation of the study. 
 
Storage and Disposal of Specimens and Documents, etc. 
12.3
The principal investigator or the chief executive of the study site shall store human-derived 
specimens and the following materials (information, etc.), including those specified in Section 12.1 
and study-specific documents to be used by the regulatory authority and the sponsor or its designee 
for investigation and audit. The documents shall include, but shall not be limited to the materials 
related to the information used in the study such as the subject ID number list, subjects’ medical 
records, study work sheet, original signed and dated informed consent forms, an electronic copy of 
the EDC system with audit trails, and the drug management records. The principal investigator and 
the chief executive of the study site shall appropriately retain the specimens/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. When disposing the 
specimens, documents, etc., the chief executive of the study site shall dispose them anonymously. 
 


Trelagliptin-4003 
Page 47 of 61
Version 1   
June 6, 2017
 
CONFIDENTIAL 
13.0 
STATISTICAL 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. 
 
Statistical and Analytical Plans 
13.1
The person in charge of analysis shall prepare a statistical analysis plan (SAP) before the acquisition 
of the informed consent of the earliest subject, and issue the first edition. Detailed definition of 
endpoints and analysis methods should be specified in the SAP to deal with all the purposes of the 
study. 
13.1.1 Analysis Sets 
In this study, 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 study drugs”. The safety population is defined as “subjects 
who receive at least 1 dose of study drugs”.  
13.1.2 
Analysis of Demographics and Other Baseline Characteristics 
Using FAS, major demographic and other baseline characteristics shall be aggregated. 
13.1.3 
Efficacy Analysis 
The primary endpoint for this study is patient preference for treatment interviewed from the subjects 
using the standardized questions* at the end of treatment period (treatment selection rate) 
*: Questions 
Regarding the drug therapy after the end of this research, which treatment do you select from 
the following choices from 1 to 4? 
1. Either once-weekly DPP-4 inhibitor or daily DPP-4 inhibitor 
2. Once-weekly DPP-4 inhibitor 
3. Daily DPP-4 inhibitor 
4. Neither once-weekly DPP-4 inhibitor nor daily DPP-4 inhibitor 
Among the subjects who were randomized and treated with the study drugs, the treatment selection 
rate will be calculated by merging the subjects from whom preference for treatment was interviewed 
by treatment group with the treatment groups. Also, the treatment selection rates for once-weekly 
DPP-4 inhibitor and daily DPP-4 inhibitor are compared by applying the Mainland-Gart test. 
 
The secondary endpoints: 
• 
Preference for treatment (treatment selection rate) by drug (trelagliptin or alogliptin) selected by 
subjects at the end of treatment period and by background factor 


Trelagliptin-4003 
Page 48 of 61
Version 1   
June 6, 2017
 
CONFIDENTIAL 
13.1.4 
Safety Analysis 
• 
Incidence of AEs (TEAEs) 
[Analytical methods] 
A treatment-emergent AE (TEAE) is defined as any AE occurring after the start of study or control 
treatment for the healing phase. For TEAEs in the maintenance phase, the analyses listed below shall 
be performed for each treatment group. TEAEs shall be reported using MedDRA terminology and 
summarized using the Preferred Term (PT) and System Organ Class (SOC) of the MedDRA.  
• 
Aggregation of frequencies of all TEAEs 
• 
Aggregation of frequencies of TEAEs related to the study drug 
• 
Aggregation of frequencies of all TEAEs by severity 
• 
Aggregation of frequencies of TEAEs related to the study drug  
• 
Aggregation of frequencies of TEAEs leading to discontinuation of study treatment  
• 
Aggregation of frequencies of serious TEAEs 
Frequency tables will be prepared for the incidences of adverse events and severe hypoglycemia 
after the first administration of the study drug or comparative drug administration in the “safety 
population” in each treatment group. 
13.1.5 
Other Analyses 
Using FAS, the followings shall be analyzed. 
1) Efficacy endpoint: HbA1c 
The mean and SD of HbA1c levels at each assessment time and changes in HbA1C from the 
baseline (Week 0) to each assessment time point will be calculated and represented in graphs.  
2) Treatment compliance  
Treatment compliance of each study subject will be calculated and summary statistics of 
compliance per treatment group will be presented. 
 
Interim Analysis and Criteria for Early Termination 
13.2
No interim analysis is planned. 
 
Determination of Sample Size 
13.3
60 subjects 
<Rationale for the number of planned subjects>  
By referring to the results of the questionnaire for treatment selection rate after dosing of 
once-weekly DPP-4 inhibitor, the treatment selection rate of once-weekly DPP-4 inhibitor is 
assumed to be 60%, treatment selection rate of daily DPP-4 inhibitor 20%, and rate of subjects who 


Trelagliptin-4003 
Page 49 of 61
Version 1   
June 6, 2017
 
CONFIDENTIAL 
do not show any preference for treatment (either is fine/prefer neither) 20%, respectively. 
In doing so, a total of 54 subjects will be necessary in order to secure 90% power in the binomial test 
with two-sided significance level at 5%. With the estimated rate of discontinuation at 10%, the 
number of randomized subjects was set to be 30 subjects per group or 60 subjects in total. 


Trelagliptin-4003 
Page 50 of 61
Version 1   
June 6, 2017
 
CONFIDENTIAL 
14.0 
QUALITY CONTROL AND QUALLITY ASSURANCE 
 
Study-Site Monitoring Visits 
14.1
The sponsor or its designee shall perform periodic monitoring of study sites during the study to 
confirm that the study is conducted in accordance with all specifications in the 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 its designee and 
the Ethics Review Committee, etc., have access to the source documents. 
The sponsor or its designee shall access the records, including the list of subject ID codes, medical 
records of the subjects, and signed and dated original consent forms, to confirm that the study is 
appropriately conducted in compliance with the protocol. Also, confirm the consistency between 
CRF and the related source documents. The 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 in a procedure manual prepared separately. 
 
Deviation from the Ethical Guideline for Clinical Research and the Protocol 
14.2
The investigator shall record all deviations from the Ethical Guideline for Clinical Research and the 
protocol. 
If any deviation is found, the principal investigator shall promptly notify the chief executive of the 
study site 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 study site for approval of the committee such as ethics review committee. 
 
Quality Assurance Audits and Regulatory Agency Inspections 
14.3
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 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 
principal investigator and the chief executive of the study site shall ensure that the auditor has access 
to all the study-related source documents.  


Trelagliptin-4003 
Page 51 of 61
Version 1   
June 6, 2017
 
CONFIDENTIAL 
15.0 
ETHICAL ASPECT OF THE STUDY 
This study shall be conducted with the highest respect for the individual participants (i.e., subjects) 
according to the protocol, the ethical principles that have their origin in the Declaration of Helsinki, 
and the Ethical Guideline for Clinical Research. Each investigator will conduct the study according 
to regulatory requirements and in accordance with “Responsibilities of the Investigator” that are 
listed in Appendix B.  
 
IEC Approval 
15.1
The IEC, etc., shall be constituted in accordance with the regulations. 
The sponsor or its designee should obtain the document listing the name and title of each committee 
member. When a committee member directly participates in this 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 provide related documents for review and approval of the protocol 
to the Ethical Review Board, etc. In addition to the protocol, a copy of the informed consent form 
and information sheet, written materials related to 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 Ethics Review Committee to obtain approval. The sponsor or the 
designee shall obtain records of approval by the Ethical Review Board, etc., for the protocol and the 
informed consent form and information sheet before the start of the protocol therapy. The records of 
approval by the Ethical Review Board, etc., shall include the study title, protocol number, 
preparation / revision date of the protocol, and version number and approval date of other reviewed 
documents (Example: informed consent and information sheet). The sponsor shall notify the study 
site and the 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 and 
investigator receive notification.  
The study site shall observe all requirements that the Ethical Review Board prescribes. The 
requirements may include notifications to committees such as ethics review committee, for example, 
revision of the protocol, revision of the informed consent form and information sheet, revision of 
materials related to 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 Ethics Review Committee, and submission of the study completion report. 
The sponsor or its designee shall obtain written approval from a study site committee such as the 
Ethics Review Committee related to the above mentioned items and all related materials.  
 
Conflict of Interests  
15.2
This study shall be conducted with the support of the sponsor. 


Trelagliptin-4003 
Page 52 of 61
Version 1   
June 6, 2017
 
CONFIDENTIAL 
Prior to the initiation of this study, the investigators involved in this 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.14)-18) 
The study site shall comply with all requirements specified by a committee such as an ethics review 
committee, including the COI self-statement form, the protocol, and the informed consent form and 
information sheet.  
 
Informed Consent and Information Sheet, and the Agreement of the 
15.3
Subjects 
The informed consent and information sheet form shall contain specific requirements of the 
Declaration of Helsinki, Ethical Guideline for Clinical Research and all applicable laws and 
regulations. The informed consent form and information sheet shall specify the use of personal 
information and medical information of subjects in this study (both in and outside Japan: supply to a 
third party), and disclosure. The informed consent form and the information sheet will explain in 
detail the nature of the study, its objectives, and potential risks and benefits. The informed consent 
form will detail the requirements of the participant and the fact that subject is free to withdraw at any 
time without giving a reason and without any negative effect on the further medical care. 
The principal investigator is responsible for the preparation, contents, and approval of the informed 
consent form and subject information sheet by the committee such as ethics review committee. The 
informed consent form and information sheet must be approved by the committee prior to use. 
The informed consent form and information sheet shall be written in language that can be easily 
understood by the potential subjects. The investigator shall be responsible for providing detailed 
explanation of the informed consent form and information sheet to the potential subjects. 
Information should be given in both oral and written form whenever possible and in manner deemed 
appropriate by the committee such as ethics review committee. 
The investigator shall ensure that the potential subjects have (1) an opportunity to inquire about the 
study and (2) sufficient time to decide on their participation. If a potential subject decides to 
participate in the study, then the informed consent form must be signed and dated by the potential 
subject prior to entering into the study as a subject. The investigator shall instruct the potential 
subject to sign using their legal names, not nicknames, using a blue or black ball point ink pen. Also 
the investigator shall sign and date the informed consent form prior to entering into the study. 
Once signed, the original informed consent form shall be retained by the investigator. The 
investigator shall record the date that the potential 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 subject. 
The investigator shall follow the same procedure as for obtaining the initial consent when newly 
obtaining re-consent from the concerned subject when the informed consent form is revised. The 


Trelagliptin-4003 
Page 53 of 61
Version 1   
June 6, 2017
 
CONFIDENTIAL 
date of obtaining new consent shall be recorded in the subject’s medical record, and a copy of the 
revised consent form shall be provided to the subject.  
 
Personal Information of Subjects 
15.4
The sponsor or the designee shall affirm the principle of the protection of subjects’ private/personal 
information. Throughout this 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 subjects such 
as gender, age, and date of birth may be used within the scope of all applicable laws and regulations 
for identification of subjects and confirmation of accuracy of subject ID code. 
For verification of the conduct of the study in compliance with this protocol and the Ethical 
Guideline for Clinical Research, 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 subjects’ original medical records 
(source data or documents), including laboratory test results, ECG results, admission and discharge 
records during a subject’s study participation, and autopsy reports. The investigator shall obtain 
specific authorization of the subject as part of the informed consent process for access to 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 investigator shall delete information 
that may lead to identification of an individual (name and address of subject, other personal 
information not recorded on the CRF of the subject).  
 
Consultation for Subjects or Persons Related to the Study 
15.5
The principal investigator shall establish a contact service to respond to inquiries concerning this 
study from subjects or concerned people. Details of the contacts for inquiries will be described in the 
informed consent form.  
 
Financial Burden or Reward to Subjects 
15.6
Regarding the expenses for this study, the sponsor shall pay for medical treatment not covered by 
health insurance and examinations necessary for the study as study expenses. The 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 study to the subjects at each visit from the study funds. Details of the financial 
burden on the subjects and rewards shall be described in the informed consent form and information 
sheet.  


Trelagliptin-4003 
Page 54 of 61
Version 1   
June 6, 2017
 
CONFIDENTIAL 
 
Benefits and Inconveniences to Subjects 
15.7
15.7.1 
Benefits to Subjects 
The subjects will obtain detailed information on the status of their type 2 diabetes mellitus and their 
treatment satisfaction through participation in this study. 
15.7.2 
Inconveniences to Subjects 
Participation in this study may increase burden on the subjects due to requirement for answering 
questionnaires and DTSQ, as compared with routine medical practice.  
 
Attribution of Study Results and Access Rights 
15.8
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 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.  
 
Reporting of Results, Publication, Disclosure, and Clinical Study 
15.9
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 investigators or regulatory 
authorities during the study period, except when required by laws and regulations. The sponsor shall 
be responsible for publication of the protocol and study-related results (including the public web 
site) except for other cases permitted in the study contract. 
During and after the study, the sponsor or its designee should promptly summarize the results and 
present them to medical journals and academic conferences, etc. The sponsor 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. 


Trelagliptin-4003 
Page 55 of 61
Version 1   
June 6, 2017
 
CONFIDENTIAL 
The investigators should obtain the prior written approval from the sponsor when publishing the 
information obtained in this study at an academic conference, etc. 
The sponsor shall report to the chief executive of the study site when final publication of the study 
results has been made. 
15.9.2 
Clinical Study Registration 
In order to ensure that information on clinical trials reaches the public in a timely manner and to 
comply with applicable laws, regulations and guidance, Takeda will, at a minimum register all 
interventional clinical trials it sponsors anywhere in the world on ClinicalTrials.gov and Japan 
Pharmaceutical Information Center Clinical Trials Information (JAPIC) before start of study. Takeda 
contact information, along with investigator’s city, country, and recruiting status will be registered 
and available for public viewing.  
15.9.3 
Clinical Study Results Disclosure 
Takeda will post the results of clinical trials on ClinicalTrials.gov and JAPIC, as required by 
applicable laws and/or regulations.  
 Insurance and Compensation for Injury 
15.10
Each subject in the study must be insured in accordance with the regulations applicable to the site 
where the subject is participating. If a local underwriter is required, then the sponsor or sponsor’s 
designee will obtain clinical study insurance against the risk of injury to study subjects. Refer to the 
study site agreement regarding the sponsor’s policy on subject compensation and treatment for 
injury. If the investigator has questions regarding this policy, he or she should contact the sponsor or 
sponsor’s designee.  


Trelagliptin-4003 
Page 56 of 61
Version 1   
June 6, 2017
 
CONFIDENTIAL 
16.0 
REFERENCES 
1. 
Krapek K, King K, Warren SS, George KG, Caputo DA, Mihelich K, et al. Medication 
adherence and associated hemoglobin A1c in type 2 diabetes. Ann Pharmacother. 2004; 38: 
1357-62. 
2. 
Farmer AJ, Rodgers LR, Lonergan M, Shields B, Weedon MN, Donnelly L, et al. Adherence 
to oral glucose-lowering therapies and associations with 1-Year HbA1c: A retrospective 
cohort analysis in a large primary care database. Diabetes Care. 2016; 39: 258-63. 
3. 
Paes AH, Bakker A, Soe-Agnie CJ. Impact of dosage frequency on patient compliance. 
Diabetes Care. 1997; 20: 1512-7. 
4. 
Attitude survey for patients who continues to work while being treated for type 2 diabetes 
with oral drugs only. Eli Lilly Japan K.K. Press Release, August 25, 2017. (Press release in 
Japanese) 
5. 
Tanaka R, Hayakawa K, Oshima H. Drug compliance of bisphosphonate in Japan: Cohort 
study of bisphosphonate in a private clinic. Osteoporosis Japan. 2009; 17; 252-5. (A Japanese 
Journal published in Japanese) 
6. 
Suzuki D, Kuroki H, Tsukada A, Ito Y, Iyori N, Tosaka M. et al. Do the patients prefer to 
take once weekly DPP-4 inhibitors? Prog Med. 2016; 36: 389-92. (A Japanese Journal 
published in Japanese) 
7. 
Higuchi K, Higuchi S. Survey for patients with diabetes: Adherence to oral glucose-lowering 
drugs and treatment preference for once weekly drugs. Prog Med. 2016; 36: 1415 -19. (A 
Japanese Journal published in Japanese) 
8. 
Uchida D. DPP-4 inhibitor: Efficacy of once weekly drugs and their effective dosing. 
Japanese Journal of Diabetes Master Clinician. 2017; 15: 26-31. 
9. 
Nakamura T, Tsukamoto K. Survey for once weekly DPP-4 inhibitor trelagliptin. The Japan 
Diabetes Society, Chugoku Shikoku 54th meeting. January 29th, 2017 
10. Bradley C: Diabetes treatment satisfaction questionnaire (DTSQ). In: Handbook of 
psychology and diabetes (ed. by Bradley C.). Harwood Academic Pubi., Chur, 1994 
11. Ishii H, Bradley C, Riazi A, Barendse S, Yamamoto T. The Japanese Version of the Diabetes 
Treatment Satisfaction Questionnaire (DTSQ): translation and clinical evaluation. J Clin Exp 
Med. 2000; 192: 809-14. (A Japanese Journal published in Japanese)  
12. Inagaki N, Onouchi H, Maezawa H, Kuroda S, Kaku K. Once-weekly trelagliptin versus 
daily alogliptin in Japanese patients with type 2 diabetes: a randomised, double-blind, phase 
3, non-inferiority study. Lancet Diabetes Endocrinol. 2015; 3: 191-7. 
13. Lally P, van Jaarsveld CHM, Potts HMM, Wardle J. How are habits formed: Modelling habit 
formation in the real world. Eur J Soc Psychol: 2010; 40:998-1009. 


Trelagliptin-4003 
Page 57 of 61
Version 1   
June 6, 2017
 
CONFIDENTIAL 
14. Report of the Working Group on Conflict of Interest (Ministry of Education, Culture, Sports, 
Science and Technology dated November 1, 2002). 
15. Guidelines for determining the conflict of interest polity for clinical study (Review group for 
ethical aspects of clinical study and conflict of interest, March 2006).  
16. Guidelines on the Management of Conflict of Interest (COI) in Health and Labour Sciences 
Study (March 31, 2008). 
17. Guidelines for management of COI in medical study (COI Committee of Japan Association 
of Medical Sciences, February 2011). 
18. Common guidelines for conflict of interest (COI) in clinical study (Japanese Society of 
Internal Medicine, Japan Society of Hematology, Japanese Circulation Society, Japan 
Endocrine Society, Japan Diabetes Society, Japanese Respiratory Society, Japanese Society 
of Hematology, Japanese Society of Allergology, Japanese Association for Infectious 
Diseases, Aug 2011).  
 
 


Trelagliptin-4003 
Page 58 of 61
Version 1   
June 6, 2017
 
CONFIDENTIAL 
Appendix A 
Clinical Research Schedule 
Treatment 
At 
discontinuation(c) 
Timing of visit 
Week 
0 
8 
16 
Day 
-1(b) 
56 
112 
Acceptable range (days) 
-1 
49-63 
105-119 
Until 14 days 
after the last 
dose 
Visit No. 
1 
2 
3 
  
Informed consent 
X 
Demographics and medication history 
X 
 
 
 
Inclusion/exclusion criteria 
X 
Questionnaire for patient background 
X 
Physical examination 
X 
X 
X 
X 
Height / weight / BMI 
X 
Concomitant medications (a) 
X 
X 
X 
X 
Concurrent medical condition 
X 
HbA1c 
X 
X 
X 
X 
Prescription of study drug 
X 
X 
Treatment compliance 
X 
X 
X 
DTSQ 
X 
X 
X 
X 
Questionnaire for patient preference  
X 
 
Adverse event 
X→ 
←X→ 
←X 
←X 
(a) Record all concomitant medications. 
(b) Start the dosing of the study drug from the following date after all tests at Week 0 are completed. 
Set the start date of dosing as Day 1 and the day before the start date of dosing as Day 0. 
(c) Conduct as much as possible. 
 
 

SAP_001.pdf: 
 
 
Title: Treatment preference for weekly DPP-4 inhibitors versus daily DPP-4 inhibitors 
in patients with type 2 diabetes mellitus < TRINITY > 
 
NCT Number: NCT03231709 
Statistical analysis plan Approve Date: 15-Mar-2018 
 
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. 


Treatment preference  
for weekly DPP-4 inhibitors versus daily DPP-4 inhibitors 
in patients with type 2 diabetes mellitus 
(TRINITY) 
(Protocol number: Trelagliptin-4003) 
Statistical Analysis Plan
(Ver.2.0: 15 Mar 2018) 
Sponsor:  Takeda Pharmaceutical Company Limited 
Authorizer: 
Takeda Pharmaceutical Company Limited 
Biostatistics Manager: 
PPD
PPD
PPD


TABLE of CONTENTS 
1. 
DEFINITIONS of TERMS ................................................................................................. 1 
2. 
ANALYSIS SET ................................................................................................................ 1 
3. 
CONSIDERATIONS on STATISTICAL ANALYSIS ........................................................... 1 
3.1. Adjustments for Covariates .............................................................................................. 1 
3.2. Handling of Dropouts or Missing Data.............................................................................. 1 
3.3. Criteria for Interim Analysis and Early Stopping ............................................................... 1 
3.4. Multicenter Study............................................................................................................ 1 
3.5. Multiple Comparisons/Multiplicity ................................................................................... 1 
3.6. Examination of Subgroups ............................................................................................... 1 
3.7. Considerations for Creating Analysis Results .................................................................... 2 
3.8. Time Window ................................................................................................................. 2 
4. 
SUBJECTS, DEMOGRAPHIC and OTHER BASELINE CHARACTERISTICS ................... 3 
4.1. Subject Disposition ......................................................................................................... 3 
4.2. Demographics and Other Baseline Characteristics ............................................................. 5 
5. 
EFFICACY EVALUATIONS ............................................................................................. 7 
5.1. Primary Endpoint and the Analytical Methods ................................................................... 7 
5.2. Secondary Endpoints and the Analytical Methods .............................................................. 8 
5.3. Other Endpoints and the Analytical Methods ..................................................................... 8 
6. 
SAFETY EVALUATION ................................................................................................... 9 
6.1. Brief Summary of Adverse Events (TEAE) ....................................................................... 9 
6.2. Display of TEAE .......................................................................................................... 10 
7. 
LISTING.......................................................................................................................... 11 
8. 
REFERENCE .................................................................................................................. 12 
9. 
REVISION HISTORY ..................................................................................................... 13 
 


 
1 
 
1. 
DEFINITIONS of TERMS 
・ MedDRA: Medical Dictionary for Regulatory Activities 
・ PT: Preferred Term 
・ SOC: System Organ Class 
・ TEAE: Treatment-Emergent Adverse Event 
・ Summary Statistics: Number of Subjects, Mean, SDs, Maximum values, Minimum values, 
and Quartiles 
・ DTSQ: Diabetes Treatment Satisfaction Questionnaire 
 
 
2. 
ANALYSIS SET 
・ Full Analysis Set 
The subjects who were randomized and given at least one dose of the study drug 
・ Safety Analysis Set 
The subjects who were given at least one dose of the study drug 
 
 
3. 
CONSIDERATIONS on STATISTICAL ANALYSIS 
3.1. Adjustments for Covariates 
 
Adjustment for covariates is not performed. 
 
3.2. Handling of Dropouts or Missing Data 
Missing values will not be complemented.   
 
3.3. Criteria for Interim Analysis and Early Stopping 
Interim analysis will be not performed. 
 
3.4. Multicenter Study 
Analyses for consideration of medical institution will not be performed. 
 
3.5. Multiple Comparisons/Multiplicity 
  It does not adjust multiplicity. 
 
3.6. Examination of Subgroups 
  Subgroup analysis will not be performed. 
 


 
2 
 
3.7. Considerations for Creating Analysis Results 
・ Confidence Coefficient 
95% (two-sided estimation)  
・ Significance Level 
The level of significance should be 5%. 
・ Summary Statistics 
Number of Subjects, mean, SDs, Maximum values, Minimum values, and Quartiles 
・ Display Digit 
[Mean, Confidence Coefficient, Quartiles] 
Round statistics off to the 1 digits lower than significant digits of the data. 
   [Standard Deviation] 
Round statistics off 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 off 2 decimal places and display up to 1 decimal place. 
[p-value] 
Round off 5 decimal places and display up to 4 decimal places. However, when the 
p-value is less than 0.0001, it is expressed as "p <0.0001". 
 
3.8. Time Window 
For each inspection, observation and evaluation item, evaluable data is handled according to the 
following table. Administration of the study medicine starts from the day after completion of all 
the examination of Week 0. The date of the first dose is defined as "Day 1" and the day before of 
the first dose is defined as "Day -1". The criteria of adoption of data on the data obtained after 
discontinuation in discontinued subjects are as follows. 
・HbA1c (NGSP) :  
If data up to 14 days after the last dose is included in a time window, it is treated as data 
of that visit. 
・DTSQ treatment satisfaction and Medication Compliance:  
As long as the criteria for the analysis set is satisfied, if an evaluation date is included in 
a time window, it is treated as data of that visit.  
When there are multiple data that can be evaluated at the same visit, the one with the closest 
inspection date, observation date and evaluation date to the reference implementation date is 
adopted. If the magnitude of the difference from the reference implementation date is the same, 
the later data is adopted.  


 
3 
 
The 16th week (Week 16) of the treatment period in the following analysis is handled as the visit 
of 8 weeks after start of administration of the study drug after switching. 
 
[HbA1c (NGSP), DTSQ treatment satisfaction] 
Visit 
Reference Date 
Time Allowance 
Week 0 of the Treatment Period 
Number of days after administration: 
-1 
-1 
Week 8 of the Treatment Period 
Number of days after administration: 
56 
49 - 63 
Week 16 of the Treatment Period 
Number of days after administration: 
112 
105 - 119 
 
[Medication Compliance] 
Visit 
Reference Date 
Time Allowance 
Week 8 of the Treatment Period 
Number of days after administration: 
56 
49 - 63 
Week 16 of the Treatment Period 
Number of days after administration: 
112 
105 - 119 
 
 
4. 
SUBJECTS, DEMOGRAPHIC and OTHER BASELINE CHARACTERISTICS 
4.1. Subject Disposition 
4.1.1. Study Information 
Analysis Set: All subjects who were obtained informed consent 
Analysis Variables: 
 
Analysis Methods: For the above analysis items, the following analysis is performed. 
(1)  Show above items. 
If the last administration date of the study drug is missing, the last 
visit date of the study is used. 
 
4.1.2. Subject Disposition 
Analysis Set: All subjects who were obtained informed consent 
Analysis Variables: All subjects who were obtained informed consent, Randomized 
Subjects, Full Analysis Set, Safety Analysis Set 
Analysis Methods: For the above analysis items, the following analysis is performed. 
(1) Tabulation of subjects included in/excluded from each 
analysis set 
 
4.1.3. Eligibility of Subjects 
Analysis Set: All subjects who were obtained informed consent 


 
4 
 
Analysis Variables: Eligibility for the study  
[Yes, No (and the reason)]  
Analysis Methods: For the above analysis items, the following analysis is performed. 
(1) Calculate the number of subjects and Proportions (%). 
 
4.1.4. Treatment Exit Status 
Analysis Set: Full Analysis Set 
Analysis Variables: Treatment Exit Status [Complete, Incomplete (and the 
reason)]  
Analysis Methods: For the above analysis items, the following analysis is performed. 
(1) Calculate the number of subjects and Proportions (%). 
 
4.1.5. Protocol Deviations and Analysis Datasets 
4.1.5.1. 
Protocol Deviations 
Analysis Set: Randomized Subjects 
Analysis Variables: Protocol Deviations 
[Major GCP Violations, Deviations of Protocol Entry Criteria, 
Deviations of Discontinuation Criteria, Deviations Related to 
Treatment Procedure or Dose, Deviations Concerning Excluded 
Medication or Therapy, Deviations to Avoid Emergency Risk, 
Deviations Related to Efficacy Evaluation, Deviations Related to 
Safety Evaluation, Other Deviations] 
Analysis Methods: For the above analysis items, the following analysis is performed. 
Summarize the number of subjects who have deviated from the 
protocol, classify the deviations into above category, and show 
the breakdown of deviations. Subjects applicable for multiple 
categories will be counted once in each category. 
(1) Calculate the number of subjects and Proportions (%). 
 
4.1.5.2. 
Datasets for Analyses 
Analysis Set: Randomized Subjects  
Analysis Variables: Subjects excluded from analysis datasets [Reason of exclusion] 
Inclusion of Subjects 
Full Analysis Set [Adopted] 
Safety Analysis Set [Adopted] 
Analysis Methods: For the above analysis items, the following analysis is performed. 


 
5 
 
(1) Calculate the number of subjects and Proportions (%) in 
each analysis set about handling for subjects (and reasons 
for exclusion). Subjects applicable for multiple categories in 
reason for excluded will be counted once in each category. 
(2) Calculate the number of subjects and proportions (%) of 
adopted subjects of each analysis set in randomized 
subjects. 
 
4.2. Demographics and Other Baseline Characteristics 
4.2.1. Distribution of Demographics Items 
Analysis Set: Full Analysis Set 
Analysis Variables:  
Age (years old)  [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,  
25.0<= - <=Max] 
Duration of Diabetes 
[3 Years or More, Less than 3 Years] 
Work Status    [Worker, Unemployed] 
Alcohol Intake History 
[Regular Drinker, Occasional Drinker, Non-Drinker] 
Smoking Habits [Yes, No] 
Experience of Educational Hospitalization on DM 
[Yes, No] 
Presence of Cohabiter 
[Living Alone, Living Together] 
Compliance with DPP-4 Inhibitors During 4 weeks before the Start of 
Treatment Period 


 
6 
 
[90 Percent or More, Less than 90 Percent] 
Number of Oral Drugs per Day at the Beginning of the Treatment Period 
[1 or 2 Tablet(s), 3 - 5 Tablets, 6 Tablets or More] 
Complication of Metabolic Syndrome 
[Yes, No] 
HbA1c (NGSP) Level at the Time of Informed Consent 
[<7.0%, 7.0=<-<8.0%, 8.0%=<] 
DTSQ Treatment Satisfaction Level (Except for question 2 and 3) at the 
Time of Informed Consent  
Analysis Methods: For the above analysis items, the following analysis is 
performed. 
(1) Tabulation for discrete variables and summary statistics 
for continuous variables 
 
4.2.2. Concurrent Medical Conditions 
Analysis Set: Full Analysis Set 
Analysis Variables:  Concurrent Medical Conditions 
Analysis Methods: For the above analysis items, the following analysis is 
performed. 
(1) Calculate the number of subjects and Proportions (%). 
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. The method of accounting for 
the frequency is as follows. 
[Method of Accounting for the Frequency] 
Within each summary, subjects with one or more events 
within a level of SOC term is counted only once in that 
level. Similarly, subjects with one or more events within a 
level of PT term is counted only once in that level. 
 
4.2.3. Prior and Concomitant Medication 
Analysis Set: Full Analysis Set 
Analysis Variables: Prior Medication, Concomitant Medication 
Analysis Methods: For the above analysis items, the following analysis is 
performed.  


 
7 
 
(1) Calculate the number of subjects and Proportions (%). 
Analysis variables will be coded using the WHO (World 
Health Organization) Drug and be summarized into 
Preferred Name. Coded medications will be sorted in 
frequency order. Medications used more than once within 
a subject will be counted only once for the subject. 
 
 
5. 
EFFICACY EVALUATIONS 
5.1. Primary Endpoint and the Analytical Methods 
5.1.1. Treatment Preference (Treatment Selection Rate)  
Analysis Set:  Subjects in Full Analysis Set from whom preference for treatment 
was interviewed 
Analysis Variables: Patient preference for treatment interviewed from the subjects 
using the standardized questions 
Visit: 
 End of Treatment Period 
Analysis Methods: For the above analysis items, the following analysis is 
performed. 
(1) Calculate the treatment selection rate (%) for each 
treatment group and all subjects in the analysis set 
(2) Applying the Mainland-Gart test, the treatment selection 
rates for once-weekly DPP-4 inhibitor and daily DPP-4 
inhibitor are compared by p-value.  
Fisher's exact test for the following 2 × 2 table is 
performed and p-value will be calculated for subjects 
who selected either one (excluding subjects who selected 
"Neither good" nor "Neither wanted").  
 
 (×, ○)  
Prefer to the second 
treatment. 
 (○, ×)  
Prefer to the first 
treatment. 
T-A  
xx 
xx 
A-T  
xx 
xx 
(3) As sensitivity analysis, performed the same analysis as 
(1) - (2) on the subjects in the Full Analysis Set who 
were administered both of Trelagliptin and Alogliptin at 


 
8 
 
least once and were interviewed the treatment 
preference. 
 
5.2. Secondary Endpoints and the Analytical Methods 
5.2.1. Patient Preference by Background Factors 
Analysis Set: Subjects in Full Analysis Set from whom preference for treatment was 
interviewed 
Analysis Variables: Patient preference for treatment interviewed from the subjects 
using the standardized questions 
Visit: End of Treatment Period 
Analysis Methods: For the above analysis items, the following analysis is 
performed. 
(1) Calculate the treatment selection rate (%) for each 
treatment group and all subjects in the analysis set by 
background factors. 
(2) Regarding the ratio (odds) of the selection rate of 
once-weekly dosing of DPP-4 inhibitor to the selection 
rate of once-daily dosing of DPP-4 inhibitor by each 
background factor, the odds ratio between the 
background factor and their both sides 95 % confidence 
interval are calculated for all subjects in the analysis set 
(treatment group are combined). 
 
5.3. Other Endpoints and the Analytical Methods 
5.3.1. DTSQ Treatment Satisfaction for Each Study Drug at 8 Weeks after Start of Each 
Study Drug Administration 
Analysis Set: Full Analysis Set 
Analysis Variables: DTSQ Treatment Satisfaction *1 
DTSQ Treatment Satisfaction (each item)  
Visit: 8 weeks after start of administration of each study drug  
Analysis Methods: For the above analysis items, the following analysis is 
performed. 
(1) Calculate summary statistics for each study drug. 
*1 Evaluated with the total points of questions 1, 4, 5, 6, 7, and 8 
Items that refer to blood glucose levels (questions 2 and 3) are excluded in order 
to prevent the assessment of satisfaction from being influenced by the blood 


 
9 
 
glucose level-related part. 
 
5.3.2. HbA1c (NGSP) for Each Study Drug at 8 Weeks after Start of Each Study Drug 
Administration 
Analysis Set: Full Analysis Set 
Analysis Variables: HbA1c (NGSP) 
Visit: 8 weeks after start of administration of each study drug 
Analysis Methods: For the above analysis items, the following analysis is 
performed. 
(1) Calculate summary statistics for each study drug. 
 
5.3.3. Treatment Compliance for Each Study Drug at 8 Weeks after Start of Each Study  
Drug Administration 
Analysis Set: Full Analysis Set 
Analysis Variables: Treatment Compliance [Properly (90 Percent or More), 
Generally (70 Percent or More), Half (50 
Percent or More), Less than Half (Less 
than 50 Percent)] 
Visit: 8 weeks after start of administration of each study drug 
Analysis Methods: For the above analysis items, the following analysis is 
performed. 
(1) Calculate the number of subjects and Proportions (%) for 
each study drug. 
 
 
6. 
SAFETY EVALUATION 
6.1. Brief Summary of Adverse Events (TEAE) 
Analysis Set: Safety Analysis Set 
Analysis Variables: TEAE 
1) All of the TEAEs 
2) TEAEs Related to Study Drug 
3) TEAEs by Severity 
4) TEAEs Related to Study Drug by Severity 
5) TEAEs Leading to Discontinuation of Study Drug 
6) Serious TEAEs 
7) Serious TEAEs Related to Study Drug 


 
10 
 
8) Serious TEAEs Leading to Discontinuation of Study Drug  
9) TEAEs Leading to Death 
Analysis Methods:  The following analyses are performed on TEAEs. 
(1) Calculate the number of subjects and Proportions (%) by Study 
Drug. 
Incidence rates will be calculated as following. 
[Frequency of Subjects] 
· Frequency by Severity 
Subjects with one or more adverse events within a level of 
MedDRA term is counted only once in that level using the most 
severe incident. The denominator when calculating the 
incidence of adverse events is the number of subjects of safety 
analysis set. 
· Analyses Other Than the Above 
Subjects with one or more adverse events within a level of 
MedDRA term is counted only once for that MedDRA term. 
The denominator when calculating the incidence of adverse 
events is the number of subjects of safety analysis set. 
(2) For TEAE described in the CRF, prepare a replacement table for 
SOP and PT. SOCs will be sorted in alphabetical order, then PTs 
will be sorted in frequency order. 
 
6.2. Display of TEAE 
Analysis Set: Safety Analysis Set 
Analysis Variables: TEAE 
1) 
All of the TEAEs 
2) 
TEAEs Related to Study Drug 
3) 
TEAEs by Severity 
4) 
TEAEs Related to Study Drug by Severity 
5) 
TEAEs Leading to Discontinuation of Study Drug 
6) 
Serious TEAEs 
7) 
Serious TEAEs Related to Study Drug 
8) 
Serious TEAEs Leading to Discontinuation of Study Drug 
9) 
TEAEs Leading to Death 
10) Non-serious TEAE with Incidence of over 5% 
Analysis Methods: For the above analysis items, the following analysis is performed by 


 
11 
 
Study drug. 
(1) Tabulation of frequencies of all adverse events about number of 
subjects, its proportions (%) and number of cases. 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. 
Incidence rates will be calculated as following. 
[Frequency of Subjects] 
· Frequency (by SOC/PT) 
Within each summary, subjects with one or more adverse 
events within a level of SOC term is counted only once in that 
level. Similarly, subjects with one or more adverse events 
within a level of PT term is counted only once in that level. The 
denominator when calculating the incidence of adverse events 
is the number of subjects of safety analysis set. 
· Frequency by Severity (by SOC/PT) 
Subjects with one or more adverse events within a level of SOC 
term is counted only once in that level using the most severe 
incident. Subjects with one or more adverse events within a 
level of 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. 
 
 
7. 
LISTING 
Following lists will be created for Full Analysis Set. 
・Demographics 
・Eligibility for the Study (Inclusion/Exclusion Criteria) 
・Discontinuation 
・Protocol Deviation 
・Concurrent Disease 
・Prior Medication 
・Concomitant Medication 
・Treatment Preference 
・DTSQ 


 
12 
 
・HbA1c 
・Study Drug Compliance 
・Study Drug Overdose 
・TEAE 
 
 
8. 
REFERENCE 
1. 
Byron Jones, and Michael G. Kenward, Design and analysis of cross-over trials  (Third 
Edition) , New York, 2014, pp.96-100. 
 
 
 


 
13 
 
9. 
REVISION HISTORY 
Ver. 
Date 
Author 
Revised Content 
Reason for Revision 
1.0 
2017/8/9 
- 
- 
2.0 
2018/3/15 
・ In order to clarify a part of the 
analysis content, description 
was adjusted. 
・ Add description of “3.8. Time 
Window”. 
・ Description in "4.1.5.2. 
Datasets for Analyses" was 
broken up into tabulation bout 
the reasons for exclusion from 
analysis sets and tabulation 
about adopted subjects. 
・ Add sensitivity analysis to 
"5.1.1. Treatment Preference 
(Treatment Selection Rate)" 
・ Add creation of replacement 
table of adverse events to "6.1. 
Brief Summary of Adverse 
Events (TEAE)" 
・ Revision of "7. LISTING" 
In the process of creation of 
analysis 
result 
layout, 
some 
descriptions and clause titles in 
SAP were reconsidered so that 
analysis content become easy to 
be understood. 
As for Time Window was added 
by necessity. 
The sensitivity analysis of the 
treatment preference had been 
considered by the results of the 
data review and added. 
The contents of LISTING has 
been revised as it has been 
changed to a policy that it should 
cyclopaedically 
reflect 
the 
contents of CRF. 
 
PPD
PPD