Conditions: Type 2 Diabetes Mellitus
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 107
Healthy volunteers: no

Brief summary:
The purpose of this study is to evaluate the efficacy and safety of trelagliptin when administered at a dose of 25 mg once weekly using placebo as a control in patients with type 2 diabetes mellitus complicated by severe renal impairment or end-stage renal disease and inadequate glycemic control despite diet and/or exercise therapy (if given) or despite treatment with one antidiabetic drug in addition to diet and/or exercise therapy (if given); and to evaluate the long-term efficacy and safety of trelagliptin when administered at a dose of 25 mg once weekly to patients with type 2 diabetes mellitus complicated by severe renal impairment or end-stage renal disease.

Detailed description:
This is a phase 3, multicenter, randomized, double-blind, placebo-controlled, parallel-group, comparative study (Treatment Period I) and a phase 3, multicenter, open-label, long-term study (Treatment Period II) to evaluate the efficacy and safety of trelagliptin when administered orally at a dose of 25 mg once weekly to patients with type 2 diabetes mellitus complicated by severe renal impairment or end-stage renal disease and inadequate glycemic control despite diet and/or exercise therapy (if given) or despite treatment with one antidiabetic drug in addition to diet and/or exercise therapy (if given).

Arms:
arm 1: Trelagliptin 25 mg tablet, orally, once weekly before breakfast for up to Week 52 (Period I + II) arm 2: Placebo tablet, orally, once weekly before breakfast for up to Week 12 (Period I), followed by trelagliptin 25 mg tablet, orally, once weekly before breakfast for up to Week 52 (Period II)

Interventions: intervention 1: Trelagliptin 25 mg intervention 2: Placebo
Intervention descriptions: intervention 1: Trelagliptin 25 mg Tablets intervention 2: Placebo Tablets

Protocol document:
Prot_000.pdf: 
 
 
Title: A Phase 3, Multicenter, Randomized, Double-Blind, Placebo-Controlled, 
Parallel-Group, Comparative Study and a Phase 3, Multicenter, Open-Label, Long-term 
Study to Evaluate the Efficacy and Safety of SYR-472 When Orally Administered at a 
Dose of 25 mg Once Weekly in Patients with Type 2 Diabetes Mellitus Complicated by 
Severe Renal Impairment or End-Stage Renal Failure 
 
NCT Number: NCT02512068 
Protocol Approve Date: 12-Sep-2016 
 
Certain information within this protocol has been redacted (ie, specific content is 
masked irreversibly from view with a black/blue bar) to protect either personally 
identifiable information or company confidential information. 
 
This may include, but is not limited to, redaction of the following: 
 
Named persons or organizations associated with the study. 
 
Patient identifiers within the text, tables, or figures or in by-patient data listings. 
 
Proprietary information, such as scales or coding systems, which are considered 
confidential information under prior agreements with license holder. 
 
Other information as needed to protect confidentiality of Takeda or partners, 
personal information, or to otherwise protect the integrity of the clinical study. 
 
If needed, certain appendices that contain a large volume of personally identifiable 
information or company confidential information may be removed in their entirety if it 
is considered that they do not add substantially to the interpretation of the data (eg, 
appendix of investigator’s curriculum vitae). 
 
Note; This document was translated into English as the language on original version 
was Japanese. 


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PROTOCOL 
A Phase 3, Multicenter, Randomized, Double-Blind, Placebo-Controlled, 
Parallel-Group, Comparative Study and a Phase 3, Multicenter, Open-Label, 
Long-term Study to Evaluate the Efficacy and Safety of SYR-472 When Orally 
Administered at a Dose of 25 mg Once Weekly in Patients with Type 2 Diabetes 
Mellitus Complicated by Severe Renal Impairment or End-Stage Renal Failure 
A Phase 3, Randomized, Double-Blind, Parallel-Group, Comparative Study and a 
Phase 3, Multicenter, Open-Label, Long-term Study of SYR-472 (25 mg) in Patients 
with Type 2 Diabetes Mellitus Complicated by Severe Renal Impairment or 
End-Stage Renal Failure 
Sponsor: 
Takeda Pharmaceutical Company Limited 
1-1, Doshomachi 4-chome, Chuo-ku, Osaka 
Study Number: 
SYR-472-3003 
IND Number: 
Not Applicable 
EudraCT Number: 
Not Applicable 
Compound: 
SYR-472 
Date: 
12 September 2016 
Amendment Number: 
1 
Amendment History: 
Date 
Amendment Number 
Region 
1 April 2015 
Initial Protocol 
All study sites 
12 September 2016 
Amendment 1 
All study sites 
 
CONFIDENTIAL PROPERTY 
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. 


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1.0 
ADMINISTRATIVE INFORMATION AND PRINCIPLES OF CLINICAL 
STUDIES 
1.1 
Contacts and Responsibilities of Study-Related Activities 
See Annex 1. 
1.2 
Principles of Clinical Studies 
This study will be conducted with the highest respect for the individual participants in 
accordance with the requirements of this clinical study protocol and also in accordance 
with the following: 
• The ethical principles that have their origin in the Declaration of Helsinki. 
• International Conference on Harmonisation (ICH) E6 Good Clinical Practice (GCP): 
Consolidated Guideline. 
• All applicable laws and regulations, including, without limitation, data privacy laws, 
clinical trial disclosure laws, and regulations. 


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TABLE OF CONTENTS 
1.0 
ADMINISTRATIVE INFORMATION AND PRINCIPLES OF CLINICAL 
STUDIES ......................................................................................................... 2 
1.1 
Contacts and Responsibilities of Study-Related Activities .......................... 2 
1.2 
Principles of Clinical Studies ...................................................................... 2 
2.0 
STUDY SUMMARY ....................................................................................... 7 
3.0 
LIST OF ABBREVIATIONS ......................................................................... 12 
4.0 
INTRODUCTION .......................................................................................... 13 
4.1 
Background .............................................................................................. 13 
4.2 
Rationale for the Proposed Study .............................................................. 14 
5.0 
STUDY OBJECTIVES AND ENDPOINTS ................................................... 15 
5.1 
Objectives................................................................................................. 15 
5.2 
Endpoints ................................................................................................. 15 
5.2.1 
Primary Endpoints ............................................................................ 15 
5.2.2 
Secondary Endpoints ........................................................................ 15 
5.2.3 
Additional Endpoints........................................................................ 15 
6.0 
STUDY DESIGN AND DESCRIPTION ........................................................ 16 
6.1 
Study Design ............................................................................................ 16 
6.2 
Justification for Study Design, Dose, and Endpoints ................................. 17 
6.3 
Premature Termination or Suspension of Study or Investigational Site ...... 19 
6.3.1 
Criteria for Premature Termination or Suspension of the Study ........ 19 
6.3.2 
Criteria for Premature Termination or Suspension of Investigational 
Sites ................................................................................................. 19 
6.3.3 
Procedures for Premature Termination or Suspension of the Study 
or the Participation of Investigational Site(s) .................................... 19 
7.0 
SELECTION AND DISCONTINUATION/WITHDRAWAL OF 
SUBJECTS .................................................................................................... 20 
7.1 
Inclusion Criteria ...................................................................................... 20 
7.2 
Exclusion Criteria ..................................................................................... 23 
7.3 
Excluded Medications and Treatments ...................................................... 25 
7.4 
Diet, Fluid, Activity Control ..................................................................... 29 
7.5 
Criteria for Discontinuation or Withdrawal of a Subject ............................ 30 
7.6 
Procedures for Discontinuation or Withdrawal of a Subject ...................... 32 
8.0 
CLINICAL TRIAL MATERIAL MANAGEMENT ....................................... 33 
8.1 
Study Drug ............................................................................................... 33 
8.1.1 
Dosage Form, Manufacturing, Packaging, and Labeling ................... 33 
8.1.2 
Storage ............................................................................................. 34 
8.1.3 
Dose and Regimen ........................................................................... 34 
8.1.4 
Overdose .......................................................................................... 34 


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8.2 
Study drug Assignment and Dispensing Procedures .................................. 35 
8.3 
Randomization Code Creation and Storage ............................................... 35 
8.4 
Study Drug Blind Maintenance ................................................................. 35 
8.5 
Unblinding Procedure ............................................................................... 35 
8.6 
Accountability and Destruction of Sponsor-Supplied Drugs ...................... 35 
9.0 
STUDY PLAN ............................................................................................... 37 
9.1 
Study Procedures ...................................................................................... 37 
9.1.1 
Informed Consent Procedure ............................................................ 37 
9.1.2 
Demographics, Medical History, and Medication History Procedure 37 
9.1.3 
Antidiabetic Drugs Administered During the Study .......................... 37 
9.1.4 
Physical Examination Procedure ...................................................... 38 
9.1.5 
Weight ............................................................................................. 38 
9.1.6 
Vital Sign Procedure ........................................................................ 38 
9.1.7 
Documentation of Concomitant Medications .................................... 39 
9.1.8 
Documentation of Concurrent Medical Conditions ........................... 39 
9.1.9 
Procedures for Clinical Laboratory Samples ..................................... 39 
9.1.10 
Contraception and Pregnancy Avoidance Procedure ......................... 40 
9.1.11 
Pregnancy ........................................................................................ 41 
9.1.12 
ECG Procedure ................................................................................ 41 
9.1.13 
Fasting C-peptide ............................................................................. 42 
9.1.14 
HbA1c (NGSP Value) ...................................................................... 42 
9.1.15 
Fasting Blood Glucose, Fasting Glucagon ........................................ 42 
9.1.16 
Glycoalbumin................................................................................... 42 
9.1.17 
DPP-4 Activity ................................................................................. 42 
9.1.18 
Blood Transfusion ............................................................................ 42 
9.1.19 
Introduction of Hemodialysis ........................................................... 42 
9.1.20 
Presence or Absence of Changes and Compliance of Diet and/or 
Exercise Therapy.............................................................................. 42 
9.1.21 
Self-Monitoring of Blood Glucose ................................................... 43 
9.1.22 
Hypoglycemia .................................................................................. 43 
9.1.23 
PGx Sample Collection .................................................................... 44 
9.1.24 
Pharmacokinetic Sample Collection and Analysis ............................ 44 
9.1.25 
Documentation of Screen Failure ..................................................... 45 
9.1.26 
Documentation of Randomization .................................................... 45 
9.1.27 
Hospitalization ................................................................................. 46 
9.2 
Monitoring Subject Treatment Compliance ............................................... 46 
9.3 
Schedule of Observations and Procedures ................................................. 46 
9.3.1 
Screening (Week -6 to Week 0) ........................................................ 46 
9.3.2 
Randomization ................................................................................. 46 


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9.3.3 
Treatment Period .............................................................................. 47 
9.3.4 
Week 52 in the Treatment Period or Early Termination .................... 47 
9.3.5 
Follow-up......................................................................................... 47 
9.3.6 
Post Study Care ................................................................................ 47 
9.4 
Biological Sample Retention and Destruction ........................................... 47 
10.0 
PRETREATMENT EVENTS AND ADVERSE EVENTS ............................. 48 
10.1 
Definitions ................................................................................................ 48 
10.1.1 
PTEs ................................................................................................ 48 
10.1.2 
AEs .................................................................................................. 48 
10.1.3 
Additional Points to Consider for PTEs and AEs .............................. 48 
10.1.4 
SAEs ................................................................................................ 50 
10.1.5 
Adverse Events of Special Interest ................................................... 51 
10.1.6 
Intensity of PTEs and AEs................................................................ 52 
10.1.7 
Causality of AEs .............................................................................. 52 
10.1.8 
Relationship to Study Procedures ..................................................... 52 
10.1.9 
Start Date ......................................................................................... 52 
10.1.10 Stop Date ......................................................................................... 53 
10.1.11 Frequency ........................................................................................ 53 
10.1.12 Action Concerning Study Drug ........................................................ 53 
10.1.13 Outcome .......................................................................................... 53 
10.2 
Procedures ................................................................................................ 54 
10.2.1 
Collection and Reporting of AEs ...................................................... 54 
10.2.2 
Collection and Reporting of SAEs .................................................... 56 
10.2.3 
Reporting of Abnormal Liver Function Tests ................................... 56 
10.3 
Follow-up of SAEs ................................................................................... 57 
10.3.1 
Safety Reporting to Investigators, IRBs, and Regulatory Authorities 57 
11.0 
STUDY-SPECIFIC COMMITTEES .............................................................. 58 
12.0 
DATA HANDLING AND RECORDKEEPING............................................. 59 
12.1 
CRFs ........................................................................................................ 59 
12.2 
Record Retention ...................................................................................... 59 
13.0 
STATISTICAL METHODS ........................................................................... 61 
13.1 
Statistical and Analytical Plans ................................................................. 61 
13.1.1 
Analysis Sets .................................................................................... 61 
13.1.2 
Analysis of Demographics and Other Baseline Characteristics ......... 61 
13.1.3 
Efficacy Analysis ............................................................................. 61 
13.1.4 
Safety Analysis ................................................................................ 63 
13.2 
Interim Analysis and Criteria for Early Termination ................................. 64 
13.3 
Determination of Sample Size................................................................... 64 
14.0 
QUALITY CONTROL AND QUALITY ASSURANCE ............................... 66 


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14.1 
Study-Site Monitoring Visits .................................................................... 66 
14.2 
Protocol Deviations .................................................................................. 66 
14.3 
Quality Assurance Audits and Regulatory Agency Inspections ................. 66 
15.0 
ETHICAL ASPECTS OF THE STUDY ......................................................... 67 
15.1 
IRB Approval ........................................................................................... 67 
15.2 
Subject Information, Informed Consent, and Subject Authorization .......... 67 
15.3 
Subject Confidentiality ............................................................................. 68 
15.4 
Publication, Disclosure, and Clinical Trial Registration Policy.................. 69 
15.4.1 
Publication and Disclosure ............................................................... 69 
15.4.2 
Clinical Trial Registration ................................................................ 69 
15.4.3 
Clinical Trial Results Disclosure ...................................................... 69 
15.5 
Insurance and Compensation for Injury..................................................... 70 
16.0 
REFERENCES ............................................................................................... 71 
 
LIST OF IN-TEXT TABLES 
Table 2.a 
Concomitant Antidiabetic Drugs Permitted in the Study........................ 7 
Table 6.a 
Concomitant Antidiabetic Drugs Permitted in the Study...................... 16 
Table 8.a 
Dose and Regimen (Treatment Period I) ............................................. 34 
Table 9.a 
Clinical Laboratory Tests .................................................................... 40 
Table 10.a 
Takeda Medically Significant AE List ................................................ 51 
 
LIST OF IN-TEXT FIGURES 
Figure 6.a 
Schematic of Study Design ................................................................. 17 
 
 


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2.0 
STUDY SUMMARY 
Name of Sponsor: 
Takeda Pharmaceutical Company Limited 
Compound: 
SYR-472 
Title of Protocol: 
A phase 3, multicenter, randomized, double-blind, 
placebo-controlled, parallel-group, comparative study 
and a phase 3, multicenter, open-label, long-term study to 
evaluate the efficacy and safety of SYR-472 when orally 
administered at a dose of 25 mg once weekly in patients 
with type 2 diabetes mellitus complicated by severe renal 
impairment or end-stage renal failure 
IND No.: 
Not Applicable 
EudraCT No.: 
Not Applicable 
Study Number: SYR-472-3003 
Phase: 3 
Study Design: 
This is a phase 3, multicenter, randomized, double-blind, placebo-controlled, parallel-group, comparative 
study (Treatment Period I) and a phase 3, multicenter, open-label, long-term study (Treatment Period II) to 
evaluate the efficacy and safety of SYR-472 when administered orally at a dose of 25 mg once weekly in 
patients with type 2 diabetes mellitus complicated by severe renal impairment or end-stage renal failure and 
with inadequate glycemic control despite diet and/or exercise therapy (if any) or despite treatment with 1 
antidiabetic drug (Table 2.a) in addition to diet and/or exercise therapy (if any). 
Table 2.a 
Concomitant Antidiabetic Drugs Permitted in the Study 
Type 
Drug Name (Nonproprietary Name or Class) 
Rapid-acting insulin secretagogues 
Mitiglinide calcium hydrate, repaglinide 
α-glucosidase inhibitors 
Acarbose, miglitol, voglibose 
Insulin preparations 
Mixed, intermediate-acting, or long-acting soluble insulin (40 units/day or 
less*) 
*For change in the dosing unit of insulin preparations, see 2 (2) in Section 7.3. 
Subjects who enter the screening period after signing informed consent and are considered eligible 
according to the inclusion and exclusion criteria will be randomly assigned to either of the SYR-472 25 mg 
group or placebo group. Subjects who are assigned to the SYR-472 25 mg group in Treatment Period I will 
continue to be treated with SYR-472 25 mg in Treatment Period II, while those assigned to the placebo 
group will be switched to SYR-472 25 mg in Treatment Period II. 
In Treatment Period I, 1 SYR-472 25 mg tablet or placebo tablet will be orally administered once weekly 
before breakfast. In Treatment Period II, 1 SYR-472 25 mg tablet will be orally administered once weekly 
before breakfast. 
The study period consists of 6 weeks of screening, 52 weeks of treatment, and 2 weeks of follow-up, a total 
of 60 weeks. The treatment period consists of Treatment Period I (double-blind) from Week 0 to Week 12 
and Treatment Period II (open-label) between Week 12 and Week 52. Subjects will visit the site at the start 
of the screening period (Week -6), Week -2 of the screening period, end of the screening period (Week 0), 
Week 2 and Week 4 of the treatment period, and at every 4 weeks until Week 52 of the treatment period, 
and at the end of the follow-up period (Week 54) (total of 18 visits). 
The planned sample size is 106 randomized subjects (53 per group). 
Objectives: 
To evaluate the efficacy and safety of SYR-472 when administered at a dose of 25 mg once weekly using 
placebo as a control in patients with type 2 diabetes mellitus complicated by severe renal impairment or 
end-stage renal failure and inadequate glycemic control despite diet and/or exercise therapy (if any) or 
despite treatment with 1 antidiabetic drug in addition to diet and/or exercise therapy (if any); and to evaluate 
the long-term safety and efficacy of SYR-472 when administered at a dose of 25 mg once weekly in 
patients with type 2 diabetes mellitus complicated by severe renal impairment or end-stage renal failure. 


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Subject Population: 
Patients with type 2 diabetes mellitus complicated by severe renal impairment or end-stage renal failure and 
inadequate glycemic control despite diet and/or exercise therapy (if any) or despite treatment with 1 
antidiabetic drug in addition to diet and/or exercise therapy (if any) 
Number of Subjects: 
Randomized: 
53 subjects per group, 106 in total 
(Changed as of 12 September 2016) 
Number of Sites: 
Approximately 50 sites 
Dose Level: 
<Treatment Period I> 
One SYR-472 25 mg tablet or placebo tablet will be orally administered 
once weekly before breakfast. 
<Treatment Period II> 
One SYR-472 25 mg tablet will be orally administered once weekly 
before breakfast. 
Route of Administration: 
Oral 
Duration of Treatment: 
<Treatment Period I> 
SYR-472 25 mg tablet or placebo tablet: 12 weeks 
<Treatment Period II> 
SYR-472 25 mg tablet: 40 weeks 
Period of Evaluation: 
Screening period 
: 6 weeks 
Treatment Period I : 12 weeks 
Treatment Period II : 40 weeks 
Follow-up period : 2 weeks 
Total 
: 60 weeks 
Criteria for Inclusion: 
1. The subject has a diagnosis of type 2 diabetes mellitus. 
2. The subject has a fasting C-peptide value of 0.6 ng/mL or higher at the start of the screening period 
(Week -6) and Week -2 of the screening period. 
3. The subject has a hemoglobin value of 10.0 g/dL or higher at the start of the screening period (Week -6) 
and Week -2 of the screening period. 
4. The subject has an hemoglobin A1c (HbA1c) value of 7.0% or higher but less than 10.0% at Week -2 of 
the screening period. However, subjects on hemodialysis (patients with end-stage renal failure) with an 
HbA1c value of less than 7.0% at Week -2 of the screening period are permitted to be enrolled if they 
have a glycoalbumin value of 20% or higher. 
5. <Subjects with an HbA1c value of 7.0% or higher but less than 10.0% at Week -2 of the screening 
period> 
The subject has an HbA1c value difference between the start of the screening period (Week -6) and 
Week -2 of the screening period within 10.0%* of the HbA1c value at the start of the screening period 
(Week -6). 
<Subjects on hemodialysis (patients with end-stage renal failure) with an HbA1c value of less than 
7.0% and glycoalbumin value of 20% or higher at Week -2 of the screening period> 
The subject has a glycoalbumin value difference between the start of the screening period (Week -6) 
and Week -2 of the screening period within 10.0%* of the glycoalbumin value at the start of the 
screening period (Week -6). 
*: rounded to one decimal place 
6. The subject has been on a fixed diet and/or exercise therapy (if any) from at least 6 weeks prior to the 
start of the screening period (Week -6). 
7. The subject meets any of the following: 
• 
The subject has not received any antidiabetic medications (including insulin preparations) from 
at least 6 weeks prior to the start of the screening period (Week -6). 
• 
The subject is being treated with 1 oral hypoglycemic drug* starting from at least 6 weeks prior 
to the start of the screening period (Week -6) at a fixed dose and regimen. 
*: Any of the following medications: mitiglinide calcium hydrate, repaglinide, acarbose, miglitol, or 


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voglibose 
• 
The subject is being treated with 1 insulin preparation** from at least 6 weeks prior to the start of 
the screening period (Week -6) at a fixed dose and regimen (≤40 units/day). 
**: Any of the following insulin monotherapies: mixed (rapid-acting or ultrarapid-acting insulin containing 
no more than 30% of volume), intermediate-acting, or long-acting soluble insulin preparations 
8. The subject is not undergoing hemodialysis or peritoneal dialysis and has severe renal impairment 
(creatinine clearance [Ccr] <30 mL/min at the start of the screening period [Week -6]), or the subject is 
undergoing hemodialysis and has end-stage renal failure. 
9. In the opinion of the investigator or sub-investigator, the initiation of hemodialysis or peritoneal 
dialysis within 12 weeks after initiation of the study drug is not expected. (in cases where the subject is 
not undergoing hemodialysis or peritoneal dialysis [patients with severe renal impairment]) 
10. The subject has been undergoing hemodialysis started from at least 6 months prior to informed consent 
and, in the opinion of the investigator or sub-investigator, the subject is clinically stable. (in cases 
where the subject is undergoing hemodialysis [patient with end-stage renal failure]) 
11. The subject is male or female and is aged 20 years or older at the time of informed consent. 
12. A female subject of childbearing potential who is sexually active with a nonsterilized male partner 
agrees to routinely use adequate contraception from signing of informed consent until 1 month after the 
end of the study. 
13. In the opinion of the investigator or sub-investigator, the subject is capable of understanding and 
complying with protocol requirements. 
14. The subject signs and dates a written, informed consent form prior to the initiation of any study 
procedures. 
Criteria for Exclusion: 
1. The subject has clinically evident hepatic impairment (e.g., AST or ALT >=2.5 times the upper limit of 
normal or total bilirubin of >=2.0 mg/dL at the start of the screening period [Week -6] or at Week -2 of 
the screening period). 
2. The subject has any serious cardiac diseases, cerebrovascular disorders, or serious pancreatic or 
hematological diseases (e.g., subjects who require inpatient treatment or had been hospitalized for 
treatment within 24 weeks prior to the start of the screening period). 
3. The subject has severe ketosis, diabetic coma or pre coma, type 1 diabetes, severe infection, or severe 
external injury, or is immediately before or after surgery. 
4. The subject has hemoglobinopathy (sickle cell disease, thalassemia, etc.). 
5. The subject experienced hypoglycemia (subjects with a blood glucose value of ≤70 mg/dL or 
hypoglycemic symptoms) within 6 weeks prior to the start of the screening period or during the 
screening period (at least twice per week). 
6. The subject has inadequately controlled hypertension. 
7. For subjects who are being treated with 1 antidiabetic agent, the subject had been treated with at least 2 
antidiabetic agents on the day before 6 weeks prior to the start of the screening period (Week -6) (43 
days prior to the start of the screening period). 
8. The subject has malignancies. 
9. The subject has a history of hypersensitivity or allergies to dipeptidyl peptidase-4 (DPP-4) inhibitors. 
10. The subject has a history of gastrectomy or small intestinal resection. 
11. The subject is a habitual drinker and consumes a daily average of more than 100 mL of alcohol. 
12. The subject has a history of drug abuse (defined as any illicit drug use) or a history of alcohol abuse. 
13. The subject is required to take excluded medications during the study period. 
14. The subject has received SYR-472 in a previous clinical study. 
15. The subject received any investigational products (including investigational drugs in a post-marketing 
clinical study) within 12 weeks prior to the start of the screening period. 
16. The subject is participating in other clinical studies at the time of informed consent. 


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17. If female, the subject is pregnant or lactating or intending to become pregnant from the time of 
informed consent to within 1 month after the end of the study; or intending to donate ova during such 
time period. 
18. The subject is an immediate family member, study site employee, or is in a dependant relationship with 
a study site employee who is involved in conduct of this study (e.g., spouse, parent, child, sibling) or 
may consent under duress. 
19. The subject is hospitalized during the screening period or is deemed as requiring hospitalization during 
the study period by the investigator or sub-investigator, unless the hospitalization is for short-term 
evaluations including complete health checkups or for short-term admission for shunt operation 
(including shunt maintenance). 
20. The subject is deemed ineligible for the study for any other reason by the investigator or 
sub-investigator. 
Criteria for Evaluation and Analyses: 
1. 
Primary Endpoints 
Efficacy: Change in HbA1c at the end of Treatment Period I from the end of the screening period (Week 
0)  
Safety: Adverse events (AEs) 
2. 
Secondary Endpoints 
Efficacy: HbA1c, fasting blood glucose, glycoalbumin 
Safety: Vital signs, 12-lead electrocardiogram (ECG), clinical laboratory values 
3. 
Additional Endpoints 
Efficacy 
: Fasting C-peptide, fasting glucagon, DPP-4 activity, weight 
Safety 
: Hypoglycemia (only for subjects using insulin preparations) 
Pharmacokinetics 
: Plasma concentration of unchanged SYR-472 (SYR-472Z) 
Statistical Considerations: 
1. 
Efficacy Analysis 
<Efficacy endpoint (primary endpoint)> 
Change in HbA1c at the end of Treatment Period I from the end of the screening period (Week 0) 
<Analytical methods (primary analysis)> 
The following analyses will be performed in the Full Analysis Set (FAS). 
The population mean change in HbA1c at the end of Treatment Period I from the end of the screening 
period (Week 0) will be compared between SYR-472 25 mg group and placebo group based on an analysis 
of covariance (ANCOVA) model for the change in HbA1c at the end of Treatment Period I from the end of 
the screening period (Week 0) with factors of treatment group and HbA1c at the end of the screening period 
(Week 0). 
The same ANCOVA model will be used to calculate the least square (LS) mean and the two-sided 95% 
confidence interval (CI) for each treatment group, as well as the intergroup difference in the LS mean 
between the treatment groups (SYR-472 25 mg group - placebo group) and the two-sided 95% CI. 
2. 
Safety Analysis 
<Safety endpoint (primary endpoint)> 
AEs 
<Analytical methods> 
The following analyses will be performed in the Safety Analysis Set. 
The following analyses will be performed for TEAEs that occur prior to the start of the study drug for 
Treatment Period II by treatment group, and for those that occur after the start of SYR-472 25 mg tablet. In 
the analysis of TEAEs occurring after the start of SYR-472 25 mg tablet, subjects who received SYR-472 
25 mg tablet will be included in the analyses. 
TEAEs will be coded using MedDRA dictionary. Frequency distributions will be provided using System 


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Organ Class and Preferred Term for each treatment group as follows: 
• 
All TEAEs 
• 
Drug-related TEAEs 
• 
Intensity of TEAEs 
• 
Intensity of drug-related TEAEs 
• 
TEAEs leading to study drug discontinuation 
• 
Serious TEAEs 
• 
TEAEs over time 
Sample Size Justification: 
In Study CCT-002, the intergroup difference (two-sided 95% CI) in the mean change in HbA1c (JDS value) 
at the end of the treatment period (value at the end of the treatment period - value at the end of the screening 
period) between the SYR-472 100 mg group and placebo group was -0.56 ([-0.753, -0.367])%. In the same 
study, the standard deviation of the change in HbA1c (JDS value) at the end of the treatment period (value 
at the end of the treatment period - value at the end of the screening period) for each treatment group ranged 
from 0.523% to 0.628%. 
In this study, which will administer SYR-472 at a dose of 25 mg once weekly to patients with type 2 
diabetes mellitus complicated by severe renal impairment or end-stage renal failure, the intergroup 
difference in the mean change in HbA1c at the end of Treatment Period I from the end of the screening 
period (Week 0) between the SYR-472 25 mg group and placebo group is assumed to be -0.40%, given that 
the efficacy of SYR-472 25 mg in this study is similar to that of SYR-472 100 mg administered once 
weekly to patients with type 2 diabetes mellitus not complicated by renal impairment. The common 
standard deviation in each treatment group is assumed to be 0.80%. 
Based on these assumptions, 86 subjects per group will be required to provide a 90% power in a two-sample 
t-test with a significance level of 5% (two-sided). Therefore, the sample size was set at 90 as randomized 
subjects per group at the start of the study allowing for the possibility that there exits some subjects whose 
primary endpoint cannot be evaluated. 
However, achievement of the sample size as originally planned at the start of the study was found difficult 
because there were more than expected numbers of candidate subjects who did not provide consent and 
who dropped out during screening after providing consent for the study. It was therefore decided to change 
some of the inclusion and exclusion criteria for this study. After these changes, the ultimate number of 
subjects randomized and evaluable for the primary endpoints are expected to be around 53 and 51, 
respectively, per group. 
Assuming the number of subjects per group as 51 under these assumptions, the study will provide a 70.6% 
power in a two-sample t-test with a significance level of 5% (two-sided). 


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3.0 
LIST OF ABBREVIATIONS 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AUC 
area under the plasma concentration-time curve 
BMI 
body mass index 
Ccr 
creatinine clearance 
CKD 
chronic kidney disease 
CRO 
contract research organization 
DPP-4 
dipeptidyl-peptidase-4 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GLP-1 
glucagon like peptide-1 
γ-GTP 
γ-glutamyl transpeptidase 
hCG 
human chorionic gonadotropin 
HbA1c 
hemoglobin A1c 
HDL 
high density lipoprotein 
ICH 
International Conference on Harmonisation 
INR 
international normalized ratio 
JAPIC-CTI Japan Pharmaceutical Information Center- Clinical Trials Information 
JDS 
The Japan Diabetes Society 
LDH 
lactate dehydrogenase 
LDL 
low density lipoprotein 
MedDRA 
Medical Dictionary for Regulatory Activities 
MHRA 
Medicines and Healthcare Products Regulatory Agency 
NGSP 
national glycohemoglobin standardization program 
PGx 
pharmacogenomics 
PMDA 
Pharmaceuticals and Medical Devices Agency 
PTE 
pretreatment event 
QTcF 
corrected QT interval by Fridericia formula 
SGLT 
sodium glucose co- transporter  
SUSARs 
suspected unexpected serious adverse reactions 
TEAE 
treatment-emergent adverse event 
WHO 
World Health Organization 
 


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4.0 
INTRODUCTION 
4.1 
Background 
Type 2 diabetes mellitus is thought to be mainly caused by a combination of deficient 
insulin secretion and insulin resistance. Currently used oral medications for type 2 
diabetes mellitus (oral hypoglycemic drugs) include sulfonylureas (SUs), rapid-acting 
insulin secretagogues, and dipeptidyl peptidase-4 (DPP-4) inhibitors, which stimulate 
insulin secretion; α-glucosidase inhibitors, which delay glucose absorption through the 
digestive tract; biguanides and thiazolidinediones, which improve insulin resistance: and 
sodium-glucose co-transporter 2 inhibitors, which exhibit hypoglycemic effects by 
inhibiting glucose reabsorption in the renal proximal tubules and promoting glucose 
excretion into the urine. 
It has been believed that deficient insulin secretion is mainly associated with the etiology 
of type 2 diabetes mellitus in Japanese people, and SUs and DPP-4 inhibitors are widely 
used in the Japanese clinical setting. Compared with other oral hypoglycemic drugs, SUs 
exhibit more potent hypoglycemic effects, but have longer-lasting insulinotropic effects; 
therefore, several issues such as hypoglycemic risk and secondary failure resulting from 
pancreatic beta cell exhaustion associated with long-term treatment have been pointed 
out. 
Meanwhile, DPP-4 inhibitors are oral hypoglycemic drugs that increase the blood 
concentrations of glucagon-like peptide-1 (GLP-1), and thereby stimulate insulin 
secretion glucose-dependently. GLP-1 is an incretin hormone that has a crucial role in 
glucose metabolism, and stimulates insulin secretion glucose-dependently. It is also 
reported that GLP-1 has a protective effect on pancreatic beta cells and an inhibitory 
effect on glucagon secretion [1][2]. 
SYR-472, a DPP-4 inhibitor synthesized by Takeda California, Inc, is expected to 
stimulate insulin secretion glucose-dependently via an increase of GLP-1 concentration 
and preserve pancreatic function. SYR-472 is also expected to be useful as a once-weekly 
oral antidiabetic drug, since prolonged inhibition of DPP-4 activity has been shown in 
pharmacodynamic assessments. 
Of clinical studies conducted in Japan, non-inferiority of SYR-472 100 mg once weekly 
to alogliptin 25 mg once daily has been assessed in a confirmatory study conducted in 
Japanese patients with type 2 diabetes mellitus using the once-daily DPP-4 inhibitor 
alogliptin 25 mg as a comparator (Study CCT-002). In addition, the efficacy and safety of 
SYR-472 in long-term monotherapy and combination therapy with SYR-472 and other 
approved oral hypoglycemic drug shaving different mechanisms of action, such as 
α-glucosidase inhibitors, thiazolidinediones, sulfonylureas, biguanides, and rapid-acting 
insulin secretagogues have been confirmed (Study-OCT 001, SYR-472 administered 
100 mg/week). 
Based on these findings, the manufacture and marketing approval of SYR-472 was 
obtained in March 2015 as a drug for the treatment of type 2 diabetes mellitus 
administered once weekly. 


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Currently, a confirmatory and long-term study to evaluate the efficacy and safety of 
SYR-472 in combination with insulin preparations in patients with type 2 diabetes 
mellitus (Study CCT-101) is ongoing. 
4.2 
Rationale for the Proposed Study 
The clinical dose of SYR-472 is 100 mg once weekly as a usual dose [3]. 
Meanwhile, in an overseas clinical pharmacology study in subjects with renal impairment 
(Study 101; SYR-472 50 mg given as a single dose), the AUC(0-tlqc) of unchanged 
SYR-472 (SYR-472Z) was 1.56, 2.06, 3.01, and 3.68 times higher in subjects with mild 
renal impairment (Ccr: ˃50 to ≤80 mL/min), subjects with moderate renal impairment 
(Ccr: ≥30 to ≤50 mL/min), subjects with severe renal impairment (Ccr: ˂30 mL/min, but 
not performing hemodialysis), and subjects with end-stage renal failure requiring 
hemodialysis, respectively, as compared with healthy adults (Ccr: ˃80 mL/min). 
Based on this result, there is no need to adjust the SYR-472 dose for patients with mild 
renal impairment, while half the usual dose (50 mg once weekly) is recommended 
suitable for patients with moderate renal impairment, and the manufacture and marketing 
approval of SYR-472 50 mg and 100 mg tablets was obtained. In addition, SYR-472 is 
contraindicated in patients with severe renal impairment and end-stage renal failure for 
whom 1-quarter of the usual dose (25 mg once weekly) is considered appropriate [3]. 
However, since patients with type 2 diabetes mellitus often have renal impairment, it was 
decided to develop SYR-472 25 mg tablets to contribute to the treatment of diabetes 
mellitus in patients with severe or more severe renal impairment. 
Therefore a phase 3, multicenter, randomized, double-blind, placebo-controlled, 
parallel-group, comparative study and a phase 3, multicenter, open-label, long-term study 
to evaluate the efficacy and safety of SYR-472 when administered at a dose of 25 mg 
once weekly in patients with type 2 diabetes mellitus complicated by severe renal 
impairment or end-stage renal failure was planned. Currently, a clinical pharmacology 
study (Study 1005) to evaluate the bioequivalence of SYR-472 25 mg tablets and 50 mg 
tablets in healthy adults is ongoing. 
Pharmacogenomic (PGx) analysis may be conducted to investigate a possible 
contribution of genetic variance on drug response, for example, its efficacy and safety. 
Participation of study subjects in PGx sample collection is optional. 
As PGx is an evolving science, currently many genes and their function are not yet fully 
understood. Future data may suggest a role of some of these genes in drug response, 
which may lead to additional hypothesis-generating exploratory research on stored 
samples. 


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5.0 
STUDY OBJECTIVES AND ENDPOINTS 
5.1 
Objectives 
To evaluate the efficacy and safety of SYR-472 when administered at a dose of 25 mg 
once weekly using placebo as a control in patients with type 2 diabetes mellitus 
complicated by severe renal impairment or end-stage renal failure and with inadequate 
glycemic control despite diet and/or exercise therapy (if any) or despite treatment with 1 
antidiabetic drug in addition to diet and/or exercise therapy (if any); and to evaluate the 
long-term safety and efficacy of SYR-472 when administered at a dose of 25 mg once 
weekly in patients with type 2 diabetes mellitus complicated by severe renal impairment 
or end-stage renal failure. 
5.2 
Endpoints 
5.2.1 Primary Endpoints 
Efficacy: Change in Hemoglobin A1c (HbA1c) at the end of Treatment Period I from the 
end of the screening period (Week 0) 
Safety: Adverse Events (AEs) 
5.2.2 Secondary Endpoints 
Efficacy: HbA1c, fasting blood glucose, glycoalbumin 
Safety: Vital signs, 12-lead ECG, clinical laboratory values 
5.2.3 Additional Endpoints 
Efficacy 
: Fasting C-peptide, fasting glucagon, DPP-4 activity, weight 
Safety 
: Hypoglycemia (only for subjects using insulin preparations) 
Pharmacokinetics 
: Plasma concentration of SYR-472Z 


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6.0 
STUDY DESIGN AND DESCRIPTION 
6.1 
Study Design 
This is a phase 3, multicenter, randomized, double-blind, placebo-controlled, 
parallel-group, comparative study (Treatment Period I) and a phase 3, multicenter, 
open-label, long-term study (Treatment Period II) using placebo as a control to evaluate 
the efficacy and safety of SYR-472 when administered orally at a dose of 25 mg once 
weekly in patients with type 2 diabetes mellitus complicated by severe renal impairment 
or end-stage renal failure and with inadequate glycemic control despite diet and/or 
exercise therapy (if any) or despite treatment with 1 antidiabetic drug (Table 6.a) in 
addition to diet and/or exercise therapy (if any). 
Table 6.a 
Concomitant Antidiabetic Drugs Permitted in the Study 
Type 
Drug Name (Nonproprietary Name or Class) 
Rapid-acting insulin 
secretagogues 
Mitiglinide calcium hydrate, repaglinide 
α-glucosidase inhibitors 
Acarbose, miglitol, voglibose 
Insulin preparations 
Mixed, intermediate-acting, or long-acting soluble insulin (40 
units/day or less*) 
*: For change in the dosing unit of insulin preparations, see 2 (2) in Section 7.3. 
Subjects who enter the screening period after signing informed consent and are 
considered eligible according to the inclusion and exclusion criteria will be randomly 
assigned to either of the SYR-472 25 mg group or placebo group. Subjects who are 
assigned to the SYR-472 25 mg group in Treatment Period I will continue to be treated 
with SYR-472 25 mg in Treatment Period II, while those assigned to the placebo group 
will be switched to SYR-472 25 mg in Treatment Period II. 
In Treatment Period I, 1 SYR-472 25 mg tablet or placebo tablet will be orally 
administered once weekly before breakfast. In Treatment Period II, 1 SYR-472 25 mg 
tablet will be orally administered once weekly before breakfast. 
The study period consists of 6 weeks of screening, 52 weeks of treatment, and 2 weeks of 
follow-up, a total of 60 weeks. The treatment period consists of Treatment Period I 
(double-blind) between Week 0 and Week 12 and Treatment Period II (open-label) 
between Week 12 and Week 52. Subjects will visit the site at the start of the screening 
period (Week -6), Week -2 of the screening period, end of the screening period (Week 0), 
Week 2 and Week 4 of the treatment period, and at every 4 weeks until Week 52 of the 
treatment period, and at the end of the follow-up period (Week 54) (total of 18 visits). 
The planned sample size is 106 randomized subjects (53 per group). 
A schematic of the study design is included as Figure 6.a. A schedule of assessments is 
listed in Appendix A. 


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Week -6 
 
VISIT 1 
Week 0 
(randomization) 
VISIT 3 
Week 12 
 
VISIT 7 
 
Week 52 
 
VISIT 17 
Week 54 
 
VISIT 18 
 
Eligibility 
confirmation 
Start of study 
drug 
administration 
 
 
 
 
 
 
 
 
←Screening 
period→ 
←Treatment period→ 
←Follow-up 
period→ 
 
 
 
Period I 
(double-blind)* 
Period II (open-label) 
 
 
 
 
 
 
 
Placebo group 
 
Placebo tablet 
SYR-472 25 mg tablet 
 
 
SYR-472 25 mg 
group 
 
SYR-472 25 mg tablet 
 
 
*: The study drug blind in Treatment Period I will be maintained until the end of the study. 
Figure 6.a 
Schematic of Study Design 
6.2 
Justification for Study Design, Dose, and Endpoints 
(1) Justification for the study design 
This study, which aims to evaluate the efficacy and safety of SYR-472 when 
administered at a dose of 25 mg once weekly in patients with type 2 diabetes mellitus 
complicated by severe renal impairment or end-stage renal failure, will be conducted in a 
double-blind manner until Week 12 of the treatment period (Treatment Period I) to 
evaluate the efficacy and safety of SYR-472 by comparing the SYR-472 25 mg group and 
placebo group. Subsequently, it will be conducted in an open-label manner between 
Week 12 and Week 52 of the treatment period (Treatment Period II) to evaluate the 
long-term safety of SYR-472. 
(2) Justification for the dose and regimen 
The usual dose of SYR-472 is 100 mg once weekly; however, since Study 101 showed 
that the AUC of SYR-472Z in patients with severe renal impairment and end-stage renal 
failure was 3.01 and 3.68 times higher than that in healthy adults, respectively, 1-quarter 
of the usual dose is considered appropriate for patients with severe to end-stage renal 
failure, and a dose of 25 mg once weekly has thus been selected for the study. 
(3) Justification for the study period 
1) Justification for the Screening Period 
The duration of the screening period was set at 6 weeks to select subjects who meet all of 
the inclusion criteria and none of the exclusion criteria, and to select subjects with a stable 
HbA1c value in reference to the “the Guideline for Clinical Evaluation of Hypoglycemic 
Agents (Revised Draft)” [4]. 
2) Justification for the treatment period 
<Justification for Treatment Period I (double-blind period)> 
In Study CCT-002, the change (mean) in HbA1c at Week 8, 12, 16, 20, and 24 of the 
treatment period following oral administration of SYR-472 at a dose of 100 mg once 
weekly was -0.39%, -0.40%, -0.38%, -0.34%, and -0.31%, respectively, and the 


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difference from the placebo group (SYR-472 100 mg group - placebo group) was -0.42%, 
-0.53%, -0.59%, -0.63%, and -0.52%, respectively. These results suggest that the 
HbA1c-lowering effect of SYR-472 almost reaches a plateau by Week 12 of treatment. 
The incidence of AEs including hypoglycemia did not increase depending on the duration 
of treatment. In addition, the results of Study 101 suggest that administration of 1-quarter 
(25 mg/week) of the usual dose to patients with severe renal impairment or end-stage 
renal failure will result in a similar exposure level to that observed in patients with normal 
renal function. Based on these results, the HbA1c-lowering effect in patients with severe 
renal impairment or end-stage renal failure will almost reach a plateau by Week 12 when 
treated at 1-quarter (25 mg/week) of the usual dose, just as observed in patients with 
normal renal function. 
Furthermore, the basic treatment (diet and/or exercise therapy and an antidiabetic drug) of 
subjects is required to remain fixed from at least 6 weeks prior to the start of the screening 
period (Week -6) through the end of Treatment Period I in principle, with respect to the 
possible influence on assessments in the study. However, since strict glycemic control is 
required especially for patients with type 2 diabetes mellitus complicated by renal 
impairment, it is considered difficult to continue with fixed fundamental treatment over a 
long period. 
Based on the above considerations, the duration of Treatment Period I was set at 12 weeks 
as a period during which the efficacy and safety of SYR-472 25 mg can be evaluated in 
patients with severe renal impairment or end-stage renal failure and with respect to the 
safety of the subjects. 
<Justification for Treatment Period II (open-label period)> 
Treatment Period II was set as an open-label period and the total duration of Treatment 
Periods I and II was set at 1 year (52 weeks) in reference to the “The Extent of Population 
Exposure to Assess Clinical Safety for Drugs Intended for Long-Term Treatment of 
Non-Life-Threatening Conditions” [5] and “the Guideline for Clinical Evaluation of 
Hypoglycemic Agents (Revised Draft)” [4]. 
<Justification for Follow-up Period> 
In Study 101, the elimination half-life (mean) of unchanged SYR-472 following the 
administration of SYR-472 50 mg under fasted conditions (without breakfast) to patients 
with severe renal impairment and end-stage renal failure was 88.45 and 107.97 hours, 
respectively, which were longer than those in matched healthy adults (56.43 and 56.75 
hours). Based on these results, the time of assessment at the end of the follow-up period 
was set at Week 54 by reference to 5 times the elimination half-life (18.4 and 22.5 days, 
or longer) from the last administration of SYR-472 25 mg tablets (Week 51). 
(4) Justification for the primary endpoints 
According to “the Guideline for Clinical Evaluation of Hypoglycemic Agents (Revised 
Draft)” [4], HbA1c should be used as an efficacy endpoint in phase 3 studies in principle. 
In addition, the safety of the study drug should be used as the primary endpoint in 
long-term studies. Therefore, HbA1c at the end of Treatment Period I will be evaluated as 
the efficacy endpoint and AEs throughout the treatment period will be evaluated as the 
safety endpoint. 


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(5) Justification for the secondary endpoints 
In reference to “the Guideline for Clinical Evaluation of Hypoglycemic Agents (Revised 
Draft)” [4] and based on the results of clinical studies of SYR-472 conducted so far, 
HbA1c, fasting blood glucose, and glycoalbumin were set as efficacy endpoints, and vital 
signs, 12-lead ECG, and clinical laboratory test values were set as safety endpoints to 
evaluate the efficacy and safety of SYR-472 25 mg. 
(6) Justification for the inclusion criteria 
See Section 7.1. 
(7) Justification for the exclusion criteria 
See Section 7.2. 
(8) Justification for the excluded medications and other exclusions 
See Section 7.3. 
(9) Justification for the sample size 
See Section 13.3. 
6.3 
Premature Termination or Suspension of Study or Investigational Site 
6.3.1 Criteria for Premature Termination or Suspension of the Study 
The study will be completed as planned unless 1 or more of the following criteria are 
satisfied that require temporary suspension or early termination of the study. 
• New information or other evaluation regarding the safety or efficacy of the study 
medication that indicates a change in the known risk/benefit profile for the 
compound, such that the risk/benefit is no longer acceptable for subjects 
participating in the study. 
• Significant violation of GCP that compromises the ability to achieve the primary 
study objectives or compromises subject safety. 
6.3.2 Criteria for Premature Termination or Suspension of Investigational Sites 
A study site may be terminated prematurely or suspended if the study site (including the 
investigator) is found in significant violation of GCP, 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 Investigational Site(s) 
In the event that the sponsor, an institutional review board (IRB) or regulatory authority 
elects to terminate or suspend the study or the participation of an investigational site, a 
study-specific procedure for early termination or suspension will be provided by the 
sponsor; the procedure will be followed by applicable investigational sites during the 
course of termination or study suspension. 


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7.0 
SELECTION AND DISCONTINUATION/WITHDRAWAL OF 
SUBJECTS 
All entry criteria, including test results, need to be confirmed prior to randomization. 
7.1 
Inclusion Criteria 
Subject eligibility is determined according to the following criteria prior to entry into the 
study: 
1. The subject has a diagnosis of type 2 diabetes mellitus. 
2. The subject has a fasting C-peptide value of 0.6 ng/mL or higher at the start of the 
screening period (Week -6) and Week -2 of the screening period. 
3. The subject has a hemoglobin value of 10.0 g/dL or higher at the start of the screening 
period (Week -6) and Week -2 of the screening period. 
4. The subject has an HbA1c value of 7.0% or higher but less than 10.0% at Week -2 of 
the screening period. However, subjects on hemodialysis (patients with end-stage 
renal failure) with an HbA1c value of less than 7.0% at Week -2 of the screening 
period are permitted to be enrolled if they have a glycoalbumin value of 20% or 
higher. 
5. <Subjects with a HbA1c value of 7.0% or higher but less than 10.0% at Week -2 of 
the screening period> 
The subject has an HbA1c value difference between the start of the screening period 
(Week -6) and Week -2 of the screening period within 10.0%* of the HbA1c value at 
the start of the screening period (Week -6). 
<Subjects on hemodialysis (patients with end-stage renal failure) with an HbA1c 
value of less than 7.0% and glycoalbumin value of 20% or higher at Week -2 of the 
screening period> 
The subject has a glycoalbumin value difference between the start of the screening 
period (Week -6) and Week -2 of the screening period within 10.0%* of the 
glycoalbumin value at the start of the screening period (Week -6). 
*: rounded to one decimal place 
6. The subject has been on a fixed diet and/or exercise therapy (if any) from at least 6 
weeks prior to the start of the screening period (Week -6). 
7. The subject meets any of the following: 
• 
The subject has not received any antidiabetic medications (including insulin 
preparations) from at least 6 weeks prior to the start of the screening period 
(Week -6). 
• 
The subject is being treated with 1 oral hypoglycemic drug* starting from at least 
6 weeks prior to the start of the screening period (Week -6) at a fixed dose and 
regimen. 
*: Any of the following medications: mitiglinide calcium hydrate, repaglinide, acarbose, miglitol, 
or voglibose 


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• 
The subject is being treated with 1 insulin preparation** from at least 6 weeks 
prior to the start of the screening period (Week -6) at a fixed dose and regimen 
(≤40 units/day). 
**: Any of the following insulin monotherapies: mixed (rapid-acting or ultrarapid-acting insulin 
containing no more than 30% of volume), intermediate-acting, or long-acting soluble insulin 
preparations 
8. The subject is not undergoing hemodialysis or peritoneal dialysis and has severe renal 
impairment (Ccr <30 mL/min at the start of the screening period [Week -6]), or the 
subject is undergoing hemodialysis and has end-stage renal failure. 
9. In the opinion of the investigator or sub-investigator, the initiation of hemodialysis or 
peritoneal dialysis within 12 weeks after the initiation of the study drug is not 
expected. (in cases where the subject is not undergoing hemodialysis or peritoneal 
dialysis [patients with severe renal impairment]) 
10. The subject has been undergoing hemodialysis started from at least 6 months prior to 
informed consent and, in the opinion of the investigator or sub-investigator, the 
subject is clinically stable. (in cases where the subject is undergoing hemodialysis 
[patient with end-stage renal failure]) 
11. The subject is male or female and is aged 20 years or older at the time of informed 
consent. 
12. A female subject of childbearing potential who is sexually active with a nonsterilized 
male partner agrees to routinely use adequate contraception from signing of informed 
consent until 1 month after the end of the study. 
Definitions and acceptable methods of contraception are defined in Section 9.1.10 
Contraception and Pregnancy Avoidance Procedure and reporting responsibilities 
are defined in Section 9.1.11 Pregnancy. 
13. In the opinion of the investigator or sub-investigator, the subject is capable of 
understanding and complying with protocol requirements. 
14. The subject signs and dates a written, informed consent form prior to the initiation of 
any study procedures. 
<Justification of Inclusion Criteria> 
1. 
The criterion was set as the target disease of the study. 
2. 
In order to select subjects who maintain capacity for secreting intrinsic insulin, 
the lower limit of the fasting C-peptide value was set at 0.6 ng/mL based on 
Training Guidebook for Board Certified Diabetologists (the revised 6th 
edition)[6]. 
3. 
The criterion was set to require a blood hemoglobin value of 10.0 g/dL or 
higher in reference to the therapeutic target for renal anemia provided in the 
“Clinical Practice Guidebook for Diagnosis and Treatment of Chronic Kidney 
Disease 2012” [7] and “Evidence-based Clinical Practice Guideline for CKD 
2013” [8] because a low blood hemoglobin level may affect HbA1c, which is 
defined as an efficacy endpoint. 


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4. 
The criterion was set to define a lower limit of 7.0% because The 
Evidence-based Practice Guideline for the Treatment for Diabetes in Japan 
2013 [9] recommends that the target value of HbA1c should be less than 7.0% 
from the perspective of prevention of complications. However, since subjects 
on hemodialysis (patients with end-stage renal failure) may have a low HbA1c 
level because of factors such as increased immature erythrocytes and shorter 
erythrocyte lifespan [8], it was decided to take glycoalbumin value 
additionally into consideration in evaluating subjects with the lower limit of 
HbA1c level of less than 7.0%. The acceptable glycoalbumin level for such 
subjects was set at 20% or higher in reference to Best Practice for Diabetic 
Patients on Hemodialysis 2012 [10]. In addition, the upper limit of HbA1c 
level was set at 10.0% to exclude subjects with very poor glycemic control 
with respect to the safety of the subjects. 
5. 
The criterion was set to select subjects with stable glycemic control. 
6. 
The Evidence-based Practice Guideline for the Treatment of Diabetes 2013 
[9] recommends to change treatment for patients who cannot achieve the 
target glucose level despite continuous diet and exercise therapy for 2 to 3 
months; therefore, patients who have been on a fixed diet and/or exercise 
therapy (if any) from at least 6 weeks prior to the start of the screening period 
(Week -6), i.e., at least 12 weeks prior to the start of Treatment Period I, will 
be included in this study. 
7. 
The Guideline for Clinical Evaluation of Hypoglycemic Agents (Revised 
Draft)” [4] stipulates that subjects for phase 3 confirmatory and long-term 
studies should be “adults patients with type 2 diabetes mellitus who are stable 
and are not treated with any hypoglycemic drugs,” while subjects for 
long-term combination therapy studies should be “adult patients with type 2 
diabetes mellitus refractory to 1 of commercially available hypoglycemic 
drugs treated over a certain period.” Therefore, patients who are not using 
antidiabetic drugs (including insulin preparations) from at least 6 weeks prior 
to the start of the screening period (Week -6) (i.e., at least 12 weeks prior to 
the start of Treatment Period I) or those who are using 1 antidiabetic drug 
(including insulin preparations) at a fixed dose and regimen will be included 
in this study. 
With respect to the safety of the subjects, the antidiabetic drug should be any 1 
of mitiglinide calcium hydrate, repaglinide, acarbose, miglitol, voglibose, or 
insulin preparations, which can be used for patients with severe renal 
impairment or end-stage renal failure according to the package insert. Similar 
DPP-4 inhibitors and GLP-1 receptor agonists are excluded with respect to the 
safety of the subjects and possible influence on the evaluation of efficacy and 
safety. 
8. 
The criterion was set to exclude patients with moderate or milder renal 
impairment in reference to the “Clinical Practice Guidebook for Diagnosis 
and Treatment of Chronic Kidney Disease 2012” [7]. In addition, 
hemodialysis was set as the only dialysis method permitted for patients with 


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end-stage renal failure with respect to the possible influence on the evaluation 
of efficacy and safety in the study. 
9. 
The criterion was set to select subjects who are not receiving hemodialysis 
and do not have the possibility of starting hemodialysis during Treatment 
Period I with respect to the safety of the subjects and possible influence on the 
evaluation of efficacy and safety in the study. 
10. 
The criterion was set to select subjects showing stable effects of hemodialysis 
with respect to the possible influence on the evaluation of efficacy and safety 
in the study. 
11 
The criterion was set to define a minimum of 20 years of age at which subjects 
can voluntarily consent to participation in the study. An upper limit of age was 
not set in order to collect results in elderly patients as much as possible. 
12. to 14. These criteria were set as basic matters to conduct clinical studies. 
7.2 
Exclusion Criteria 
Any subject who meets any of the following criteria will not qualify for entry into the 
study: 
1. The subject has clinically evident hepatic impairment (e.g., AST or ALT >=2.5 times 
the upper limit of normal or total bilirubin of >=2.0 mg/dL at the start of the screening 
period [Week -6] or at Week -2 of the screening period). 
2. The subject has any serious cardiac diseases, cerebrovascular disorders, or serious 
pancreatic or hematological diseases (e.g., subjects who require inpatient treatment or 
had been hospitalized for treatment within 24 weeks prior to the start of the screening 
period). 
3. The subject has severe ketosis, diabetic coma or pre coma, type 1 diabetes, severe 
infection, or severe external injury, or immediately before or after surgery. 
4. The subject has hemoglobinopathy (sickle cell disease, thalassemia, etc.). 
5. The subject experienced hypoglycemia (subjects with a blood glucose value of 
≤70 mg/dL or hypoglycemic symptoms) within 6 weeks prior to the start of the 
screening period or during the screening period (at least twice per week). 
6. The subject has inadequately controlled hypertension. 
7. For subjects who are being treated with 1 antidiabetic agent, the subject had been 
treated with at least 2 antidiabetic agentss on the day before 6 weeks prior to the start 
of the screening period (Week -6) (43 days prior to the start of the screening period). 
8. The subject has malignancies. 
9. The subject has a history of hypersensitivity or allergies to dipeptidyl peptidase-4 
(DPP-4) inhibitors. 
10. The subject has a history of gastrectomy or small intestinal resection. 
11. The subject is a habitual drinker and consumes a daily average of more than 100 mL 
of alcohol. 


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12. The subject has a history of drug abuse (defined as any illicit drug use) or a history of 
alcohol abuse. 
13. The subject is required to take excluded medications during the study period. 
14. The subject has received SYR-472 in a previous clinical study. 
15. The subject received any investigational products (including investigational drugs in 
a post-marketing clinical study) within 12 weeks prior to the start of the screening 
period. 
16. The subject is participating in other clinical studies at the time of informed consent. 
17. If female, the subject is pregnant or lactating or intending to become pregnant from 
the time of informed consent to within 1 month after the end of the study; or intending 
to donate ova during such time period. 
18. The subject is an immediate family member, study site employee, or is in a dependant 
relationship with a study site employee who is involved in conduct of this study (e.g., 
spouse, parent, child, sibling) or may consent under duress. 
19. The subject is hospitalized during the screening period or is deemed as requiring 
hospitalization during the study period by the investigator or sub-investigator, unless 
the hospitalization is for short-term evaluations including complete health checkups 
or for short-term admission for shunt operation (including shunt maintenance). 
20. The subject is deemed ineligible for the study for any other reason by the investigator 
or sub-investigator. 
Reference) Alcohol Conversion Chart 
Type 
Type 
Alcohol Content 
Volume Equivalent to 100 mL of Alcohol 
Brewages 
Sake 
15% 
670 mL (approximately 3 gou) 
Beer 
5% 
2000 mL (approximately 3 beer bottles in large 
size) 
Low-malt beer 
5% 
2000 mL 
Wine 
12% 
830 mL 
Shaoxing rice wine 
18% 
560 mL 
Distilled liquors 
Distilled spirit 
(Kou-type shouchu) 
35% 
290 mL 
Distilled spirit 
(Otsu-type shouchu) 
25% 
400 mL 
Whiskey 
40% 
250 mL (approximately 3 double shots) 
Brandy 
40% 
250 mL (approximately 3 double shots) 
Vodka 
40% 
250 mL (approximately 3 double shots) 
Mixed liquors 
Plum wine 
13% 
770 mL 
Synthetic sake 
16% 
630 mL 
 
<Justification of Exclusion Criteria> 
1., 2., 6., 8., and 9. 
These criteria were set with respect to the safety of the subjects. 


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3. 
The criterion was set with respect to the safety of the subjects and possible 
influence on the evaluation of efficacy in the study. 
4., 10. to 12., and 14. 
These criteria were set because they could influence the evaluation of efficacy 
and safety in the study. 
5. 
The criterion was set with respect to the safety of the subjects and possible 
influence on the evaluation of safety in the study. 
7. 
The criterion was set because if excluded antidiabetic drugs are discontinued 
in order to participate in the study under informed consent, the discontinuation 
of 2 or more drugs may jeopardize the safety of the subject. 
13. 
The criterion was set with respect to the safety of the subjects and possible 
influence on the evaluation of efficacy and safety in the study. 
15. to 18. and 20. 
These criteria were set as basic requirements to conduct clinical studies. 
19. 
The criterion was set because intervention in lifestyles due to hospitalization 
is likely to influence the glucose metabolism of subjects. 
7.3 
Excluded Medications and Treatments 
Subjects must be instructed not to take any medications including over-the-counter 
products, without first consulting with the investigator or sub-investigator. 
1. Excluded Medications 
Use of the following medications is prohibited in each period: 
(1) Screening Period and Treatment Period I 
• New antidiabetic drugs* 
• Other DPP-4 inhibitors and GLP-1 receptor agonists 
• Sulfonylureas, biguanides, thiazolidinediones, nateglinide, and SGLT-2 inhibitors 
*: Except for antidiabetic drugs that are being used at the start of the screening period (Week -6) and 
will be concomitantly used during the study period 
(2) Treatment Period II and Follow-up Period 
• New insulin preparations* 
• Other DPP-4 inhibitors and GLP-1 receptor agonists 
• Sulfonylureas, biguanides, thiazolidinediones, nateglinide, and SGLT-2 inhibitors 
*: Except for insulin preparations that are being used at the start of the screening period (Week -6) and 
will be concomitantly used during the study period 


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<Justification for Excluded Medications> 
In the screening period and Treatment Period I, changes in the basic treatment are 
prohibited with respect to the possible influence on the efficacy and safety evaluation of 
SYR-472. However, the addition of new insulin preparations is only prohibited in 
Treatment Period II and thereafter with respect to the safety of the subjects. In addition, 
the use of antidiabetic drugs that are contraindicated in patients with serious renal 
impairment and SGLT-2 inhibitors that cannot be used over a long period as of the start of 
the study is prohibited with respect to the safety of the subjects. Furthermore, the use of 
similar DPP-4 inhibitors and GLP-1 receptor agonists is prohibited with respect to the 
safety of the subjects and possible influence on the evaluation of efficacy and safety. 
2. Restricted Medications 
(1) Oral Hypoglycemic Agents 
1) Screening Period and Treatment Period I 
Changes in the dose/regimen or discontinuations/interruptions of oral hypoglycemic 
drugs that are being used at the start of the screening period (Week -6) and will be 
concomitantly used in the study period are prohibited. 
2) Treatment Period II and Follow-up Period 
• Changes in the dose/regimen or discontinuations/interruptions of oral hypoglycemic 
drugs that are being used at the start of the screening period (Week -6) and will be 
concomitantly used in the study period are allowed. 
• For subjects who are not using any other antidiabetic drug in Treatment Period I 
(those who are only treated with the study drug), the use of 1 new oral 
hypoglycemic drug* is allowed at Week 16 of the treatment period and thereafter. 
*: Any 1 of the following medications: mitiglinide calcium hydrate, repaglinide, acarbose, miglitol, or 
voglibose 
(2) Insulin Preparations 
For subjects who are receiving insulin preparations at the start of the screening period 
(Week -6) and continue to receive in the study period, insulin preparations should be 
administered as specified below. 
• Type of Insulin Preparation 
Any 1 of the mixed (rapid-acting or ultrarapid insulin containing no more than 30% of 
volume), intermediate-acting, or long-acting soluble insulin preparations should be used 
alone, and should not be changed throughout the study period. 
• Daily Dose (Unit) of Insulin Preparation 
1) Screening Period 
The daily dose (unit) of insulin preparation should be 40 units/day or less at the start of 
the screening period (Week -6), and the dose and regimen should not be changed during 
the screening period (for subjects on hemodialysis who receive different daily doses 
[unit] of insulin preparation on days of hemodialysis and on other days, each dose and 
regimen of insulin preparation should not be changed). 


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2) Treatment Period I 
The dose and regimen of insulin preparations at the start of the screening period 
(Week -6) should be maintained and no changes will allowed, in principle. 
However, the investigator or sub-investigator should consider reduction or increase in the 
daily dose (unit) of insulin preparation if the criteria described below are met. After dose 
reduction or increase, the unit after reduction or increase should be continued. 
Even if reduction in the daily dose (unit) of insulin preparation results in the 
discontinuation of insulin use, the study may be continued. If increase in the daily dose 
(unit) of insulin preparation results in a dose exceeding 40 units/day on a continuing basis, 
the investigator or sub-investigator should determine whether the study should be 
continued or discontinued, with respect to the safety of the subject. 
Criteria for dose reduction: If either criterion (i) or (ii) described below is met, the daily 
dose (unit) of insulin preparation may be reduced from the unit administered at the start of 
the screening period (Week -6) by up to 4 units (regardless of the number of changes). 
If it is necessary to reduce the dose from the unit administered at the start of the screening 
period (Week -6) by more than 4 units/day, the study should be discontinued and 
appropriate measures should be taken. 
i) 
A subject shows hypoglycemic symptoms, and the investigator or sub-investigator 
considers that the dose reduction of insulin preparation is necessary in view of the 
safety of the subjects. 
ii) Hypoglycemia is suspected since a subject has had 2 or more consecutive 
self-monitoring blood glucose values of ≤70 mg/dL, and the investigator or 
sub-investigator considers that the risk of developing hypoglycemia is high. 
Criteria for dose increase: If a subject has had 2 or more consecutive self-monitoring 
blood glucose values of >240 mg/dL and the investigator or sub-investigator considers 
that the increase of insulin preparation is necessary in view of the safety of the subjects, 
the daily dose (units) of insulin preparation at the start of the screening period (Week -6) 
can be increased by up to 4 units (regardless of the number of dose changes). 
If dose increase greater than 4 units/day from the unit administered at the start of the 
screening period (Week -6) is required, the subject will be withdrawn from the study and 
receive appropriate treatment. 
3) Treatment Period II and Follow-up Period 
The investigator or sub-investigator should consider reduction or increase in the daily 
dose (unit) of insulin preparation if the criteria described below are met. After dose 
reduction or increase, the unit after reduction or increase should be continued. 
Even if reduction in the daily dose (unit) of insulin preparation results in the 
discontinuation of insulin use, the study may be continued. If increase in the daily dose 
(unit) of insulin preparation results in a dose exceeding 40 units/day on a continuing basis, 
the investigator or sub-investigator should determine whether the study should be 
continued or discontinued, with respect to the safety of the subject. 
Criteria for dose reduction: If either criterion (i) or (ii) described below is met, reduction 
in the daily dose (unit) of insulin preparation should be considered. 


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i) 
A subject shows hypoglycemic symptoms, and the investigator or sub-investigator 
considers that the dose reduction of insulin preparation is necessary in view of the 
safety of the subjects. 
ii) Hypoglycemia is suspected since the subject has had 2 or more consecutive 
self-monitoring blood glucose values of ≤70 mg/dL, and the investigator or 
sub-investigator considers that the risk of developing hypoglycemia is high. 
Criteria for dose increase: If a subject has had 2 or more consecutive self-monitoring 
blood glucose values of >200 mg/dL and the investigator or sub-investigator considers 
that the increase of insulin preparation is necessary in view of the safety of the subjects, 
whether or not to increase the daily dose (units) of insulin preparation should be 
considered. 
<Justification of Restricted Medications> 
For oral hypoglycemic drugs, changes in the basic treatment are prohibited in the 
screening period and Treatment Period I with respect to the possible influence on the 
efficacy and safety evaluation of SYR-472. In Treatment Period II and the follow-up 
period, changes in the dose or regimen as well as discontinuations and interruptions are 
allowed due to ethical considerations on the state of glycemic control for patients with 
type 2 diabetes mellitus complicated by renal impairment during the 54-week study 
period. In addition, for subjects who do not receive any other antidiabetic drug in 
Treatment Period I and still show inadequate glycemic control after 4 weeks following 
entry into Treatment Period II (Week 16 of the treatment period or thereafter), 1 oral 
hypoglycemic drug only may be additionally administered at the discretion of the 
investigator and sub-investigator. 
For insulin preparations, changes in the daily dose (unit) are permitted according to the 
fixed criteria for dose reduction or increase, if the investigator or sub-investigator 
considers it necessary from the perspective of the safety of the subject. 
3. Other medications 
For medications other than those specified in 1 and 2 above, the daily dose administered 
at the start of the screening period (Week -6) should not be changed in Treatment Period I, 
in principle. However, if deemed necessary for treatment by the investigators due to the 
occurrence of an AE or other reasons, changes in the daily dose and administration of a 
new medication are permitted. It should be confirmed that the medication can 
administered to individuals with renal impairment. Caution should be exercised for 
medications that require careful use with the study drug and/or antidiabetic drug that is 
used at the start of the screening period (Week -6) and continued during the study period 
as recommended in the package insert. 
<Justification for Medications Other Than Excluded Medications and Restricted 
Medications> 
The use of other medications is permitted because they are unlikely to influence the 
evaluation of drug effects unless the daily dose is changed. The daily dose of such 
medications should not be changed in principle; however, changes in the daily dose and 
administration of a new medication due to the onset of an AE or other reasons are 
permitted for ethical considerations. 


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4. Other prohibitions 
Hospitalization is prohibited during the study period, excluding short-term 
hospitalization for medical evaluations including complete health checkups or for 
short-term admission for shunt operation (including shunt maintenance). 
<Justification for Other prohibitions> 
Hospitalization during the study period is prohibited because intervention in lifestyle due 
to hospitalization is likely to influence glucose metabolism (for example, continued 
hospitalization for 1 week or longer), possibly affecting the evaluation of drug effects. 
7.4 
Diet, Fluid, Activity Control 
The investigator, sub-investigator, and study coordinator will pay attention to the 
following requirements and provide necessary instructions to subjects: 
1. For diet and/or exercise therapy (if any), the investigator or sub-investigator should 
provide fixed instructions on diet and/or exercise therapy throughout the study period. 
In addition, subjects should be instructed to follow instructions on diet and/or exercise 
therapy. 
2. Subjects are required to comply with the prescribed dose and regimen of the study 
drug. Subjects are required to bring study drug sheet to the study site at each visit. 
Study drug administration should be started after all procedures scheduled for the end 
of the screening period (Week 0) are completed (the day when study drug 
administration is started is defined as the first day of dosing). The SYR-472 25 mg or 
placebo tablets should be taken once weekly (on the same day of the week as the day 
of the first dose). If a dose is missed, just 1 tablet for the last missed dose should be 
taken immediately after the subject notices it. Subjects should not take more than 1 
SYR-472 25 mg or placebo tablet for several missed doses prior to the next scheduled 
dosing day. 
3. Subjects should be instructed to ingest glucose or sucrose (sugar) in case any 
hypoglycemic symptom (e.g., unusual hunger, weakness, finger tremor, cold sweat, 
or palpitations) appears, and to visit the study site immediately if the symptom does 
not improve despite glucose or sucrose ingestion. 
4. For subjects using insulin preparations, the investigator or sub-investigator should 
provide explanations and instructions about the method and timing of self-monitoring 
of blood glucose at the end of the screening period (Week 0). Subjects should also be 
instructed to report the results of self-monitoring of blood glucose to the investigator 
or sub-investigator at each visit. In particular, they should be instructed to report to 
the investigator or sub-investigator whether or not they have experienced a blood 
glucose value exceeding 240 mg/dL (Treatment Period I) or 200 mg/dL (Treatment 
Period II and follow-up period), or a blood glucose value of 70 mg/dL or less as 
measured by self-monitoring, and whether or not they have experienced any 
hypoglycemic symptoms. 
For the time points of self-monitoring of blood glucose, refer to Section 9.1.21. 
5. If a subject plans to use any drugs (including over-the-counter [OCT] drugs) other 
than those prescribed by the investigator or sub-investigator, he/she should consult 


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with the investigator or sub-investigator in advance, whenever possible. In case these 
drugs have already been used, immediate notification is required. 
6. If a subject plans to visit another physician, prior notification to the investigator or 
sub-investigator is required. If a subject has already been treated by another physician, 
immediate notification is required. 
7. Subjects are required to be punctual for visit appointments and undergo physical 
examinations and prescribed tests as scheduled. If a subject cannot visit the study site 
on the scheduled day, immediate contact to the study site is required. 
8. Subjects should be instructed to avoid excessive drinking and eating, extreme 
changes in diet (e.g. ingestion of a high-fat diet), or excessive exercises and live as 
usual on the days before the study visit. 
9. On the day of the visit, subjects should visit the site under fasted conditions (at least 
10 hours of fasting). Subjects using oral hypoglycemic drugs or insulin preparations 
should visit the site without taking them on the day of the visit. 
10. Subjects are required to undergo routine ophthalmologic examination and pay 
attention to complications including diabetic retinopathy. 
7.5 
Criteria for Discontinuation or Withdrawal of a Subject 
The primary reason for discontinuation or withdrawal of the subject from the study 
should be recorded in the case report form (eCRF) using the following categories. For 
screen failure subjects, refer to Section 9.1.25. 
1. Pretreatment event (PTE) or AE 
The subject has experienced a PTE or 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 PTE or AE. 
Liver Function Test (LFT) Abnormalities 
Study drug should be discontinued immediately with appropriate clinical follow-up 
(including repeat laboratory tests, until a subject’s laboratory profile has returned to 
normal/baseline status [value at immediately after the inforned consent for PTEs and 
at immediately before the initiation of the study drug for AEs], see Section 9.1.9), if 
the following circumstances occur at any time during study drug treatment: 
– alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >8 × upper 
limit of normal (ULN), or 
– ALT or AST >5 × ULN and persists for more than 2 weeks, or 
– ALT or AST >3 × ULN in conjunction with elevated total bilirubin >2 × ULN 
or international normalized ratio (INR) >1.5, or 
– ALT or AST >3 × ULN with appearance of fatigue, nausea, vomiting, right 
upper quadrant pain or tenderness, fever, rash and/or eosinophilia (>5%). 
• Renal Function Test Abnormalities 
For subjects not on hemodialysis at the start of the screening period (Week -6) 
(patients with severe renal impairment), the study drug should be discontinued with 


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appropriate clinical follow-up until a subject’s laboratory profile has returned to 
normal/baseline status for subjects not on hemodialysis at the start of the screening 
period (Week -6) (patients with severe renal impairment) if the subject shows 
worsening of renal function that may necessitate hemodialysis in Treatment Period I 
and is considered inappropriate to continue the study in the opinion of the investigator 
or sub-investigator, or if the subject shows rapid worsening of Ccr (e.g., reduction of 
30% or more) on 2 consecutive post dose measurements, as compared with the value 
at the end of the screening period (Week 0), and is considered inappropriate to 
continue the study in the opinion of the investigator or sub-investigator. 
• Serious hypoglycemia 
A serious hypoglycemic symptom (coma, depressed consciousness, etc.; severe 
enough to require active sugar or glucagon administration or other resuscitation by 
other people) appears. For reporting in the event of serious hypoglycemia, refer to 
Section 10.2.1.3 and Section 10.2.2. 
• Serious hyperglycemia 
A serious hyperglycemic symptom (coma, ketosis, ketoacidosis, etc.; severe enough 
to require assistance by other people) appears. For reporting in the event of serious 
hyperglycemia, refer to Section 10.2.2. 
• Acute pancreatitis 
Acute pancreatitis is conclusively diagnosed. For reporting in the event of acute 
pancreatitis, refer to Section 10.2.1.3. 
• Abnormal QT/QTc interval 
Serious arrhythmia or significant QT interval prolongation (e.g., an absolute QTcF 
interval of >500 msec or a change of >60 msec from the end of the screening period 
[Week 0]) is observed, and the investigator or sub-investigator considers it 
inappropriate for the subject to continue the study. For reporting in the event of 
abnormal QT/QTc interval, refer to Section 10.2.1.3. 
2. Significant protocol deviation. 
The discovery postrandomization 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 study site and attempts to contact the subject were 
unsuccessful. Attempts to contact the subject must be documented. 
4. Voluntary withdrawal. 
The subject wishes to withdraw from the study. The reason for withdrawal, if 
provided, should be recorded in the eCRF. 
NOTE: All attempts should be made to determine the underlying reason for the 
withdrawal and, where possible, the primary underlying reason should be 
recorded (i.e., withdrawal due to an AE or lack of efficacy should not be 
recorded in the “voluntary withdrawal” category). 


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5. Study termination. 
The sponsor, IRB, or regulatory agency terminates the study. 
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 9.1.11. 
7. Lack of efficacy. 
The investigator or sub-investigator has determined that the subject is not benefiting 
from the study drug treatment; and, continued participation would pose an 
unacceptable risk to the subject. 
8. Other. 
NOTE: The specific reasons should be recorded in the “specify” field of the eCRF. 
7.6 
Procedures for Discontinuation or Withdrawal of a Subject 
The investigator or sub-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 
or sub-investigator. In addition, efforts should be made to perform all procedures 
scheduled for the Early Termination Visit. 


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8.0 
CLINICAL TRIAL MATERIAL MANAGEMENT 
8.1 
Study Drug 
8.1.1 Dosage Form, Manufacturing, Packaging, and Labeling 
8.1.1.1 Study drug 
The study drug refers to SYR-472DB tablets (SYR-472 25 mg tablets or placebo tablets) 
for Treatment Period I and SYR-472 25 mg tablets for Treatment Period II. 
1. Dosage Form 
(i) SYR-472DB tablets (for Treatment Period I) 
Genetic name: Trelagliptin Succinate (JAN) 
Chemical name: 2-({6-[(3R)-3-aminopiperidin-1-yl]-3-methyl-2,4-dioxo-3,4-
 
dihydropyrimidin-1(2H)-yl}methyl)-4-fluorobenzonitrile monosuccinate 
Dose: 
• SYR-472 25 mg tablets: 1 tablet contains 25 mg of SYR-472 (as free base). 
• SYR-472 placebo tablets: the placebo tablet does not contain SYR-472. 
Dosage form: Yellow-red film-coated tablets 
The appearance of SYR-472 25 mg tablets and SYR-472 placebo tablets is mutually 
indistinguishable. 
(ii) SYR-472 25 mg tablets (for Treatment Period II) 
Genetic name: Trelagliptin Succinate (JAN) 
Chemical name: 2-({6-[(3R)-3-aminopiperidin-1-yl]-3-methyl-2,4-dioxo-3,4-
 
dihydropyrimidin-1(2H)-yl}methyl)-4-fluorobenzonitrile monosuccinate 
Dose: 
• SYR-472 25 mg tablets: 1 tablet contains 25 mg of SYR-472 (as free base). 
Dosage form: Yellow-red film-coated tablets 
2. Manufacturing 
SYR-472 25 mg and placebo tablets were manufactured by Takeda Pharmaceutical 
Company Limited. 
3. Packaging and Labeling 
For Treatment Period I, 2 AL-AL blister sheets each containing 8 tablets (12 tablets 
for 12 weeks and 4 spare tablets for 4 weeks) are packed in a carton for 1 subject. For 
Treatment Period II, 16 AL-AL blister sheets each containing 8 tablets (128 tablets) 
are packed in a carton. The study drug for Treatment Period II can be used in 
common among all subjects in each study site. 


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The outer carton is labeled with a statement that it is for clinical study use, and with 
information such as the name of the study drug, quantity, sponsor’s name and address, 
manufacturing number, and storage conditions. 
8.1.2 Storage 
The study drug will be stored at room temperature (1 to 30°C). 
Study drug must be kept in an appropriate, limited-access, secure place until it is used or 
returned to the sponsor or designee for destruction. All drugs provided by the sponsor 
must be stored under the conditions specified on the label, and remain in the original 
container until dispensed. A daily temperature log of the drug storage area must be 
maintained every working day. 
8.1.3 Dose and Regimen 
In Treatment Period I, 1 tablet of SYR-472 25 mg or placebo will be orally administered 
once weekly before breakfast. In Treatment Period II, 1 tablet of SYR-472 25 mg tablet 
will be orally administered once weekly before breakfast. 
Subjects will start study drug administration after all procedures scheduled for the end of 
the screening period (Week 0) are completed. At subsequent visits when the study drug is 
administered, all specified procedures should be performed prior to study drug 
administration. 
Table 8.a describes the dose and regimen that will be provided to each group in Treatment 
Period I. 
Table 8.a 
Dose and Regimen (Treatment Period I) 
Treatment Group 
Dose 
Treatment Description 
SYR-472 25 mg tablet 
SYR-472 placebo 
tablet 
SYR-472 25 mg group 
SYR-472 25 mg tablet 
once weekly 
×1 
×0 
Placebo group 
SYR-472 placebo tablet 
once weekly 
×0 
×1 
8.1.4 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 study protocol. 
All cases of overdose (with or without associated AEs) will be documented on an 
Overdose page of the eCRF, in order to capture this important safety information 
consistently in the database. AEs associated with an overdose will be documented on AE 
CRFs according to Section 10.0, PRETREATMENT EVENTS AND ADVERSE 
EVENTS. 
Serious adverse events (SAEs) associated with overdose should be reported according to 
the procedure outlined in Section 10.2.2, Collection and Reporting of SAEs. 
In the event of drug overdose, the subject should be treated symptomatically. 


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8.2 
Study drug Assignment and Dispensing Procedures 
After judging and confirming eligibility of a subject, the investigator or sub-investigator 
will assign the subject to receive the study drugs for Treatment Period I which have been 
allocated to each study site (SYR-472DB tablets) in consecutive order of medication ID 
number. The investigator or investigator’s designee will record the medication ID 
number in the eCRF. 
In Treatment Period II, the investigator or sub-investigator will start administration of the 
study drug for Treatment Period II (SYR-472 25 mg tablet) after performing all physical 
examinations/examinations/assessments scheduled for Week 12 in the treatment period. 
8.3 
Randomization Code Creation and Storage 
Randomization personnel of the sponsor or designee will generate the randomization 
schedule. All randomization information will be stored in a secured area, accessible only 
by authorized personnel. 
8.4 
Study Drug Blind Maintenance 
Emergency Key Code Administration Center will maintain the subject's study drug blind 
information until emergency key code breaking or data lock of all subjects. 
Since the measured values of study drug concentration and DPP-4 may hinder study drug 
blind maintenance in this study, the central laboratory institute should retain the final 
results of these parameters until the key code breaking without disclosing them 
externally; the final results will be reported to the investigator via the sponsor after the 
code breaking. 
The study blind in Treatment Period I will be maintained until the end of the study. 
8.5 
Unblinding Procedure 
The study drug blind shall not be broken by the investigator or sub-investigator unless 
information concerning the study drug is necessary for the medical treatment of the 
subject. 
For unblinding a subject, the study drug blind can be obtained by contacting the 
Emergency Key Code Administration Center (Annex 1). 
If the study drug blind is broken, the date, time, and reason the blind is broken must be 
recorded in the document called Record of Early Blind-Breaking and submitted to the 
sponsor. The same information (except the time) must be recorded on the eCRF. 
If any site personnel are unblinded, study drug must be discontinued immediately and the 
subject must be withdrawn from the study. 
8.6 
Accountability and Destruction of Sponsor-Supplied Drugs 
The site designee will receive the procedures for handling, storage and management of 
study drugs created by the sponsor, according to which the site designee will 
appropriately manage the sponsor-supplied drug. The investigator will also receive those 
procedures from the sponsor. The procedures include those for ensuring appropriate 
receipt, handling, storage, management, dispensation of the sponsor-supplied drug, and 


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collection of unused medications from the subject as well as return of them to the sponsor 
or destruction of them. 
The site designee will immediately return unused medications to the sponsor after the 
study is closed at the site. 


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9.0 
STUDY PLAN 
9.1 
Study Procedures 
The following sections describe the study procedures and data to be collected. For each 
procedure, subjects are to be assessed by the same investigator or sub-investigator 
whenever possible. The Schedule of Study Procedures is located in Appendix A. 
If a subject undergoing hemodialysis (patients with end-stage renal failure) receive 
hemodialysis on the day of study site visit, all procedures should be performed before 
hemodialysis. 
9.1.1 Informed Consent Procedure 
The requirements of the informed consent are described in Section 15.2. 
Informed consent must be obtained prior to the subject entering into the study, and before 
any protocol-directed procedures are performed. 
A unique subject identification number (subject number) will be assigned to each subject 
at the time that informed consent is explained; this subject number will be used 
throughout the study. 
PGx Informed Consent Procedure 
A separate informed consent form pertaining to storage of the sample must be obtained 
prior to collecting a blood sample for PGx Research for this study. The provision of 
consent to collect and analyze the PGx sample is independent of consent to the other 
aspects of the study. 
9.1.2 Demographics, Medical History, and Medication History Procedure 
Demographic information to be obtained will include date of birth, sex, height, weight, 
body mass index (BMI), alcohol use, smoking status, onset time of type 2 diabetes, 
presence or absence of hemodialysis and diet and/or exercise therapy. 
The BMI will be calculated by the sponsor using the formula provided below: 
Metric: BMI = weight (kg)/[height (m)]2 
Height should be measured in centimeters without decimal places (rounding off the first 
decimal place). For measurement of weight, refer to Section 9.1.5. 
Medical history to be obtained will include determining whether the subject has any 
significant conditions or diseases relevant to the disease under study that stopped within 1 
year prior to signing of informed consent. Ongoing conditions are considered concurrent 
medical conditions (see Section 9.1.8). 
Medication history information to be obtained includes drug name, route of 
administration, daily dose, and end date of any antidiabetic drug stopped between 24 
weeks prior to the end of the screening period (Week 0) and the start of the screening 
period (Week -6). 
9.1.3 Antidiabetic Drugs Administered During the Study 
1. Screening Period 


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For antidiabetic drugs administered at the start of the screening period (Week -6) and 
concomitantly used during the study period, the drug name, type (for insulin 
preparations), and daily dose of antidiabetic drugs used at the start of the screening period 
(Week -6) and concomitantly used during the study will be recorded in the eCRF. 
2. Treatment Period I 
For antidiabetic drugs administered at the start of the screening period (Week -6) and 
concomitantly used during the study period, the drug name, type (for insulin 
preparations), and daily dose of antidiabetic drugs used at the start of the screening period 
(Week -6) and concomitantly used during the study period will be recorded in the eCRF. 
In case concomitant use of other antidiabetic drugs in addition to an antidiabetic drug 
used at the start of the screening period (Week -6) is judged to be appropriate, the 
investigator or sub-investigator should record the reason for the judgment in the eCRF 
according to the following categories: 
• Combination therapy is expected to be more effective. 
• Development of AEs due to dose increase is concerned. 
• The maximum dose has already been administered. 
• Others 
3. Treatment Period II 
For subjects who do not receive 1 antidiabetic drug other than the study drug in Treatment 
Period I and start the administration of 1 new oral hypoglycemic drug from Week 16 of 
the Treatment Period II (or thereafter), the drug name, daily dose, date of the start and end 
of administration, will be recorded in the eCRF. 
9.1.4 Physical Examination Procedure 
A baseline physical examination (defined as the assessment prior to first dose of study 
drug) will consist of the following body systems: (1) eyes; (2) ears, nose, throat; (3) 
cardiovascular system; (4) respiratory system; (5) gastrointestinal system; (6) 
dermatologic system; (7) extremities; (8) musculoskeletal system; (9) nervous system; 
(10) lymph nodes; and (11) other. 
All subsequent physical examinations should assess clinically significant changes from 
the assessment prior to the first dose examination. 
9.1.5 Weight 
Weight should be measured in kilograms to one decimal place (rounding off the second 
decimal place) under fasting conditions (at least 10 hours of fasting) to avoid the effect of 
meal. For subjects receiving hemodialysis (patients with end-stage renal failure), dry 
weight should be used. 
9.1.6 Vital Sign Procedure 
Vital signs will include sitting or supine blood pressure (resting more than 5 minutes) 
(systolic and diastolic) and pulse. 


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9.1.7 Documentation of Concomitant Medications 
Concomitant medication is any drug given in addition to the study drug and antidiabetic 
drugs. These may be prescribed by a physician or obtained by the subject over the counter. 
Concomitant medication is not provided by Takeda. At each study visit, subjects will be 
asked whether they have taken any medication other than the study drug (including 
vitamin supplements, over-the-counter medications, and herbal preparations) used from 
the start of the screening period (Week -6) through the end of the study, and the drug 
name, route of administration, dates of the start and end of administration, and purpose of 
use must be recorded in the eCRF. 
9.1.8 Documentation of Concurrent Medical Conditions 
Concurrent medical conditions are those significant ongoing conditions or diseases that 
are present at signing of informed consent. This includes clinically significant laboratory, 
ECG, or physical examination abnormalities noted at baseline examination. The 
condition (i.e., diagnosis) should be described. 
9.1.9  Procedures for Clinical Laboratory Samples 
Clinical laboratory tests that will be performed in this study are shown in Table 9.a. 
All samples will be collected in accordance with acceptable laboratory procedures. The 
maximum volume of blood at any single visit is approximately 27 mL, and the 
approximate total volume of blood for the study is 322 mL. 


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Table 9.a 
Clinical Laboratory Tests 
Hematology 
Serum Chemistry 
Red blood cells 
Reticulocytes 
White blood cells 
Hemoglobin 
Hematocrit 
Platelets 
White blood cells with differential 
(neutrophils, lymphocytes, monocytes, 
eosinophils, basophils) 
Erythrocyte indices (MCV, MCH, MCHC) 
Alanine aminotransferase 
Aspartate aminotransferase 
γ-Glutamyl transferase 
Alkaline phosphatase 
Total bilirubin 
Total protein 
Albumin 
Creatinine 
Amylase 
Lipase 
Blood urea nitrogen 
Uric acid 
Creatine kinase 
Lactate dehydrogenase 
Total cholesterol 
Triglyceride (fasting) 
Low-density lipoprotein (LDL) cholesterol (direct 
measurement) 
High-density lipoprotein (HDL) cholesterol 
high-sensitivity CRP 
Potassium 
Sodium 
Calcium 
Chloride 
Phosphate 
Ferrum 
Other: 
Pregnancy test (serum or urine human chorionic gonadotropin [hCG]) (female subjects of childbearing 
potential) 
 
The central laboratory (Annex 1) will perform laboratory tests listed above except for the 
pregnancy test. Creatinine clearance (Ccr) will be calculated by the sponsor using the 
Cockcroft-Gault equation. 
Cockcroft-Gault equation 
Male: Ccr = {(140 - age) × weight (kg)} / {72 × serum creatinine (mg/dL)} 
Female: Ccr = 0.85 × {(140 - age) × weight (kg)} / {72 × serum creatinine (mg/dL)} 
If subjects experience ALT or AST >3 × ULN, follow-up laboratory tests (at a minimum, 
serum alkaline phosphatase, ALT, AST, total bilirubin, GGT, and INR) should be 
performed within a maximum of 7 days and preferably within 48-72 hours after the 
abnormality was noted. (Refer to Section 7.5 and Section 10.2.3) 
The results of laboratory tests will be returned to the investigator or sub-investigator, who 
is responsible for reviewing and filing these results. The investigator will also maintain a 
copy of the reference ranges including their amendment for the laboratory used. 
9.1.10 Contraception and Pregnancy Avoidance Procedure 
From signing of informed consent and throughout the duration of the study and for 1 
month after the end of the study, female subjects of childbearing potential (i.e., 


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nonsterilized, premenopausal female subjects) who are sexually active must use 
acceptable methods of contraception. Such subjects will be provided with information on 
acceptable methods of contraception as part of the subject informed consent process, and 
will be asked to sign a consent form stating that they understand the requirements for 
avoidance of pregnancy during the course of the study. During the course of the study, 
regular serum/urine hCG pregnancy tests will be performed, and subjects will receive 
continued guidance with respect to avoiding pregnancy as part of the study procedures 
(Appendix A). 
In addition to a negative serum/urine hCG pregnancy test at the start of the screening 
period (Week -6), subjects also must have a negative serum/urine hCG pregnancy test 
immediately before randomization. Subjects must also have a negative serum or urine 
hCG pregnancy test at Week 24 and Week 52 of the treatment period or early termination. 
9.1.11 Pregnancy 
If any subject is found to be pregnant during the study she should be withdrawn and any 
sponsor-supplied drug should be immediately discontinued. 
If the pregnancy occurs during the study period or within 1 month after the end of the 
study, the pregnancy should be reported immediately, using a pregnancy notification 
form, to the contact listed in Annex 1. 
Should the pregnancy occur during or after administration of blinded drug, the 
investigator or sub-investigator must inform the subject of their right to receive treatment 
information. If the subject chooses to receive unblinded treatment information, the 
individual blind should be broken by the investigator or sub-investigator. Subjects 
randomized to placebo who discontinued in Treatment Period I without proceeding to 
Treatment Period II need not be followed. 
If the female subject agrees to the primary care physician being informed, the investigator 
or sub-investigator should notify the primary care physician that the subject was 
participating in a clinical study at the time she became pregnant and provide details of 
treatment the subject received (blinded or unblinded, as applicable). 
All reported pregnancies will be followed up to final outcome under the agreement from 
the female subject, using the pregnancy form. The outcome, including any premature 
termination, must be reported to the sponsor. An evaluation after the birth of the child will 
also be conducted. 
9.1.12 ECG Procedure 
A standard 12-lead ECG will be recorded after a rest of at least 5 minutes. The 
investigator or sub-investigator will interpret the ECG using 1 of the following 
categories: within normal limits, abnormal but not clinically significant, or abnormal and 
clinically significant. 
The following parameters will be recorded on the eCRF from the subject’s ECG trace: 
heart rate, RR interval, PR interval, QRS interval, QT interval, and QTcF interval. 


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9.1.13 Fasting C-peptide 
Fasting C-peptide will be measured in the central laboratory. Blood samples will be 
collected under fasting condition (after at least 10-hour fasting). 
9.1.14 HbA1c (NGSP Value) 
HbA1c will be measured in the central laboratory. 
9.1.15 Fasting Blood Glucose, Fasting Glucagon 
Fasting blood glucose and fasting glucagon will be measured in the central laboratory. 
Blood samples will be collected under fasting condition (after at least 10-hour fasting). 
9.1.16 Glycoalbumin 
Glycoalbumin will be measured in the central laboratory. 
9.1.17 DPP-4 Activity 
DPP-4 activity will be measured in the central laboratory. For study drug blind 
maintenance, refer to Section 8.4. 
9.1.18 Blood Transfusion 
Whether or not the subject has received a blood transfusion from the start of the screening 
period (Week -6) through the end of the study (if yes, the date and type of blood 
transfusion [whole blood, red blood cells, plasma, or platelets]) will be recorded in the 
eCRF. 
9.1.19 Introduction of Hemodialysis 
For subjects not receiving hemodialysis (patients with severe renal impairment), whether 
or not hemodialysis has been introduced between the start of the study drug 
administration (Day 1 of administration of the study drug for Period I) through the end of 
the study (if yes, the date of introduction) will be recorded in the eCRF. 
9.1.20 Presence or Absence of Changes and Compliance of Diet and/or Exercise 
Therapy 
Presence or absence of changes in diet and/or exercise therapy should be recorded in the 
eCRFs. If any instruction for diet and/or exercise therapy has to be changed, the date, 
contents, and reason for the change should be recorded in the source document. 
Instructions for diet and/or exercise therapy (if any) given to subjects by the investigator 
or sub-investigator should be consistent throughout the study. 
Compliance with diet and/or exercise therapy (if any) will be monitored and rated on the 
4-grade scale shown below: 
1. Fully complied (90% or more) 
2. Almost complied (70% or more) 
3. Occasionally complied (50% or more) 


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CONFIDENTIAL 
hypoglycemia and treatment is required, the contents of treatment should also be recorded 
in the eCRF (refer to Section 9.1.21). 
If any hypoglycemic symptoms are observed and no blood glucose values have been 
obtained at appropriate time points, whether or not the symptoms was caused by 
decreased blood glucose (≤ 70 mg/dL) should be assessed and recorded in the eCRF. 
Hypoglycemia will be classified according to the following definitions in reference to the 
“The Guideline for Clinical Evaluation of Hypoglycemic Agents (Revised draft)” [4]. 
• Significant hypoglycemia: an event requiring assistance of another person to 
actively administer carbohydrate, glucagon, or other resuscitative actions. 
• Symptomatic hypoglycemia: an event accompanied by typical symptoms of 
hypoglycemia with a measured plasma glucose concentration of ≤70 mg/dL 
(including self-monitoring of blood glucose values). 
• Asymptomatic hypoglycemia: an event not accompanied by typical symptoms of 
hypoglycemia but with a measured plasma glucose concentration of ≤70 mg/dL 
(including sself-monitoring of blood glucose values). 
• Probable symptomatic hypoglycemia: an event accompanied by symptoms of 
hypoglycemia without a plasma glucose determination but that was presumably 
caused by a plasma glucose concentration of ≤70 mg/dL (including self-monitoring 
of blood glucose values). 
• Relative hypoglycemia: an event accompanied by the typical symptoms of 
hypoglycemia observed in patients with diabetes mellitus is assumed, but with a 
measured plasma glucose concentration >70 mg/dL (including self-monitoring of 
blood glucose values). 
9.1.23 PGx Sample Collection 
One 5-mL whole blood sample for PGx should be collected at the end of the screening 
period (Week 0) from the subject who signed PGx informed consent after the study drug 
was assigned for possible exploratory investigation of markers enabling the prediction of 
drug response. 
PGx sample should not be collected from any subject who has received bone marrow 
transplant or whole blood transfusion within 6 months of any sample collection. 
See the separately created procedure for directions on collecting, handling, and storage of 
PGx samples. 
9.1.24 Pharmacokinetic Sample Collection and Analysis 
9.1.24.1 Collection of Plasma for Pharmacokinetic Sampling 
Blood samples (5 mL/sample) for pharmacokinetic analysis of SYR-472Z will be 
collected in blood sampling tubes containing anticoagulant according to the schedule 
shown in Appendix A, and plasma will be taken. 
Instructions for sample processing and shipment are provided in the separately prepared 
Procedures for Handling of Biological Samples for Drug Concentration Measurement. 


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9.1.27 Hospitalization 
If a subject is hospitalized for 1 week or longer during the study period due to a SAE or 
other reasons, the investigator or sub-investigator will record the hospitalization in the 
eCRF. 
9.2 
Monitoring Subject Treatment Compliance 
Subjects will be required to bring unused study drugs and antidiabetic drugs (if any) to the 
study site at each visit. 
For the SYR-472DB tablets (for use in Treatment Period I) and the SYR-472 25 mg 
tablets (for use in Treatment Period II), the date of dosing will be recorded in the eCRFs. 
For antidiabetic drugs (if any), treatment compliance during the study will be assessed 
and rated on the 4-point scale shown below at each visit: 
1. Fully Complied (90% or more) 
2. Almost complied (70% or more) 
3. Occasionally complied (50% or more) 
4. Rarely complied (less than 50%) 
If a subject is persistently noncompliant with the study drug (e.g., 70% of the allocated 
medication for the period since the last visit), it may be appropriate to withdraw the 
subject from the study. The authorized study personnel conducting the re-education must 
document the process in the subject source records. 
9.3 
Schedule of Observations and Procedures 
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 Screening (Week -6 to Week 0) 
At the start of the screening period (Week -6), subjects will be screened within 49 to 35 
days prior to study drug administration. 
Subjects will be screened in accordance with predefined inclusion and exclusion criteria 
as described in Section 7.0. 
Subjects will be randomized at the end of the screening period (Week 0). 
See Section 9.1.25 for procedures for documenting screening failures. 
9.3.2 Randomization 
If the subject has satisfied all of the inclusion criteria and none of the exclusion criteria for 
randomization, the subject should be randomized as described in Section 8.2. 
Subjects will be instructed on when to take the first dose of study drug as described in 
Section 6.1. 


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9.3.3 Treatment Period 
All specified procedures will be performed at each visit. 
9.3.4 Week 52 in the Treatment Period or Early Termination 
All procedures scheduled for the final visit will be performed at Week 52 of the treatment 
period. 
For subjects prematurely withdrawn from the study during the treatment period, all 
procedures scheduled for Week 52 will be performed within 7 days after the final dose of 
the study drug (reckoned from the day after the final dose) whenever possible. 
For all subjects receiving study drug, the investigator or sub-investigator must complete 
the End of Study eCRF page. 
9.3.5 Follow-up 
All procedures scheduled for the end of the follow-up period will be performed at the 21st 
day after the final dose of the study drug (reckoned from the day after the final dose). 
For subjects who discontinued study treatment, all procedures scheduled for the end of 
the follow-up period should be performed wherever possible. 
9.3.6 Post Study Care 
The study drug will not be available upon completion of the subject’s participation in the 
study. 
9.4 
Biological Sample Retention and Destruction 
Samples of 5-mL whole blood collected for PGx will be stored frozen at the storage site 
for PGx samples (Annex 1). 
The collected samples will be retained for 20 years from the day when a first PGx sample 
was collected during the study. 
When subjects request disposal of a stored sample during the retention period, the site 
will ask the storage site for PGx samples (Annex 1) to destroy the sample via the sponsor 
according to the procedure. The storage site for PGx samples (Annex 1) will destroy the 
sample in accordance with the procedure, and notify the site and sponsor. However, any 
samples should not be destroyed if all the documents (including medical records) have 
been destroyed which could identify the subject and it is impossible to link the sample to 
the subject. 
Even if the sample can be linked to the subject, when PGx investigation has been 
conducted, the remaining samples will be destroyed and the results of PGx investigation 
of anonymized subject will be retained by the sponsor. 
The sponsor will build a management system required for protection of the subject’s 
personal information, define standards for collecting store and destruction of samples, 
and prepare appropriate procedures. 


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10.0 
PRETREATMENT EVENTS AND ADVERSE EVENTS 
10.1 
Definitions 
10.1.1 PTEs 
A PTE is defined as any untoward medical occurrence in a clinical investigation subject 
who has signed informed consent to participate in a study but prior to administration of 
any study drug; it does not necessarily have to have a causal relationship with study 
participation. 
10.1.2 AEs 
An AE is defined as any untoward medical occurrence in a clinical investigation subject 
administered a drug; it does not necessarily have to have a causal relationship with this 
treatment. 
An AE can therefore be any unfavorable and unintended sign (e.g., a clinically significant 
abnormal laboratory finding), symptom, or disease temporally associated with the use of 
a drug whether or not it is considered related to the drug. 
10.1.3 Additional Points to Consider for PTEs and AEs 
An untoward finding generally may: 
• 
Indicate a new diagnosis or unexpected worsening of a pre-existing condition. 
(Intermittent events for pre-existing conditions underlying disease should not be 
considered PTEs or AEs.) 
• 
Necessitate therapeutic intervention. 
• 
Require an invasive diagnostic procedure. 
• 
Require discontinuation or a change in dose of study drug or a concomitant 
medication. 
• 
Be considered unfavorable by the investigator for any reason. 
Diagnoses 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 a PTE(s) or as an AE(s). 
Laboratory values and ECG findings: 
Changes in laboratory values or ECG parameters are only considered to be PTEs or AEs 
if they are judged to be clinically significant (i.e., if some action or intervention is 
required or if the investigator or sub-investigator judges the change to be beyond the 
range of normal physiologic fluctuation). A laboratory re-test and/or continued 
monitoring of an abnormal value 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. 


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If abnormal laboratory values or ECG findings are the result of pathology for which there 
is an overall diagnosis (e.g., increased creatinine in renal failure), the diagnosis only 
should be reported appropriately as a PTE or as an AE. 
Pre-existing conditions: 
Pre-existing conditions (present at the time of signing of informed consent) are 
considered concurrent medical conditions and should NOT be recorded as PTEs or AEs. 
Baseline evaluations (e.g., laboratory tests, ECG, X-rays) should NOT be recorded as 
PTEs unless related to study procedures. However, any abnormal finding related to study 
procedures (e.g., bruise after blood draw) should be recorded as a PTE. If the subject 
experiences a worsening or complication of a concurrent condition, the worsening or 
complication should be recorded appropriately as a PTE (worsening or complication 
occurs before start of study drug) or an AE (worsening or complication occurs after start 
of study drug). Investigators or sub-investigator should ensure that the event term 
recorded captures the change in the condition from baseline (e.g., “worsening of 
hypertension”). 
If a subject has a pre-existing episodic condition (e.g., asthma, epilepsy) any occurrence 
of an episode should only be captured as a PTE/AE if the episodes become more frequent, 
serious or severe in nature. If a subject has a degenerative concurrent condition (e.g., 
cataracts, rheumatoid arthritis), worsening of the condition should only be captured as a 
PTE/AE if occurring to a greater extent to that which would be expected. The investigator 
or sub-investigator should ensure that the AE term recorded captures the change in the 
condition (e.g., “worsening of…”). 
Worsening of PTEs or AEs: 
If the subject experiences a worsening or complication of a PTE after starting 
administration of the study drug, the worsening or complication should be recorded 
appropriately as an AE. The investigator or sub-investigator should ensure that the AE 
term recorded captures the change in the condition (e.g., “worsening of…”). 
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. The investigator or 
sub-investigator should ensure that the AE term recorded captures the change in the 
condition (e.g., “worsening of…”). 
Changes in intensity of AEs /Serious PTEs: 
If the subject experiences changes in intensity of an AE/serious PTE, the event should be 
captured once with the maximum intensity recorded. 
Preplanned surgeries or procedures: 
Preplanned procedures (surgeries or therapies) that were scheduled prior to signing of 
informed consent are not considered PTEs or AEs. However, if a preplanned procedure is 
performed early (e.g., as an emergency) due to a worsening of the pre-existing condition, 
the worsening of the condition should be captured appropriately as a PTE or an AE. 
Complications resulting from any planned surgery should be reported as AEs. 


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Elective surgeries or procedures: 
Elective procedures performed where there is no change in the subject’s medical 
condition (e.g., cosmetic surgery) should not be recorded as PTEs or 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 or sub-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 PTEs or AEs, but instead will be documented on an Overdose page of the 
eCRF. Any manifested side effects will be considered PTEs or AEs and will be recorded 
on the AE page of the eCRF. 
10.1.4 SAEs 
An SAE is defined as any untoward medical occurrence that at any dose: 
1. Results in DEATH. 
2. Is LIFE THREATENING* 
* 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. 
3. Requires inpatient HOSPITALIZATION or prolongation of existing hospitalization. 
4. Results in persistent or significant DISABILITY/INCAPACITY. 
5. Leads to a CONGENITAL ANOMALY/BIRTH DEFECT. 
6. Is an IMPORTANT MEDICAL EVENT that satisfies any of the following: 
• 
May require intervention to prevent items 1 through 5 above. 
• 
May expose the subject to danger, even though the event is not immediately life 
threatening or fatal or does not result in hospitalization. 
• 
Includes any event or synonym described in the Takeda Medically Significant AE 
List (Table 10.a). 


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Table 10.a 
Takeda Medically Significant AE List 
Acute respiratory failure/acute respiratory 
distress syndrome 
Torsade de pointes / ventricular fibrillation / 
ventricular tachycardia 
Malignant hypertension 
Convulsive seizure 
Agranulocytosis 
Aplastic anemia 
Toxic epidermal necrolysis/Stevens-Johnson 
syndrome 
Hepatic necrosis 
Acute liver failure 
Anaphylactic shock 
Acute renal failure 
Pulmonary hypertension 
Pulmonary fibrosis 
Neuroleptic malignant syndrome / malignant 
hyperthermia 
Spontaneous abortion / stillbirth and fetal death 
Confirmed or suspected transmission of infectious 
agent by a medicinal product 
Confirmed or suspected endotoxin shock 
PTEs that fulfill 1 or more of the serious criteria above are also to be considered SAEs 
and should be reported and followed up in the same manner (see Sections 10.2.2 and 
10.3). 
10.1.5 Adverse Events of Special Interest 
An AE of Special Interest (AESI) (serious or non-serious) is 1 of scientific and medical 
concern specific to the compound or program, for which ongoing monitoring and rapid 
communication by the investigator to Takeda may be appropriate. Such events may 
require further investigation in order to characterize and understand them and would be 
described in protocols and instructions provided for investigators as to how and when 
they should be reported to the sponsor (refer to Section 10.2.1.3). 
• AESIs: hypoglycemia-related AEs, intestinal obstruction-related AEs, acute 
pancreatitis-related AEs, and QT/QTc interval prolongation-related AEs 
<Hypoglycemia-related AEs> 
Hypoglycemia-related AEs are defined as AESIs since special attention is generally paid 
to these events in patients with diabetes mellitus using antidiabetic drugs and severe 
hypoglycemia has been reported in combination therapy with other DPP-4 inhibitors and 
insulin preparations. 
<Intestinal obstruction-related AEs> 
Intestinal obstruction-related AEs are defined as AESIs since adverse reaction reports on 
intestinal obstruction with the use of incretin-related drugs (GLP-1 receptor agonists and 
other DPP-4 inhibitors) in the same class as SYR-472 have been accumulated. 
<Acute pancreatitis-related AEs> 
Acute pancreatitis-related AEs are defined as AESIs since adverse reaction reports on 
acute pancreatitis with the use of incretin-related drugs in the same class as SYR-472 
have been accumulated. 
<QT/QTc interval prolongation-related AEs> 
In thorough QT/QTc study (Study CPH-005), QT/QTc interval prolongation was 
reported in the SYR-472 800 mg group, although it was not reported in the SYR-472 


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200 mg group; therefore, QT/QTc interval prolongation-related AEs are defined as 
AESIs. 
10.1.6 Intensity of PTEs and 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 causes the subject discomfort and interrupts the subject’s usual activities. 
Severe: 
The event causes considerable interference with the subject’s usual activities. 
10.1.7 Causality of AEs 
The relationship of each AE to study drugs will be assessed using the following 
categories: 
Related: 
An AE that follows a reasonable temporal sequence from administration of a drug 
(including the course after withdrawal of the drug), or for which possible involvement of the 
drug cannot be ruled out, although factors other than the drug, such as underlying diseases, 
complications, concomitant drugs and concurrent treatments, may also be responsible. 
Not Related: 
An AE that does not follow a reasonable temporal sequence from administration of a drug 
and/or that can reasonably be explained by other factors, such as underlying diseases, 
complications, concomitant drugs and concurrent treatments. 
10.1.8 Relationship to Study Procedures 
Relationship (causality) to study procedures should be determined for all PTEs and AEs. 
The relationship should be assessed as Related if the investigator or sub-investigator 
considers that there is a reasonable possibility that an event is due to a study procedure. 
Otherwise, the relationship should be assessed as Not Related. 
10.1.9 Start Date 
The start date of AEs/PTEs is determined based on the following criteria: 
AE/PTE 
Start Date 
Signs, symptoms, and diseases 
(diagnosis) 
Date when the subject and/or the investigator or sub-investigator first 
notices the sign or symptom of the AE. 
Asymptomatic disease 
Date when a definite diagnosis is determined based on the results of 
diagnostic testing: 
Even if obsolete findings are indicated based on the test findings or the 
approximate time of onset can be estimated, the date when a definite 
diagnosis is made should be recorded. 
Worsening of concurrent medical 
conditions or PTE 
Date when the subject or the investigator or sub-investigator first 
notices worsening of the disease or symptom. 
Normal in the initial assessment 
after signing informed consent 
but abnormal in the subsequent 
assessment (for PTEs) 
Abnormal in the assessment after 
the start of study drug (for AEs) 
Date when the test is performed in which a clinically significant 
abnormal test value is observed. 


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Abnormal in the initial 
assessment after signing 
informed consent and has 
worsened at the subsequent 
assessment (in case of PTEs) 
Abnormal in the assessment at 
the start of study drug and has 
worsened in the subsequent 
assessment (in case of AEs) 
Date when the test is performed in which a medically significant 
elevation, reduction, increase, or decrease in clinical test values is 
observed. 
10.1.10 Stop Date 
The stop date of the AE/PTE is the date at which the subject recovered, the event resolved 
but with sequelae or the subject died. The event not has resolved at the end of the study 
will be assessed as ongoing. 
10.1.11 Frequency 
Episodic AEs/PTEs (e.g., constipation, diarrhea, or vomiting) or those which occur 
repeatedly over a period of consecutive days are intermittent. All other events are 
continuous. 
10.1.12 Action Concerning Study Drug 
Action taken for the study drug is classified and defined as follows: 
Drug withdrawn 
A study drug is stopped due to the particular AE (including withdrawal at the 
discretion of subjects). 
Dose not changed 
The dose is not changed even after the occurrence of the particular AE. 
This shall apply in case the study drug is stopped or the dose is reduced or increased 
due to another AE. 
This shall also apply, for example, in case the study drug is stopped or the dose is 
reduced for any reason other than intervention for the particular AE, such as the 
subject’s negligence. 
Unknown 
For example, attempts to contact the subject are unsuccessful and the course of the 
particular AE after the start day cannot be followed. 
Not Applicable 
For example, the study drug has already been completed or stopped before the onset 
of the particular AE. 
Dose interrupted 
The study drug is stopped (suspended) due to the particular AE and resumed 
afterwards (including temporary withdrawal at the discretion of subjects). 
10.1.13 Outcome 
The outcome of AEs/PTEs is classified as follows: 
Classification 
Assessment criteria 
Recovered/resolved 
•The diagnosis or signs/symptoms has disappeared or resolved. 
•The abnormal laboratory value has improved to the normal range or the value 
at baseline (AEs), or at the first assessment after signing of informed consent 
(PTEs). 
•The event was recorded as another AE in the eCRF due to increased intensity. 


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Classification 
Assessment criteria 
Recovering/resolving 
•The intensity is lowered by 1 or more stages. 
•The diagnosis or sign/symptom has almost disappeared. 
•The abnormal laboratory value improved, but has not returned to the normal 
range or to baseline (AEs) or to the first assessment after signing of informed 
consent (PTEs). 
•The subject died from a cause other than the particular AE/PTE with the 
condition remaining “recovering/resolving” (in this case, no need to record the 
date of death). 
Not recovered/not 
resolved 
•There is no change in the diagnosis or signs/symptoms, or laboratory values. 
•The intensity of the diagnosis or signs/symptoms, or laboratory value on the 
last day of the observed study period has got worse than when it started. 
•An irreversible congenital anomaly. 
•The subject died from another cause with the particular AE/PTE state 
remaining “Not recovered/not resolved” (in this case, no need to record the 
date of death). 
Resolved with sequelae 
•Dysfunction that interferes with the subject's daily life is observed. 
Fatal 
•There is a direct relationship between the death and the AE/PTE. 
A “direct relationship” means that the AE/PTE caused or apparently 
contributed to the death. 
•The outcome of another AE/PTE reported in the same subject that is not 
determined (considered or estimated) to cause the death is not assessed as 
“fatal.” 
•If the outcome is “fatal,” the date of death should be recorded. 
Unknown 
•The course the AE/PTE after the start day cannot be followed up as specified 
in the protocol due to hospital change or residence change. 
10.2 
Procedures 
10.2.1 Collection and Reporting of AEs 
10.2.1.1 PTE and AE Collection Period 
Collection of PTEs will commence from the time the subject signs the informed consent 
to participate in the study and continue until the subject is first administered study drug 
(Visit 3). For subjects who discontinue prior to study drug administration, PTEs are 
collected until the subject discontinues study participation. 
Collection of AEs will commence from the time that the subject is first administered 
study drug (Visit 3). Routine collection of AEs will continue until Visit 18. 
10.2.1.2 PTE and AE Reporting 
At each study visit, the investigator or sub-investigator will assess whether any subjective 
AEs have occurred. A neutral question, such as “How have you been feeling since your 
last visit?” may be asked. Subjects may report AEs occurring at any other time during the 
study. 
Subjects experiencing a serious PTE must be monitored until the symptoms subside and 
any clinically relevant changes in laboratory values have returned to baseline or there is a 
satisfactory explanation for the change (permanent or irreversible PTEs). Non-serious 


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PTEs, related or unrelated to the study procedure, need not to be followed-up for the 
purposes of the protocol. 
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 (permanent or irreversible AEs). All PTEs and AEs 
will be documented in the PTE/AE page of the eCRF, whether or not the investigator or 
sub-investigator concludes that the event is related to the drug treatment. The following 
information will be documented for each event: 
• Event term. 
• Start and stop date. 
• Frequency. 
• Intensity. 
• Causal relationship between the event and administration of study drug(s) (related or 
not related). 
• Action concerning study drug. 
• Outcome of event. 
• Causal relationship to study procedure(s) (if related, include the details of the 
suspected procedure). 
• Seriousness. 
AEs and serious PTEs should be followed up until the AEs/PTEs have resolved or 
follow-up is no longer necessary in the opinion of the investigator or sub-investigator. 
10.2.1.3 AESI Reporting 
If any AESI, which occurs during the treatment period or the follow-up period, is 
considered to be clinically significant based on the criteria below, it should be reported to 
the sponsor (Annex 1) immediately or within 1 business day of first onset or subject’s 
notification of the event. In addition, AESI Form should be completed by the investigator, 
and reported to the Safety Information Emergency Call Center (Annex 1) within 10 
business days. 
The original AESI Form should be submitted to the sponsor. 
The criteria for AESIs (hypoglycemia-related AEs, intestinal obstruction-related AEs, 
acute pancreatitis-related AEs, and QT/QTc interval prolongation-related AEs) are as 
described below. If any AE considered to be related to these condition occurs, whether or 
not to handle it as an AESI should be considered. 
<Hypoglycemia-related AEs> 
AEs related to hypoglycemia 
<Intestinal obstruction-related AEs> 


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Intestinal obstruction, ileus, subileus, gastrointestinal obstruction, 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, disturbance of consciousness, convulsion, ECG QT prolonged, and 
AEs related to these conditions. 
The AESIs have to be recorded as AEs in the eCRF. An evaluation form along with all 
other required documentation must be submitted to the sponsor. 
10.2.2 Collection and Reporting of SAEs 
When an SAE occurs through the AE collection period it should be reported according to 
the following procedure. Any PTE which meets the SAE criteria described in Section 
10.1.4 should be reported in the same manner as SAEs: 
An SAE should be reported to the sponsor (Annex 1) within 1 business day of first onset 
or subject’s notification of the event. The investigator should submit the completed SAE 
form within 10 calendar days. 
The information to be reported within 1 business day should be completed as fully as 
possible but contain, at a minimum: 
• A short description of the event and the reason why the event is categorized as 
serious. 
• Subject identification number. 
• Investigator’s or sub-investigator’s name. 
• Name of the study drug(s) 
• Causality assessment. 
Any SAE spontaneously reported to the investigator or sub-investigator’s following the 
AE collection period should be reported to the sponsor. 
10.2.3 Reporting of Abnormal Liver Function Tests 
If a subject is noted to have ALT or AST >3 × ULN and total bilirubin > 2 × ULN for 
which an alternative etiology has not been identified, the event should be recorded as an 
SAE and reported as per Section 10.2.2. The investigator or sub-investigator must contact 
sponsor, and investigate the details of the subject and possible alternative etiologies 
immediately, such as acute viral hepatitis A or B or other acute liver disease or medical 
history/concurrent medical conditions. Follow-up laboratory tests as described in Section 
9.1.9 must also be performed. 


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10.3 
Follow-up of SAEs 
If information not available at the time of the detailed report becomes available at a later 
date, the investigator or sub-investigator should complete a follow-up SAE form or 
provide other written documentation and submit it to the sponsor (Annex 1) immediately. 
Copies of any relevant data from the hospital notes (e.g., ECGs, laboratory tests, 
discharge summary, postmortem results) should be sent to the addressee, if requested by 
the sponsor or IRB. 
All SAEs should be followed up until resolution or permanent outcome of the event. 
10.3.1 Safety Reporting to Investigators, IRBs, and Regulatory Authorities 
The sponsor will be responsible for reporting all suspected unexpected serious adverse 
reactions (SUSARs) and any other applicable SAEs to regulatory authorities, 
investigators and IRBs/the head of the study site, as applicable, in accordance with 
national regulations in the countries where the study is conducted. Relative to the first 
awareness of the event by/or further provision to the sponsor or sponsor’s designee 
(contract research organization [CRO]), SUSARs will be submitted to the regulatory 
authorities as expedited report within 7 days for fatal and life-threatening events and 15 
days for other serious events. The sponsor will also prepare an expedited report for other 
safety issues where these might materially alter the current benefit-risk assessment of a 
study drug or that would be sufficient to consider changes in the study drug 
administration or in the overall conduct of the trial. The study site also will forward a 
copy of all expedited reports to his or her IRB. 


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11.0 
STUDY-SPECIFIC COMMITTEES 
No steering committee, data safety monitoring committee, or clinical endpoint committee 
will be used in this study. 


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12.0 
DATA HANDLING AND RECORDKEEPING 
The full details of procedures for data handling will be documented in the Data 
Management Plan. AEs, PTEs, medical history, and concurrent conditions will be coded 
using the Medical Dictionary for Regulatory Activities (MedDRA). Drugs will be coded 
using the World Health Organization Drug Dictionary. 
12.1 
CRFs 
Completed eCRFs are required for each subject who signs an informed consent. 
The sponsor or its designee will supply investigative sites with access to eCRFs. The 
sponsor will make arrangements to train appropriate site staff in the use of the eCRF. 
These forms are used to transmit the information collected in the performance of this 
study to the sponsor and regulatory authorities. eCRFs must be completed in Japanese. 
Data are transcribed directly onto eCRFs. 
The investigator or sub-investigator should complete assessments scheduled for 
Treatment Period I prior to starting study drug administration in Treatment Period II; the 
schedule of assessments should not be changed unless there is an appropriate reason. 
Corrections to eCRFs are recorded in an audit trail that captures the old information, new 
information, identification of the person making the correction, date the correction was 
made, and the reason for change. 
The investigator must review the eCRFs for completeness and accuracy and must sign 
and date the appropriate eCRFs as indicated. Furthermore, the investigator must retain 
full responsibility for the accuracy and authenticity of all data entered on the eCRFs. 
The following data will not be recorded directly into the eCRFs: 
• Laboratory parameters measured in the central clinical laboratory 
After the lock of the clinical study database, any change of, modification of or addition to 
the data on the eCRFs should be made by the investigator or sub-investigator with use of 
change and modification records of the eCRFs (Data Clarification Form) provided by the 
sponsor. The principal investigator must review the data change for completeness and 
accuracy, and must sign, or sign and seal, and date. 
eCRFs will be reviewed for completeness and acceptability at the study site during 
periodic visits by study monitors. The sponsor or its designee will be permitted to review 
the subject’s medical and hospital records pertinent to the study to ensure accuracy of the 
eCRFs. The completed (e)CRFs are the sole property of the sponsor and should not be 
made available in any form to third parties, except for authorized representatives of 
appropriate governmental health or regulatory authorities, without written permission of 
the sponsor. 
12.2 
Record Retention 
The investigator and the head of the institution agree to keep the records stipulated in 
Section 12.1 and documents include the study-specific documents, identification log of 
all participating subjects, medical records, source worksheets, all original signed and 
dated informed consent forms, electronic copy of eCRFs including the audit trail, and 
detailed records of drug disposition to enable evaluations or audits from regulatory 


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authorities, the sponsor or its designees. The investigator and the head of the institution 
are required to retain essential relevant documents until the day specified as 1) or 2) 
below, whichever comes later. However, if the sponsor requests a longer time period for 
retention, the head of the institution should discuss how long and how to retain those 
documents with the sponsor. 
1) The day on which marketing approval of the study drug is obtained (or the day 
3 years after the date of notification in the case that the investigation is discontinued.) 
2) The day 3 years after the date of early termination or completion of the clinical study. 
In addition, the investigator and the head of the institution should retain the essential 
relevant documents until the receipt of a sponsor-issued notification to state the retention 
is no longer required. 


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13.0 
STATISTICAL METHODS 
13.1 
Statistical and Analytical Plans 
A statistical analysis plan (SAP) will be prepared and finalized prior to unblinding of 
subject’s treatment assignment. This document will provide further details regarding the 
definition of analysis variables and analysis methodology to address all study objectives. 
A blinded data review will be conducted prior to unblinding of subject’s treatment 
assignment. This review will assess the accuracy and completeness of the study database, 
subject evaluability, and appropriateness of the planned statistical methods. 
13.1.1 Analysis Sets 
In this study, 3 kinds of analysis sets are defined: full analysis set (FAS), per protocol set 
(PPS), and safety analysis set. The FAS, the main analysis set used for efficacy analysis, 
is defined as all subjects who were randomized and received at least 1 dose of the study 
drug. The safety analysis set, is defined as all subjects who received at least 1 dose of the 
study drug. The definition of each analysis set will be described in the Handling Rules for 
Analysis Data. 
The sponsor will verify the validity of the definitions of the analysis sets as well as the 
rules for handling data and supplement descriptions about handling of the unspecified 
issues, consulting a medical expert as needed. The Handling Rules for Analysis Data 
must be finalized prior to database lock. 
13.1.2 Analysis of Demographics and Other Baseline Characteristics 
Key demographics and other baseline characteristics will be summarized for each 
treatment group and for overall treatment groups using the all randomized subjects. 
13.1.3 Efficacy Analysis 
(1) Primary endpoint and analytical methods 
[Primary endpoint] 
Change in HbA1c at the end of Treatment Period I from the end of the screening period 
(Week 0) 
[Primary analysis] 
The following analyses will be performed in the FAS. 
The population mean change in HbA1c at the end of Treatment Period I from the end of 
the screening period (Week 0) will be compared between SYR-472 25 mg group and 
placebo group based on an analysis of covariance (ANCOVA) model for the change in 
HbA1c at the end of Treatment Period I from the end of the screening period (Week 0) 
with factors of treatment group and HbA1c at the end of the screening period (Week 0). 
The same ANCOVA model will be used to calculate the least square (LS) mean and the 
two-sided 95% confidence interval (CI) for each treatment group, as well as the 
intergroup difference in the LS mean between the treatment groups (SYR-472 25 mg 
group - placebo group) and the two-sided 95% CI. 


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[Secondary analysis] 
For the change in HbA1c at the end of Treatment Period I from the end of the screening 
period (Week 0), summary statistics (number of subjects, mean, standard deviation, 
maximum, minimum, and quartiles; hereinafter the same) and two-sided 95% CI for the 
mean will be calculated for each treatment group, as well as the intergroup difference in 
the mean between treatment groups (SYR-472 25 mg group - placebo group) and the 
two-sided 95% CI. 
In addition, the same analyses as the primary analysis and the secondary analysis 
described above will be performed using the PPS to evaluate the robustness of the results 
in terms of a sensitivity analysis. 
[Adjustment for covariates] 
The following analyses will be performed in the FAS. 
The treatment effect of SYR-472 25 mg will be assessed in consideration of the effects of 
baseline characteristics based on the ANCOVA model for the change in HbA1c at the end 
of Treatment Period I from the end of the screening period (Week 0) with factors of 
treatment group, HbA1c at the end of the screening period (Week 0) and baseline 
characteristics that may affect the primary endpoint at the blind data review. 
(2) Secondary Endpoints and Analysis Methods 
[Secondary endpoints] 
HbA1c, fasting blood glucose, glycoalbumin 
[Analytical methods] 
The following analyses will be performed in the FAS. 
For each endpoint, summary statistics and two-sided 95% CI for the mean will be 
calculated for each treatment group at each time point. In addition, summary statistics for 
the change from the end of the screening period (Week 0) and two-sided 95% CI for the 
mean will be calculated for each treatment group at each time point, and the intergroup 
difference in the mean between treatment groups (SYR-472 25 mg group - placebo 
group) and the two-sided 95% CI will be calculated at each time point in Treatment 
Period I. 
For the proportions of subjects who achieved an HbA1c less than 6.0%, 7.0%, or 8.0% at 
the end of Treatment Period I and Treatment Period II, the proportions and the two-sided 
95% CIs will be calculated for each treatment group, and the intergroup difference in the 
proportions between treatment groups (SYR-472 25 mg group - placebo group) and the 
two-sided 95% CIs will be calculated at the end of Treatment Period I. In the analysis of 
each proportion, subjects who did not achieve the relevant target HbA1c at the end of the 
screening period (Week 0) will be included in the analysis. 
(3) Additional efficacy endpoints 
See Section 5.2. 
(4) Method of data conversion and handling of missing data 
Details will be specified separately in the Handling Rules for Analysis Data and the SAP. 


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(5) Significance level and confidence coefficient 
• Significance level: 5% (two-sided tests) 
• Confidence coefficient: 95% (two-sided) 
13.1.4 Safety Analysis 
The following analyses will be performed in the Safety Analysis Set. 
(1) Primary endpoint and analytical methods 
[Primary endpoint] 
AEs 
[Analytical methods] 
A treatment-emergent adverse event (TEAE) is defined as an AE whose date of onset 
occurs on or after the start of study drug administration. 
The following analyses will be performed for each treatment group for TEAEs that occur 
before the start of the study drug for Treatment Period II, and for those that occur after the 
start of SYR-472 25 mg tablet. In the analysis of TEAEs occurring after the start of 
SYR-472 25 mg tablet, subjects who received SYR-472 25 mg tablet will be included in 
the analyses. 
TEAEs will be coded using MedDRA dictionary. Frequency distributions will be 
provided using System Organ Class and Preferred Term for each treatment group as 
follows: 
• All TEAEs 
• Drug-related TEAEs 
• Intensity of TEAEs 
• Intensity of drug-related TEAEs 
• TEAEs leading to study drug discontinuation 
• Serious TEAEs 
• TEAEs over time 
(2) Secondary endpoints and analytical methods 
[Secondary endpoints] 
Vital signs, 12-lead ECGs, clinical laboratory tests 
[Analytical methods] 
For continuous variables, the observed values and change from the end of the screening 
period (Week 0) will be summarized using descriptive statistics for each treatment group 
at each time point. In addition, case plots over time for observed values will be presented 
for each treatment group. 
For 12-lead ECG findings and laboratory tests classified as "Low", "Normal" or "High" 
based on the normal reference ranges, shift tables showing the number of subjects in each 


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category at the end of the screening period (Week 0) and each post-baseline time point 
will be presented for each treatment group. 
(3) Additional endpoint and analysis methods 
[Additional endpoint] 
Hypoglycemia 
[Analytical methods] 
The following analyses will be performed for hypoglycemia that occur prior to the start of 
the study drug for Treatment Period II by treatment group, and for those occurring after 
the start of SYR-472 25 mg tablet. Subjects who concomitantly receive insulin 
preparation will be included in these analyses of hypoglycemia, while subjects who 
concomitantly receive insulin preparation and SYR-472 25 mg tablet will be included in 
the analysis of hypoglycemia occurring after the start of SYR-472 25 mg tablet. 
• Severe hypoglycemia 
• Documented symptomatic hypoglycemia 
• Asymptomatic hypoglycemia 
• Probable symptomatic hypoglycemia 
• Relative hypoglycemia 
13.2 
Interim Analysis and Criteria for Early Termination 
No interim analysis is planned. 
13.3 
Determination of Sample Size 
Randomized subjects: 53 subject per group, 106 in total 
(Changed as of 12 September 2016) 
<Justification of sample size> 
In Study CCT-002, the intergroup difference (two-sided 95% CI) in the mean change in 
HbA1c (JDS value) at the end of the treatment period (value at the end of the treatment 
period - value at the end of the screening period) between the SYR-472 100 mg group and 
placebo group was -0.56 ([-0.753, -0.367])%. In the same study, the standard deviation of 
the change in HbA1c (JDS value) at the end of the treatment period (value at the end of 
the treatment period - value at the end of the screening period) for each treatment group 
ranged from 0.523% to 0.628%. 
In this study, which will administer SYR-472 at a dose of 25 mg once weekly to patients 
with type 2 diabetes mellitus complicated by severe renal impairment or end-stage renal 
failure, the intergroup difference in the mean change in HbA1c at the end of Treatment 
Period I from the end of the screening period (Week 0) between the SYR-472 25 mg 
group and placebo group is assumed to be -0.40%, given that the efficacy of SYR-472 25 
mg in this study is similar to that of SYR-472 100 mg administered once weekly to 
patients with type 2 diabetes mellitus not complicated by renal impairment. The common 
standard deviation in each treatment group is assumed to be 0.80%. 


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Based on these assumptions, 86 subjects per group will be required to provide a 90% 
power in a two-sample t-test with a significance level of 5% (two-sided). Therefore, the 
sample size was set at 90 as randomized subjects per group at the start of the study 
allowing for the possibility that there exit some subjects whose primary endpoint cannot 
be evaluated. 
However, achievement of the sample size as originally planned at the start of the study 
was found difficult because there were more than expected numbers of candidate subjects 
who did not provide consent and who dropped out during screening after providing 
consent for the study. It was therefore decided to change some of the inclusion and 
exclusion criteria for this study. After these changes, the ultimate number of subjects 
randomized and evaluable for the primary endpoints are expected to be around 53 and 51, 
respectively, per group. 
Assuming the number of subjects per group as 51 under these assumptions, the study will 
provide a 70.6% power in a two-sample t-test with a significance level of 5% (two-sided). 


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14.0 
QUALITY CONTROL AND QUALITY ASSURANCE 
14.1 
Study-Site Monitoring Visits 
Monitoring visits to the study site will be made periodically during the study to ensure 
that all aspects of the protocol are followed. Source documents will be reviewed for 
verification of data recorded on the eCRFs. Source documents are defined as original 
documents, data, and records. The investigator and the head of the institution guarantee 
access to source documents by the sponsor or its designee and by the IRB. 
All aspects of the study and its documentation will be subject to review by the sponsor or 
designee, including but not limited to the Investigator’s Binder, study drug, subject 
medical records, informed consent documentation, and review of eCRFs and associated 
source documents. It is important that the investigator or sub-investigator and other study 
personnel are available during the monitoring visits and that sufficient time is devoted to 
the process. 
14.2 
Protocol Deviations 
The investigator or sub-investigator can deviate and change from the protocol for any 
medically unavoidable reason, for example, to eliminate an immediate hazard to study 
subjects, without a prior written agreement with the sponsor or a prior approval from IRB. 
In the event of a deviation or change, the principal investigator should notify the sponsor 
and the head of the site of the deviation or change as well as its reason in a written form, 
and then retain a copy of the written form. When necessary, the principal investigator 
may consult and agree with the sponsor on a protocol amendment. If the protocol 
amendment is appropriate, the amendment proposal should be submitted to the head of 
the site as soon as possible and an approval from IRB should be obtained. 
The investigator or sub-investigator should document all protocol deviations. 
14.3 
Quality Assurance Audits and Regulatory Agency Inspections 
The study site also may be subject to quality assurance audits by the sponsor or designees. 
In this circumstance, the sponsor-designated auditor will contact the site in advance to 
arrange an auditing visit. The auditor may ask to visit the facilities where laboratory 
samples are collected, where the medication is stored and prepared, and any other facility 
used during the study. In addition, there is the possibility that this study may be inspected 
by regulatory agencies, including those of foreign governments (e.g., the FDA, the United 
Kingdom Medicines and Healthcare products Regulatory Agency). If the study site is 
contacted for an inspection by a regulatory body, the sponsor should be notified 
immediately. The investigator and the head of the institution guarantee access for quality 
assurance auditors to all study documents as described in Section 14.1. 


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15.0 
ETHICAL ASPECTS OF THE STUDY 
This study will 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 ICH Harmonised Tripartite Guideline for GCP. Each 
investigator will conduct the study according to applicable regulatory requirements and 
align his or her conduct in accordance with the “Responsibilities of the Investigator” that 
are listed in Appendix B. 
15.1 
IRB Approval 
IRBs must be constituted according to the applicable requirements of each participating 
region. The sponsor or designee will require documentation noting all names and titles of 
members who make up the respective IRB. If any member of the IRB has direct 
participation in this study, written notification regarding his or her abstinence from 
reviewing and voting must also be obtained. 
The sponsor or designee will supply relevant documents for submission to the respective 
IRB for the protocol’s review and approval. This protocol, the Investigator’s Brochure, a 
copy of the informed consent form, and, if applicable, subject recruitment materials 
and/or advertisements and other documents required by all applicable laws and 
regulations, must be submitted to a central or local IRB for approval. The IRB’s written 
approval of the protocol and subject informed consent must be obtained and submitted to 
the sponsor or designee before commencement of the study (i.e., before conclusion of 
study contract). The IRB approval must refer to the study by exact protocol title, number, 
and version date; identify versions of other documents (e.g., informed consent form) 
reviewed; and state the approval date. The sponsor will notify site once the sponsor has 
confirmed the adequacy of site regulatory documentation. Until the site receives 
notification, no protocol activities, including the informed consent procedure, may occur. 
Sites must adhere to all requirements stipulated by their respective IRB. This may include 
notification to the IRB regarding protocol amendments, updates to the informed consent 
form, recruitment materials intended for viewing by subjects, local safety reporting 
requirements, reports and updates regarding the ongoing review of the study at intervals 
specified by the respective IRB, and submission of the investigator’s final status report to 
IRB. All IRB approvals and relevant documentation for these items must be provided to 
the sponsor or its designee. 
Subject incentives should not exert undue influence for participation. Payments to 
subjects must be approved by the IRB and sponsor. 
Regarding PGx investigation using collected and stored specimens, analysis will be 
carried out at the time when detail is determined. The sponsor will create a research 
protocol for PGx investigations and a research protocol will require prior approval of the 
company IRB in Japan. 
15.2 
Subject Information, Informed Consent, and Subject Authorization 
Written consent documents will embody the elements of informed consent as described in 
the Declaration of Helsinki and the ICH Guidelines for GCP and will be in accordance 
with all applicable laws and regulations. The informed consent form describes the 


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planned and permitted uses, transfers, and disclosures of the subject’s personal and 
personal health information for purposes of conducting the study. The informed consent 
form further explains 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 he or she is free to withdraw at any time without giving a reason and without 
prejudice to his or her further medical care. 
The investigator is responsible for the preparation, content, and IRB approval of the 
informed consent form. The informed consent form must be approved by the IRB prior to 
use. 
The informed consent form must be written in a language fully comprehensible to the 
prospective subject. It is the responsibility of the investigator or sub-investigator to 
explain the detailed elements of the informed consent form to the subject. Information 
should be given in both oral and written form whenever possible and in the manner 
deemed appropriate by the IRB. 
The subject must be given ample opportunity to: (1) inquire about details of the study and 
(2) decide whether or not to participate in the study. If the subject determines he or she 
will participate in the study, then the informed consent form must be signed or signed and 
sealed, and dated by the subject at the time of consent and prior to the subject entering 
into the study. The subject should be instructed to sign using their legal name, not 
nickname, using blue or black ballpoint ink. The investigator or sub-investigator must 
also sign or sign and seal and date the informed consent form at the time of consent and 
prior to the subject entering into the study. 
Once signed or signed and sealed, the original informed consent form will be stored in the 
investigator’s site file. The investigator or sub-investigator must document the date the 
subject signs or signs and seals the informed consent in the subject’s medical record. 
Copies of the signed or signed and sealed informed consent form shall be given to the 
subject. 
All revised informed consent forms must be reviewed and signed by relevant subjects in 
the same manner as the original informed consent. The date the revised consent was 
obtained should be recorded in the subject’s medical record, and the subject should 
receive a copy of the revised informed consent form. 
The informed consent form for PGx research in the clinical study of SYR-472 will be 
used to explain the PGx research to subjects after the study itself is explained with the 
informed consent form for the study. PGx samples will be collected from subjects who 
have consented to both the study and the PGx research. 
If a subject requests disposal of stored sample, the procedures described in Section 9.4 
should be followed. 
15.3 
Subject Confidentiality 
The sponsor and designees affirm and uphold the principle of the subject’s right to 
protection against invasion of privacy. Throughout this study, a subject’s source data will 
only be linked to the sponsor’s clinical study database or documentation via a unique 
identification number. As permitted by all applicable laws and regulations, limited 


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subject attributes, such as sex, age, or date of birth may be used to verify the subject and 
accuracy of the subject’s unique identification number. 
To comply with ICH Guidelines for GCP and to verify compliance with this protocol, the 
sponsor requires the investigator to permit its monitor or designee’s monitor, 
representatives from any regulatory authority (e.g., Food and Drug Administration, 
Medicines and Healthcare products Regulatory Agency, Pharmaceuticals and Medical 
Devices Agency), the sponsor’s designated auditors, and the appropriate IRBs to review 
the subject’s original medical records (source data or documents), including, but not 
limited to, laboratory test result reports, ECG reports, admission and discharge 
summaries for hospital admissions occurring during a subject’s study participation, and 
autopsy reports. Access to a subject’s original medical records requires the specific 
authorization of the subject as part of the informed consent process (see Section 15.2). 
Copies of any subject source documents that are provided to the sponsor must have 
certain personally identifiable information removed (i.e., subject name, address, and 
other identifier fields not collected on the subject’s eCRF). 
15.4 
Publication, Disclosure, and Clinical Trial Registration Policy 
15.4.1 Publication and Disclosure 
The investigator is obliged to provide the sponsor with complete test results and all data 
derived by the investigator from the study. During the study, only the sponsor may make 
study information available to other study investigators, sub-investigators or to regulatory 
agencies, except as required by law or regulation. Except as otherwise allowable in the 
clinical study site agreement, any public disclosure (including publicly accessible 
websites) related to the protocol or study results is the sole responsibility of the sponsor. 
The sponsor may publish any data and information from the study (including data and 
information generated by the investigator) without the consent of the investigator. 
The investigator or sub-investigator needs to obtain a prior written approval from the 
sponsor to publish any information from the study externally such as to a professional 
association. 
15.4.2 Clinical Trial 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 interventional clinical trials it sponsors anywhere in the world on the publicly 
accessible website (ClinicalTrials.gov and Japan Pharmaceutical Information Center- 
Clinical Trials Information) before start of study, as defined in Takeda Policy/Standard. 
15.4.3 Clinical Trial Results Disclosure 
Takeda will post the results of clinical trials on publicly accessible websites, as required 
by Takeda Policy/Standard, applicable laws and/or regulations. 


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15.5 
Insurance and Compensation for Injury 
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 clinical study subjects. 
Refer to the Clinical Study Site Agreement regarding the sponsor’s policy on subject 
compensation and treatment for injury. If the investigator or sub-investigator has 
questions regarding this policy, he or she should contact the sponsor or sponsor’s 
designee. 


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PROTOCOL 
A Phase 3, Multicenter, Randomized, Double-Blind, Placebo-Controlled, 
Parallel-Group, Comparative Study and a Phase 3, Multicenter, Open-Label, 
Long-term Study to Evaluate the Efficacy and Safety of SYR-472 When Orally 
Administered at a Dose of 25 mg Once Weekly in Patients with Type 2 Diabetes 
Mellitus Complicated by Severe Renal Impairment or End-Stage Renal Failure 
A Phase 3, Randomized, Double-Blind, Parallel-Group, Comparative Study and a 
Phase 3, Multicenter, Open-Label, Long-term Study of SYR-472 (25 mg) in Patients 
with Type 2 Diabetes Mellitus Complicated by Severe Renal Impairment or 
End-Stage Renal Failure 
Sponsor: 
Takeda Pharmaceutical Company Limited 
1-1, Doshomachi 4-chome, Chuo-ku, Osaka 
Study Number: 
SYR-472-3003 
IND Number: 
Not Applicable 
EudraCT Number: 
Not Applicable 
Compound: 
SYR-472 
Date: 
12 September 2016 
Amendment Number: 
1 
Amendment History: 
Date 
Amendment Number 
Region 
1 April 2015 
Initial Protocol 
All study sites 
12 September 2016 
Amendment 1 
All study sites 
 
CONFIDENTIAL PROPERTY 
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. 


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1.0 
ADMINISTRATIVE INFORMATION AND PRINCIPLES OF CLINICAL 
STUDIES 
1.1 
Contacts and Responsibilities of Study-Related Activities 
See Annex 1. 
1.2 
Principles of Clinical Studies 
This study will be conducted with the highest respect for the individual participants in 
accordance with the requirements of this clinical study protocol and also in accordance 
with the following: 
• The ethical principles that have their origin in the Declaration of Helsinki. 
• International Conference on Harmonisation (ICH) E6 Good Clinical Practice (GCP): 
Consolidated Guideline. 
• All applicable laws and regulations, including, without limitation, data privacy laws, 
clinical trial disclosure laws, and regulations. 


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TABLE OF CONTENTS 
1.0 
ADMINISTRATIVE INFORMATION AND PRINCIPLES OF CLINICAL 
STUDIES ......................................................................................................... 2 
1.1 
Contacts and Responsibilities of Study-Related Activities .......................... 2 
1.2 
Principles of Clinical Studies ...................................................................... 2 
2.0 
STUDY SUMMARY ....................................................................................... 7 
3.0 
LIST OF ABBREVIATIONS ......................................................................... 12 
4.0 
INTRODUCTION .......................................................................................... 13 
4.1 
Background .............................................................................................. 13 
4.2 
Rationale for the Proposed Study .............................................................. 14 
5.0 
STUDY OBJECTIVES AND ENDPOINTS ................................................... 15 
5.1 
Objectives................................................................................................. 15 
5.2 
Endpoints ................................................................................................. 15 
5.2.1 
Primary Endpoints ............................................................................ 15 
5.2.2 
Secondary Endpoints ........................................................................ 15 
5.2.3 
Additional Endpoints........................................................................ 15 
6.0 
STUDY DESIGN AND DESCRIPTION ........................................................ 16 
6.1 
Study Design ............................................................................................ 16 
6.2 
Justification for Study Design, Dose, and Endpoints ................................. 17 
6.3 
Premature Termination or Suspension of Study or Investigational Site ...... 19 
6.3.1 
Criteria for Premature Termination or Suspension of the Study ........ 19 
6.3.2 
Criteria for Premature Termination or Suspension of Investigational 
Sites ................................................................................................. 19 
6.3.3 
Procedures for Premature Termination or Suspension of the Study 
or the Participation of Investigational Site(s) .................................... 19 
7.0 
SELECTION AND DISCONTINUATION/WITHDRAWAL OF 
SUBJECTS .................................................................................................... 20 
7.1 
Inclusion Criteria ...................................................................................... 20 
7.2 
Exclusion Criteria ..................................................................................... 23 
7.3 
Excluded Medications and Treatments ...................................................... 25 
7.4 
Diet, Fluid, Activity Control ..................................................................... 29 
7.5 
Criteria for Discontinuation or Withdrawal of a Subject ............................ 30 
7.6 
Procedures for Discontinuation or Withdrawal of a Subject ...................... 32 
8.0 
CLINICAL TRIAL MATERIAL MANAGEMENT ....................................... 33 
8.1 
Study Drug ............................................................................................... 33 
8.1.1 
Dosage Form, Manufacturing, Packaging, and Labeling ................... 33 
8.1.2 
Storage ............................................................................................. 34 
8.1.3 
Dose and Regimen ........................................................................... 34 
8.1.4 
Overdose .......................................................................................... 34 


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8.2 
Study drug Assignment and Dispensing Procedures .................................. 35 
8.3 
Randomization Code Creation and Storage ............................................... 35 
8.4 
Study Drug Blind Maintenance ................................................................. 35 
8.5 
Unblinding Procedure ............................................................................... 35 
8.6 
Accountability and Destruction of Sponsor-Supplied Drugs ...................... 35 
9.0 
STUDY PLAN ............................................................................................... 37 
9.1 
Study Procedures ...................................................................................... 37 
9.1.1 
Informed Consent Procedure ............................................................ 37 
9.1.2 
Demographics, Medical History, and Medication History Procedure 37 
9.1.3 
Antidiabetic Drugs Administered During the Study .......................... 37 
9.1.4 
Physical Examination Procedure ...................................................... 38 
9.1.5 
Weight ............................................................................................. 38 
9.1.6 
Vital Sign Procedure ........................................................................ 38 
9.1.7 
Documentation of Concomitant Medications .................................... 39 
9.1.8 
Documentation of Concurrent Medical Conditions ........................... 39 
9.1.9 
Procedures for Clinical Laboratory Samples ..................................... 39 
9.1.10 
Contraception and Pregnancy Avoidance Procedure ......................... 40 
9.1.11 
Pregnancy ........................................................................................ 41 
9.1.12 
ECG Procedure ................................................................................ 41 
9.1.13 
Fasting C-peptide ............................................................................. 42 
9.1.14 
HbA1c (NGSP Value) ...................................................................... 42 
9.1.15 
Fasting Blood Glucose, Fasting Glucagon ........................................ 42 
9.1.16 
Glycoalbumin................................................................................... 42 
9.1.17 
DPP-4 Activity ................................................................................. 42 
9.1.18 
Blood Transfusion ............................................................................ 42 
9.1.19 
Introduction of Hemodialysis ........................................................... 42 
9.1.20 
Presence or Absence of Changes and Compliance of Diet and/or 
Exercise Therapy.............................................................................. 42 
9.1.21 
Self-Monitoring of Blood Glucose ................................................... 43 
9.1.22 
Hypoglycemia .................................................................................. 43 
9.1.23 
PGx Sample Collection .................................................................... 44 
9.1.24 
Pharmacokinetic Sample Collection and Analysis ............................ 44 
9.1.25 
Documentation of Screen Failure ..................................................... 45 
9.1.26 
Documentation of Randomization .................................................... 45 
9.1.27 
Hospitalization ................................................................................. 46 
9.2 
Monitoring Subject Treatment Compliance ............................................... 46 
9.3 
Schedule of Observations and Procedures ................................................. 46 
9.3.1 
Screening (Week -6 to Week 0) ........................................................ 46 
9.3.2 
Randomization ................................................................................. 46 


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9.3.3 
Treatment Period .............................................................................. 47 
9.3.4 
Week 52 in the Treatment Period or Early Termination .................... 47 
9.3.5 
Follow-up......................................................................................... 47 
9.3.6 
Post Study Care ................................................................................ 47 
9.4 
Biological Sample Retention and Destruction ........................................... 47 
10.0 
PRETREATMENT EVENTS AND ADVERSE EVENTS ............................. 48 
10.1 
Definitions ................................................................................................ 48 
10.1.1 
PTEs ................................................................................................ 48 
10.1.2 
AEs .................................................................................................. 48 
10.1.3 
Additional Points to Consider for PTEs and AEs .............................. 48 
10.1.4 
SAEs ................................................................................................ 50 
10.1.5 
Adverse Events of Special Interest ................................................... 51 
10.1.6 
Intensity of PTEs and AEs................................................................ 52 
10.1.7 
Causality of AEs .............................................................................. 52 
10.1.8 
Relationship to Study Procedures ..................................................... 52 
10.1.9 
Start Date ......................................................................................... 52 
10.1.10 Stop Date ......................................................................................... 53 
10.1.11 Frequency ........................................................................................ 53 
10.1.12 Action Concerning Study Drug ........................................................ 53 
10.1.13 Outcome .......................................................................................... 53 
10.2 
Procedures ................................................................................................ 54 
10.2.1 
Collection and Reporting of AEs ...................................................... 54 
10.2.2 
Collection and Reporting of SAEs .................................................... 56 
10.2.3 
Reporting of Abnormal Liver Function Tests ................................... 56 
10.3 
Follow-up of SAEs ................................................................................... 57 
10.3.1 
Safety Reporting to Investigators, IRBs, and Regulatory Authorities 57 
11.0 
STUDY-SPECIFIC COMMITTEES .............................................................. 58 
12.0 
DATA HANDLING AND RECORDKEEPING............................................. 59 
12.1 
CRFs ........................................................................................................ 59 
12.2 
Record Retention ...................................................................................... 59 
13.0 
STATISTICAL METHODS ........................................................................... 61 
13.1 
Statistical and Analytical Plans ................................................................. 61 
13.1.1 
Analysis Sets .................................................................................... 61 
13.1.2 
Analysis of Demographics and Other Baseline Characteristics ......... 61 
13.1.3 
Efficacy Analysis ............................................................................. 61 
13.1.4 
Safety Analysis ................................................................................ 63 
13.2 
Interim Analysis and Criteria for Early Termination ................................. 64 
13.3 
Determination of Sample Size................................................................... 64 
14.0 
QUALITY CONTROL AND QUALITY ASSURANCE ............................... 66 


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14.1 
Study-Site Monitoring Visits .................................................................... 66 
14.2 
Protocol Deviations .................................................................................. 66 
14.3 
Quality Assurance Audits and Regulatory Agency Inspections ................. 66 
15.0 
ETHICAL ASPECTS OF THE STUDY ......................................................... 67 
15.1 
IRB Approval ........................................................................................... 67 
15.2 
Subject Information, Informed Consent, and Subject Authorization .......... 67 
15.3 
Subject Confidentiality ............................................................................. 68 
15.4 
Publication, Disclosure, and Clinical Trial Registration Policy.................. 69 
15.4.1 
Publication and Disclosure ............................................................... 69 
15.4.2 
Clinical Trial Registration ................................................................ 69 
15.4.3 
Clinical Trial Results Disclosure ...................................................... 69 
15.5 
Insurance and Compensation for Injury..................................................... 70 
16.0 
REFERENCES ............................................................................................... 71 
 
LIST OF IN-TEXT TABLES 
Table 2.a 
Concomitant Antidiabetic Drugs Permitted in the Study........................ 7 
Table 6.a 
Concomitant Antidiabetic Drugs Permitted in the Study...................... 16 
Table 8.a 
Dose and Regimen (Treatment Period I) ............................................. 34 
Table 9.a 
Clinical Laboratory Tests .................................................................... 40 
Table 10.a 
Takeda Medically Significant AE List ................................................ 51 
 
LIST OF IN-TEXT FIGURES 
Figure 6.a 
Schematic of Study Design ................................................................. 17 
 
 


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2.0 
STUDY SUMMARY 
Name of Sponsor: 
Takeda Pharmaceutical Company Limited 
Compound: 
SYR-472 
Title of Protocol: 
A phase 3, multicenter, randomized, double-blind, 
placebo-controlled, parallel-group, comparative study 
and a phase 3, multicenter, open-label, long-term study to 
evaluate the efficacy and safety of SYR-472 when orally 
administered at a dose of 25 mg once weekly in patients 
with type 2 diabetes mellitus complicated by severe renal 
impairment or end-stage renal failure 
IND No.: 
Not Applicable 
EudraCT No.: 
Not Applicable 
Study Number: SYR-472-3003 
Phase: 3 
Study Design: 
This is a phase 3, multicenter, randomized, double-blind, placebo-controlled, parallel-group, comparative 
study (Treatment Period I) and a phase 3, multicenter, open-label, long-term study (Treatment Period II) to 
evaluate the efficacy and safety of SYR-472 when administered orally at a dose of 25 mg once weekly in 
patients with type 2 diabetes mellitus complicated by severe renal impairment or end-stage renal failure and 
with inadequate glycemic control despite diet and/or exercise therapy (if any) or despite treatment with 1 
antidiabetic drug (Table 2.a) in addition to diet and/or exercise therapy (if any). 
Table 2.a 
Concomitant Antidiabetic Drugs Permitted in the Study 
Type 
Drug Name (Nonproprietary Name or Class) 
Rapid-acting insulin secretagogues 
Mitiglinide calcium hydrate, repaglinide 
α-glucosidase inhibitors 
Acarbose, miglitol, voglibose 
Insulin preparations 
Mixed, intermediate-acting, or long-acting soluble insulin (40 units/day or 
less*) 
*For change in the dosing unit of insulin preparations, see 2 (2) in Section 7.3. 
Subjects who enter the screening period after signing informed consent and are considered eligible 
according to the inclusion and exclusion criteria will be randomly assigned to either of the SYR-472 25 mg 
group or placebo group. Subjects who are assigned to the SYR-472 25 mg group in Treatment Period I will 
continue to be treated with SYR-472 25 mg in Treatment Period II, while those assigned to the placebo 
group will be switched to SYR-472 25 mg in Treatment Period II. 
In Treatment Period I, 1 SYR-472 25 mg tablet or placebo tablet will be orally administered once weekly 
before breakfast. In Treatment Period II, 1 SYR-472 25 mg tablet will be orally administered once weekly 
before breakfast. 
The study period consists of 6 weeks of screening, 52 weeks of treatment, and 2 weeks of follow-up, a total 
of 60 weeks. The treatment period consists of Treatment Period I (double-blind) from Week 0 to Week 12 
and Treatment Period II (open-label) between Week 12 and Week 52. Subjects will visit the site at the start 
of the screening period (Week -6), Week -2 of the screening period, end of the screening period (Week 0), 
Week 2 and Week 4 of the treatment period, and at every 4 weeks until Week 52 of the treatment period, 
and at the end of the follow-up period (Week 54) (total of 18 visits). 
The planned sample size is 106 randomized subjects (53 per group). 
Objectives: 
To evaluate the efficacy and safety of SYR-472 when administered at a dose of 25 mg once weekly using 
placebo as a control in patients with type 2 diabetes mellitus complicated by severe renal impairment or 
end-stage renal failure and inadequate glycemic control despite diet and/or exercise therapy (if any) or 
despite treatment with 1 antidiabetic drug in addition to diet and/or exercise therapy (if any); and to evaluate 
the long-term safety and efficacy of SYR-472 when administered at a dose of 25 mg once weekly in 
patients with type 2 diabetes mellitus complicated by severe renal impairment or end-stage renal failure. 


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Subject Population: 
Patients with type 2 diabetes mellitus complicated by severe renal impairment or end-stage renal failure and 
inadequate glycemic control despite diet and/or exercise therapy (if any) or despite treatment with 1 
antidiabetic drug in addition to diet and/or exercise therapy (if any) 
Number of Subjects: 
Randomized: 
53 subjects per group, 106 in total 
(Changed as of 12 September 2016) 
Number of Sites: 
Approximately 50 sites 
Dose Level: 
<Treatment Period I> 
One SYR-472 25 mg tablet or placebo tablet will be orally administered 
once weekly before breakfast. 
<Treatment Period II> 
One SYR-472 25 mg tablet will be orally administered once weekly 
before breakfast. 
Route of Administration: 
Oral 
Duration of Treatment: 
<Treatment Period I> 
SYR-472 25 mg tablet or placebo tablet: 12 weeks 
<Treatment Period II> 
SYR-472 25 mg tablet: 40 weeks 
Period of Evaluation: 
Screening period 
: 6 weeks 
Treatment Period I : 12 weeks 
Treatment Period II : 40 weeks 
Follow-up period : 2 weeks 
Total 
: 60 weeks 
Criteria for Inclusion: 
1. The subject has a diagnosis of type 2 diabetes mellitus. 
2. The subject has a fasting C-peptide value of 0.6 ng/mL or higher at the start of the screening period 
(Week -6) and Week -2 of the screening period. 
3. The subject has a hemoglobin value of 10.0 g/dL or higher at the start of the screening period (Week -6) 
and Week -2 of the screening period. 
4. The subject has an hemoglobin A1c (HbA1c) value of 7.0% or higher but less than 10.0% at Week -2 of 
the screening period. However, subjects on hemodialysis (patients with end-stage renal failure) with an 
HbA1c value of less than 7.0% at Week -2 of the screening period are permitted to be enrolled if they 
have a glycoalbumin value of 20% or higher. 
5. <Subjects with an HbA1c value of 7.0% or higher but less than 10.0% at Week -2 of the screening 
period> 
The subject has an HbA1c value difference between the start of the screening period (Week -6) and 
Week -2 of the screening period within 10.0%* of the HbA1c value at the start of the screening period 
(Week -6). 
<Subjects on hemodialysis (patients with end-stage renal failure) with an HbA1c value of less than 
7.0% and glycoalbumin value of 20% or higher at Week -2 of the screening period> 
The subject has a glycoalbumin value difference between the start of the screening period (Week -6) 
and Week -2 of the screening period within 10.0%* of the glycoalbumin value at the start of the 
screening period (Week -6). 
*: rounded to one decimal place 
6. The subject has been on a fixed diet and/or exercise therapy (if any) from at least 6 weeks prior to the 
start of the screening period (Week -6). 
7. The subject meets any of the following: 
• 
The subject has not received any antidiabetic medications (including insulin preparations) from 
at least 6 weeks prior to the start of the screening period (Week -6). 
• 
The subject is being treated with 1 oral hypoglycemic drug* starting from at least 6 weeks prior 
to the start of the screening period (Week -6) at a fixed dose and regimen. 
*: Any of the following medications: mitiglinide calcium hydrate, repaglinide, acarbose, miglitol, or 


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voglibose 
• 
The subject is being treated with 1 insulin preparation** from at least 6 weeks prior to the start of 
the screening period (Week -6) at a fixed dose and regimen (≤40 units/day). 
**: Any of the following insulin monotherapies: mixed (rapid-acting or ultrarapid-acting insulin containing 
no more than 30% of volume), intermediate-acting, or long-acting soluble insulin preparations 
8. The subject is not undergoing hemodialysis or peritoneal dialysis and has severe renal impairment 
(creatinine clearance [Ccr] <30 mL/min at the start of the screening period [Week -6]), or the subject is 
undergoing hemodialysis and has end-stage renal failure. 
9. In the opinion of the investigator or sub-investigator, the initiation of hemodialysis or peritoneal 
dialysis within 12 weeks after initiation of the study drug is not expected. (in cases where the subject is 
not undergoing hemodialysis or peritoneal dialysis [patients with severe renal impairment]) 
10. The subject has been undergoing hemodialysis started from at least 6 months prior to informed consent 
and, in the opinion of the investigator or sub-investigator, the subject is clinically stable. (in cases 
where the subject is undergoing hemodialysis [patient with end-stage renal failure]) 
11. The subject is male or female and is aged 20 years or older at the time of informed consent. 
12. A female subject of childbearing potential who is sexually active with a nonsterilized male partner 
agrees to routinely use adequate contraception from signing of informed consent until 1 month after the 
end of the study. 
13. In the opinion of the investigator or sub-investigator, the subject is capable of understanding and 
complying with protocol requirements. 
14. The subject signs and dates a written, informed consent form prior to the initiation of any study 
procedures. 
Criteria for Exclusion: 
1. The subject has clinically evident hepatic impairment (e.g., AST or ALT >=2.5 times the upper limit of 
normal or total bilirubin of >=2.0 mg/dL at the start of the screening period [Week -6] or at Week -2 of 
the screening period). 
2. The subject has any serious cardiac diseases, cerebrovascular disorders, or serious pancreatic or 
hematological diseases (e.g., subjects who require inpatient treatment or had been hospitalized for 
treatment within 24 weeks prior to the start of the screening period). 
3. The subject has severe ketosis, diabetic coma or pre coma, type 1 diabetes, severe infection, or severe 
external injury, or is immediately before or after surgery. 
4. The subject has hemoglobinopathy (sickle cell disease, thalassemia, etc.). 
5. The subject experienced hypoglycemia (subjects with a blood glucose value of ≤70 mg/dL or 
hypoglycemic symptoms) within 6 weeks prior to the start of the screening period or during the 
screening period (at least twice per week). 
6. The subject has inadequately controlled hypertension. 
7. For subjects who are being treated with 1 antidiabetic agent, the subject had been treated with at least 2 
antidiabetic agents on the day before 6 weeks prior to the start of the screening period (Week -6) (43 
days prior to the start of the screening period). 
8. The subject has malignancies. 
9. The subject has a history of hypersensitivity or allergies to dipeptidyl peptidase-4 (DPP-4) inhibitors. 
10. The subject has a history of gastrectomy or small intestinal resection. 
11. The subject is a habitual drinker and consumes a daily average of more than 100 mL of alcohol. 
12. The subject has a history of drug abuse (defined as any illicit drug use) or a history of alcohol abuse. 
13. The subject is required to take excluded medications during the study period. 
14. The subject has received SYR-472 in a previous clinical study. 
15. The subject received any investigational products (including investigational drugs in a post-marketing 
clinical study) within 12 weeks prior to the start of the screening period. 
16. The subject is participating in other clinical studies at the time of informed consent. 


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17. If female, the subject is pregnant or lactating or intending to become pregnant from the time of 
informed consent to within 1 month after the end of the study; or intending to donate ova during such 
time period. 
18. The subject is an immediate family member, study site employee, or is in a dependant relationship with 
a study site employee who is involved in conduct of this study (e.g., spouse, parent, child, sibling) or 
may consent under duress. 
19. The subject is hospitalized during the screening period or is deemed as requiring hospitalization during 
the study period by the investigator or sub-investigator, unless the hospitalization is for short-term 
evaluations including complete health checkups or for short-term admission for shunt operation 
(including shunt maintenance). 
20. The subject is deemed ineligible for the study for any other reason by the investigator or 
sub-investigator. 
Criteria for Evaluation and Analyses: 
1. 
Primary Endpoints 
Efficacy: Change in HbA1c at the end of Treatment Period I from the end of the screening period (Week 
0)  
Safety: Adverse events (AEs) 
2. 
Secondary Endpoints 
Efficacy: HbA1c, fasting blood glucose, glycoalbumin 
Safety: Vital signs, 12-lead electrocardiogram (ECG), clinical laboratory values 
3. 
Additional Endpoints 
Efficacy 
: Fasting C-peptide, fasting glucagon, DPP-4 activity, weight 
Safety 
: Hypoglycemia (only for subjects using insulin preparations) 
Pharmacokinetics 
: Plasma concentration of unchanged SYR-472 (SYR-472Z) 
Statistical Considerations: 
1. 
Efficacy Analysis 
<Efficacy endpoint (primary endpoint)> 
Change in HbA1c at the end of Treatment Period I from the end of the screening period (Week 0) 
<Analytical methods (primary analysis)> 
The following analyses will be performed in the Full Analysis Set (FAS). 
The population mean change in HbA1c at the end of Treatment Period I from the end of the screening 
period (Week 0) will be compared between SYR-472 25 mg group and placebo group based on an analysis 
of covariance (ANCOVA) model for the change in HbA1c at the end of Treatment Period I from the end of 
the screening period (Week 0) with factors of treatment group and HbA1c at the end of the screening period 
(Week 0). 
The same ANCOVA model will be used to calculate the least square (LS) mean and the two-sided 95% 
confidence interval (CI) for each treatment group, as well as the intergroup difference in the LS mean 
between the treatment groups (SYR-472 25 mg group - placebo group) and the two-sided 95% CI. 
2. 
Safety Analysis 
<Safety endpoint (primary endpoint)> 
AEs 
<Analytical methods> 
The following analyses will be performed in the Safety Analysis Set. 
The following analyses will be performed for TEAEs that occur prior to the start of the study drug for 
Treatment Period II by treatment group, and for those that occur after the start of SYR-472 25 mg tablet. In 
the analysis of TEAEs occurring after the start of SYR-472 25 mg tablet, subjects who received SYR-472 
25 mg tablet will be included in the analyses. 
TEAEs will be coded using MedDRA dictionary. Frequency distributions will be provided using System 


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Organ Class and Preferred Term for each treatment group as follows: 
• 
All TEAEs 
• 
Drug-related TEAEs 
• 
Intensity of TEAEs 
• 
Intensity of drug-related TEAEs 
• 
TEAEs leading to study drug discontinuation 
• 
Serious TEAEs 
• 
TEAEs over time 
Sample Size Justification: 
In Study CCT-002, the intergroup difference (two-sided 95% CI) in the mean change in HbA1c (JDS value) 
at the end of the treatment period (value at the end of the treatment period - value at the end of the screening 
period) between the SYR-472 100 mg group and placebo group was -0.56 ([-0.753, -0.367])%. In the same 
study, the standard deviation of the change in HbA1c (JDS value) at the end of the treatment period (value 
at the end of the treatment period - value at the end of the screening period) for each treatment group ranged 
from 0.523% to 0.628%. 
In this study, which will administer SYR-472 at a dose of 25 mg once weekly to patients with type 2 
diabetes mellitus complicated by severe renal impairment or end-stage renal failure, the intergroup 
difference in the mean change in HbA1c at the end of Treatment Period I from the end of the screening 
period (Week 0) between the SYR-472 25 mg group and placebo group is assumed to be -0.40%, given that 
the efficacy of SYR-472 25 mg in this study is similar to that of SYR-472 100 mg administered once 
weekly to patients with type 2 diabetes mellitus not complicated by renal impairment. The common 
standard deviation in each treatment group is assumed to be 0.80%. 
Based on these assumptions, 86 subjects per group will be required to provide a 90% power in a two-sample 
t-test with a significance level of 5% (two-sided). Therefore, the sample size was set at 90 as randomized 
subjects per group at the start of the study allowing for the possibility that there exits some subjects whose 
primary endpoint cannot be evaluated. 
However, achievement of the sample size as originally planned at the start of the study was found difficult 
because there were more than expected numbers of candidate subjects who did not provide consent and 
who dropped out during screening after providing consent for the study. It was therefore decided to change 
some of the inclusion and exclusion criteria for this study. After these changes, the ultimate number of 
subjects randomized and evaluable for the primary endpoints are expected to be around 53 and 51, 
respectively, per group. 
Assuming the number of subjects per group as 51 under these assumptions, the study will provide a 70.6% 
power in a two-sample t-test with a significance level of 5% (two-sided). 


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3.0 
LIST OF ABBREVIATIONS 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AUC 
area under the plasma concentration-time curve 
BMI 
body mass index 
Ccr 
creatinine clearance 
CKD 
chronic kidney disease 
CRO 
contract research organization 
DPP-4 
dipeptidyl-peptidase-4 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GLP-1 
glucagon like peptide-1 
γ-GTP 
γ-glutamyl transpeptidase 
hCG 
human chorionic gonadotropin 
HbA1c 
hemoglobin A1c 
HDL 
high density lipoprotein 
ICH 
International Conference on Harmonisation 
INR 
international normalized ratio 
JAPIC-CTI Japan Pharmaceutical Information Center- Clinical Trials Information 
JDS 
The Japan Diabetes Society 
LDH 
lactate dehydrogenase 
LDL 
low density lipoprotein 
MedDRA 
Medical Dictionary for Regulatory Activities 
MHRA 
Medicines and Healthcare Products Regulatory Agency 
NGSP 
national glycohemoglobin standardization program 
PGx 
pharmacogenomics 
PMDA 
Pharmaceuticals and Medical Devices Agency 
PTE 
pretreatment event 
QTcF 
corrected QT interval by Fridericia formula 
SGLT 
sodium glucose co- transporter  
SUSARs 
suspected unexpected serious adverse reactions 
TEAE 
treatment-emergent adverse event 
WHO 
World Health Organization 
 


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4.0 
INTRODUCTION 
4.1 
Background 
Type 2 diabetes mellitus is thought to be mainly caused by a combination of deficient 
insulin secretion and insulin resistance. Currently used oral medications for type 2 
diabetes mellitus (oral hypoglycemic drugs) include sulfonylureas (SUs), rapid-acting 
insulin secretagogues, and dipeptidyl peptidase-4 (DPP-4) inhibitors, which stimulate 
insulin secretion; α-glucosidase inhibitors, which delay glucose absorption through the 
digestive tract; biguanides and thiazolidinediones, which improve insulin resistance: and 
sodium-glucose co-transporter 2 inhibitors, which exhibit hypoglycemic effects by 
inhibiting glucose reabsorption in the renal proximal tubules and promoting glucose 
excretion into the urine. 
It has been believed that deficient insulin secretion is mainly associated with the etiology 
of type 2 diabetes mellitus in Japanese people, and SUs and DPP-4 inhibitors are widely 
used in the Japanese clinical setting. Compared with other oral hypoglycemic drugs, SUs 
exhibit more potent hypoglycemic effects, but have longer-lasting insulinotropic effects; 
therefore, several issues such as hypoglycemic risk and secondary failure resulting from 
pancreatic beta cell exhaustion associated with long-term treatment have been pointed 
out. 
Meanwhile, DPP-4 inhibitors are oral hypoglycemic drugs that increase the blood 
concentrations of glucagon-like peptide-1 (GLP-1), and thereby stimulate insulin 
secretion glucose-dependently. GLP-1 is an incretin hormone that has a crucial role in 
glucose metabolism, and stimulates insulin secretion glucose-dependently. It is also 
reported that GLP-1 has a protective effect on pancreatic beta cells and an inhibitory 
effect on glucagon secretion [1][2]. 
SYR-472, a DPP-4 inhibitor synthesized by Takeda California, Inc, is expected to 
stimulate insulin secretion glucose-dependently via an increase of GLP-1 concentration 
and preserve pancreatic function. SYR-472 is also expected to be useful as a once-weekly 
oral antidiabetic drug, since prolonged inhibition of DPP-4 activity has been shown in 
pharmacodynamic assessments. 
Of clinical studies conducted in Japan, non-inferiority of SYR-472 100 mg once weekly 
to alogliptin 25 mg once daily has been assessed in a confirmatory study conducted in 
Japanese patients with type 2 diabetes mellitus using the once-daily DPP-4 inhibitor 
alogliptin 25 mg as a comparator (Study CCT-002). In addition, the efficacy and safety of 
SYR-472 in long-term monotherapy and combination therapy with SYR-472 and other 
approved oral hypoglycemic drug shaving different mechanisms of action, such as 
α-glucosidase inhibitors, thiazolidinediones, sulfonylureas, biguanides, and rapid-acting 
insulin secretagogues have been confirmed (Study-OCT 001, SYR-472 administered 
100 mg/week). 
Based on these findings, the manufacture and marketing approval of SYR-472 was 
obtained in March 2015 as a drug for the treatment of type 2 diabetes mellitus 
administered once weekly. 


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Currently, a confirmatory and long-term study to evaluate the efficacy and safety of 
SYR-472 in combination with insulin preparations in patients with type 2 diabetes 
mellitus (Study CCT-101) is ongoing. 
4.2 
Rationale for the Proposed Study 
The clinical dose of SYR-472 is 100 mg once weekly as a usual dose [3]. 
Meanwhile, in an overseas clinical pharmacology study in subjects with renal impairment 
(Study 101; SYR-472 50 mg given as a single dose), the AUC(0-tlqc) of unchanged 
SYR-472 (SYR-472Z) was 1.56, 2.06, 3.01, and 3.68 times higher in subjects with mild 
renal impairment (Ccr: ˃50 to ≤80 mL/min), subjects with moderate renal impairment 
(Ccr: ≥30 to ≤50 mL/min), subjects with severe renal impairment (Ccr: ˂30 mL/min, but 
not performing hemodialysis), and subjects with end-stage renal failure requiring 
hemodialysis, respectively, as compared with healthy adults (Ccr: ˃80 mL/min). 
Based on this result, there is no need to adjust the SYR-472 dose for patients with mild 
renal impairment, while half the usual dose (50 mg once weekly) is recommended 
suitable for patients with moderate renal impairment, and the manufacture and marketing 
approval of SYR-472 50 mg and 100 mg tablets was obtained. In addition, SYR-472 is 
contraindicated in patients with severe renal impairment and end-stage renal failure for 
whom 1-quarter of the usual dose (25 mg once weekly) is considered appropriate [3]. 
However, since patients with type 2 diabetes mellitus often have renal impairment, it was 
decided to develop SYR-472 25 mg tablets to contribute to the treatment of diabetes 
mellitus in patients with severe or more severe renal impairment. 
Therefore a phase 3, multicenter, randomized, double-blind, placebo-controlled, 
parallel-group, comparative study and a phase 3, multicenter, open-label, long-term study 
to evaluate the efficacy and safety of SYR-472 when administered at a dose of 25 mg 
once weekly in patients with type 2 diabetes mellitus complicated by severe renal 
impairment or end-stage renal failure was planned. Currently, a clinical pharmacology 
study (Study 1005) to evaluate the bioequivalence of SYR-472 25 mg tablets and 50 mg 
tablets in healthy adults is ongoing. 
Pharmacogenomic (PGx) analysis may be conducted to investigate a possible 
contribution of genetic variance on drug response, for example, its efficacy and safety. 
Participation of study subjects in PGx sample collection is optional. 
As PGx is an evolving science, currently many genes and their function are not yet fully 
understood. Future data may suggest a role of some of these genes in drug response, 
which may lead to additional hypothesis-generating exploratory research on stored 
samples. 


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5.0 
STUDY OBJECTIVES AND ENDPOINTS 
5.1 
Objectives 
To evaluate the efficacy and safety of SYR-472 when administered at a dose of 25 mg 
once weekly using placebo as a control in patients with type 2 diabetes mellitus 
complicated by severe renal impairment or end-stage renal failure and with inadequate 
glycemic control despite diet and/or exercise therapy (if any) or despite treatment with 1 
antidiabetic drug in addition to diet and/or exercise therapy (if any); and to evaluate the 
long-term safety and efficacy of SYR-472 when administered at a dose of 25 mg once 
weekly in patients with type 2 diabetes mellitus complicated by severe renal impairment 
or end-stage renal failure. 
5.2 
Endpoints 
5.2.1 Primary Endpoints 
Efficacy: Change in Hemoglobin A1c (HbA1c) at the end of Treatment Period I from the 
end of the screening period (Week 0) 
Safety: Adverse Events (AEs) 
5.2.2 Secondary Endpoints 
Efficacy: HbA1c, fasting blood glucose, glycoalbumin 
Safety: Vital signs, 12-lead ECG, clinical laboratory values 
5.2.3 Additional Endpoints 
Efficacy 
: Fasting C-peptide, fasting glucagon, DPP-4 activity, weight 
Safety 
: Hypoglycemia (only for subjects using insulin preparations) 
Pharmacokinetics 
: Plasma concentration of SYR-472Z 


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6.0 
STUDY DESIGN AND DESCRIPTION 
6.1 
Study Design 
This is a phase 3, multicenter, randomized, double-blind, placebo-controlled, 
parallel-group, comparative study (Treatment Period I) and a phase 3, multicenter, 
open-label, long-term study (Treatment Period II) using placebo as a control to evaluate 
the efficacy and safety of SYR-472 when administered orally at a dose of 25 mg once 
weekly in patients with type 2 diabetes mellitus complicated by severe renal impairment 
or end-stage renal failure and with inadequate glycemic control despite diet and/or 
exercise therapy (if any) or despite treatment with 1 antidiabetic drug (Table 6.a) in 
addition to diet and/or exercise therapy (if any). 
Table 6.a 
Concomitant Antidiabetic Drugs Permitted in the Study 
Type 
Drug Name (Nonproprietary Name or Class) 
Rapid-acting insulin 
secretagogues 
Mitiglinide calcium hydrate, repaglinide 
α-glucosidase inhibitors 
Acarbose, miglitol, voglibose 
Insulin preparations 
Mixed, intermediate-acting, or long-acting soluble insulin (40 
units/day or less*) 
*: For change in the dosing unit of insulin preparations, see 2 (2) in Section 7.3. 
Subjects who enter the screening period after signing informed consent and are 
considered eligible according to the inclusion and exclusion criteria will be randomly 
assigned to either of the SYR-472 25 mg group or placebo group. Subjects who are 
assigned to the SYR-472 25 mg group in Treatment Period I will continue to be treated 
with SYR-472 25 mg in Treatment Period II, while those assigned to the placebo group 
will be switched to SYR-472 25 mg in Treatment Period II. 
In Treatment Period I, 1 SYR-472 25 mg tablet or placebo tablet will be orally 
administered once weekly before breakfast. In Treatment Period II, 1 SYR-472 25 mg 
tablet will be orally administered once weekly before breakfast. 
The study period consists of 6 weeks of screening, 52 weeks of treatment, and 2 weeks of 
follow-up, a total of 60 weeks. The treatment period consists of Treatment Period I 
(double-blind) between Week 0 and Week 12 and Treatment Period II (open-label) 
between Week 12 and Week 52. Subjects will visit the site at the start of the screening 
period (Week -6), Week -2 of the screening period, end of the screening period (Week 0), 
Week 2 and Week 4 of the treatment period, and at every 4 weeks until Week 52 of the 
treatment period, and at the end of the follow-up period (Week 54) (total of 18 visits). 
The planned sample size is 106 randomized subjects (53 per group). 
A schematic of the study design is included as Figure 6.a. A schedule of assessments is 
listed in Appendix A. 


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Week -6 
 
VISIT 1 
Week 0 
(randomization) 
VISIT 3 
Week 12 
 
VISIT 7 
 
Week 52 
 
VISIT 17 
Week 54 
 
VISIT 18 
 
Eligibility 
confirmation 
Start of study 
drug 
administration 
 
 
 
 
 
 
 
 
←Screening 
period→ 
←Treatment period→ 
←Follow-up 
period→ 
 
 
 
Period I 
(double-blind)* 
Period II (open-label) 
 
 
 
 
 
 
 
Placebo group 
 
Placebo tablet 
SYR-472 25 mg tablet 
 
 
SYR-472 25 mg 
group 
 
SYR-472 25 mg tablet 
 
 
*: The study drug blind in Treatment Period I will be maintained until the end of the study. 
Figure 6.a 
Schematic of Study Design 
6.2 
Justification for Study Design, Dose, and Endpoints 
(1) Justification for the study design 
This study, which aims to evaluate the efficacy and safety of SYR-472 when 
administered at a dose of 25 mg once weekly in patients with type 2 diabetes mellitus 
complicated by severe renal impairment or end-stage renal failure, will be conducted in a 
double-blind manner until Week 12 of the treatment period (Treatment Period I) to 
evaluate the efficacy and safety of SYR-472 by comparing the SYR-472 25 mg group and 
placebo group. Subsequently, it will be conducted in an open-label manner between 
Week 12 and Week 52 of the treatment period (Treatment Period II) to evaluate the 
long-term safety of SYR-472. 
(2) Justification for the dose and regimen 
The usual dose of SYR-472 is 100 mg once weekly; however, since Study 101 showed 
that the AUC of SYR-472Z in patients with severe renal impairment and end-stage renal 
failure was 3.01 and 3.68 times higher than that in healthy adults, respectively, 1-quarter 
of the usual dose is considered appropriate for patients with severe to end-stage renal 
failure, and a dose of 25 mg once weekly has thus been selected for the study. 
(3) Justification for the study period 
1) Justification for the Screening Period 
The duration of the screening period was set at 6 weeks to select subjects who meet all of 
the inclusion criteria and none of the exclusion criteria, and to select subjects with a stable 
HbA1c value in reference to the “the Guideline for Clinical Evaluation of Hypoglycemic 
Agents (Revised Draft)” [4]. 
2) Justification for the treatment period 
<Justification for Treatment Period I (double-blind period)> 
In Study CCT-002, the change (mean) in HbA1c at Week 8, 12, 16, 20, and 24 of the 
treatment period following oral administration of SYR-472 at a dose of 100 mg once 
weekly was -0.39%, -0.40%, -0.38%, -0.34%, and -0.31%, respectively, and the 


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difference from the placebo group (SYR-472 100 mg group - placebo group) was -0.42%, 
-0.53%, -0.59%, -0.63%, and -0.52%, respectively. These results suggest that the 
HbA1c-lowering effect of SYR-472 almost reaches a plateau by Week 12 of treatment. 
The incidence of AEs including hypoglycemia did not increase depending on the duration 
of treatment. In addition, the results of Study 101 suggest that administration of 1-quarter 
(25 mg/week) of the usual dose to patients with severe renal impairment or end-stage 
renal failure will result in a similar exposure level to that observed in patients with normal 
renal function. Based on these results, the HbA1c-lowering effect in patients with severe 
renal impairment or end-stage renal failure will almost reach a plateau by Week 12 when 
treated at 1-quarter (25 mg/week) of the usual dose, just as observed in patients with 
normal renal function. 
Furthermore, the basic treatment (diet and/or exercise therapy and an antidiabetic drug) of 
subjects is required to remain fixed from at least 6 weeks prior to the start of the screening 
period (Week -6) through the end of Treatment Period I in principle, with respect to the 
possible influence on assessments in the study. However, since strict glycemic control is 
required especially for patients with type 2 diabetes mellitus complicated by renal 
impairment, it is considered difficult to continue with fixed fundamental treatment over a 
long period. 
Based on the above considerations, the duration of Treatment Period I was set at 12 weeks 
as a period during which the efficacy and safety of SYR-472 25 mg can be evaluated in 
patients with severe renal impairment or end-stage renal failure and with respect to the 
safety of the subjects. 
<Justification for Treatment Period II (open-label period)> 
Treatment Period II was set as an open-label period and the total duration of Treatment 
Periods I and II was set at 1 year (52 weeks) in reference to the “The Extent of Population 
Exposure to Assess Clinical Safety for Drugs Intended for Long-Term Treatment of 
Non-Life-Threatening Conditions” [5] and “the Guideline for Clinical Evaluation of 
Hypoglycemic Agents (Revised Draft)” [4]. 
<Justification for Follow-up Period> 
In Study 101, the elimination half-life (mean) of unchanged SYR-472 following the 
administration of SYR-472 50 mg under fasted conditions (without breakfast) to patients 
with severe renal impairment and end-stage renal failure was 88.45 and 107.97 hours, 
respectively, which were longer than those in matched healthy adults (56.43 and 56.75 
hours). Based on these results, the time of assessment at the end of the follow-up period 
was set at Week 54 by reference to 5 times the elimination half-life (18.4 and 22.5 days, 
or longer) from the last administration of SYR-472 25 mg tablets (Week 51). 
(4) Justification for the primary endpoints 
According to “the Guideline for Clinical Evaluation of Hypoglycemic Agents (Revised 
Draft)” [4], HbA1c should be used as an efficacy endpoint in phase 3 studies in principle. 
In addition, the safety of the study drug should be used as the primary endpoint in 
long-term studies. Therefore, HbA1c at the end of Treatment Period I will be evaluated as 
the efficacy endpoint and AEs throughout the treatment period will be evaluated as the 
safety endpoint. 


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(5) Justification for the secondary endpoints 
In reference to “the Guideline for Clinical Evaluation of Hypoglycemic Agents (Revised 
Draft)” [4] and based on the results of clinical studies of SYR-472 conducted so far, 
HbA1c, fasting blood glucose, and glycoalbumin were set as efficacy endpoints, and vital 
signs, 12-lead ECG, and clinical laboratory test values were set as safety endpoints to 
evaluate the efficacy and safety of SYR-472 25 mg. 
(6) Justification for the inclusion criteria 
See Section 7.1. 
(7) Justification for the exclusion criteria 
See Section 7.2. 
(8) Justification for the excluded medications and other exclusions 
See Section 7.3. 
(9) Justification for the sample size 
See Section 13.3. 
6.3 
Premature Termination or Suspension of Study or Investigational Site 
6.3.1 Criteria for Premature Termination or Suspension of the Study 
The study will be completed as planned unless 1 or more of the following criteria are 
satisfied that require temporary suspension or early termination of the study. 
• New information or other evaluation regarding the safety or efficacy of the study 
medication that indicates a change in the known risk/benefit profile for the 
compound, such that the risk/benefit is no longer acceptable for subjects 
participating in the study. 
• Significant violation of GCP that compromises the ability to achieve the primary 
study objectives or compromises subject safety. 
6.3.2 Criteria for Premature Termination or Suspension of Investigational Sites 
A study site may be terminated prematurely or suspended if the study site (including the 
investigator) is found in significant violation of GCP, 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 Investigational Site(s) 
In the event that the sponsor, an institutional review board (IRB) or regulatory authority 
elects to terminate or suspend the study or the participation of an investigational site, a 
study-specific procedure for early termination or suspension will be provided by the 
sponsor; the procedure will be followed by applicable investigational sites during the 
course of termination or study suspension. 


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7.0 
SELECTION AND DISCONTINUATION/WITHDRAWAL OF 
SUBJECTS 
All entry criteria, including test results, need to be confirmed prior to randomization. 
7.1 
Inclusion Criteria 
Subject eligibility is determined according to the following criteria prior to entry into the 
study: 
1. The subject has a diagnosis of type 2 diabetes mellitus. 
2. The subject has a fasting C-peptide value of 0.6 ng/mL or higher at the start of the 
screening period (Week -6) and Week -2 of the screening period. 
3. The subject has a hemoglobin value of 10.0 g/dL or higher at the start of the screening 
period (Week -6) and Week -2 of the screening period. 
4. The subject has an HbA1c value of 7.0% or higher but less than 10.0% at Week -2 of 
the screening period. However, subjects on hemodialysis (patients with end-stage 
renal failure) with an HbA1c value of less than 7.0% at Week -2 of the screening 
period are permitted to be enrolled if they have a glycoalbumin value of 20% or 
higher. 
5. <Subjects with a HbA1c value of 7.0% or higher but less than 10.0% at Week -2 of 
the screening period> 
The subject has an HbA1c value difference between the start of the screening period 
(Week -6) and Week -2 of the screening period within 10.0%* of the HbA1c value at 
the start of the screening period (Week -6). 
<Subjects on hemodialysis (patients with end-stage renal failure) with an HbA1c 
value of less than 7.0% and glycoalbumin value of 20% or higher at Week -2 of the 
screening period> 
The subject has a glycoalbumin value difference between the start of the screening 
period (Week -6) and Week -2 of the screening period within 10.0%* of the 
glycoalbumin value at the start of the screening period (Week -6). 
*: rounded to one decimal place 
6. The subject has been on a fixed diet and/or exercise therapy (if any) from at least 6 
weeks prior to the start of the screening period (Week -6). 
7. The subject meets any of the following: 
• 
The subject has not received any antidiabetic medications (including insulin 
preparations) from at least 6 weeks prior to the start of the screening period 
(Week -6). 
• 
The subject is being treated with 1 oral hypoglycemic drug* starting from at least 
6 weeks prior to the start of the screening period (Week -6) at a fixed dose and 
regimen. 
*: Any of the following medications: mitiglinide calcium hydrate, repaglinide, acarbose, miglitol, 
or voglibose 


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• 
The subject is being treated with 1 insulin preparation** from at least 6 weeks 
prior to the start of the screening period (Week -6) at a fixed dose and regimen 
(≤40 units/day). 
**: Any of the following insulin monotherapies: mixed (rapid-acting or ultrarapid-acting insulin 
containing no more than 30% of volume), intermediate-acting, or long-acting soluble insulin 
preparations 
8. The subject is not undergoing hemodialysis or peritoneal dialysis and has severe renal 
impairment (Ccr <30 mL/min at the start of the screening period [Week -6]), or the 
subject is undergoing hemodialysis and has end-stage renal failure. 
9. In the opinion of the investigator or sub-investigator, the initiation of hemodialysis or 
peritoneal dialysis within 12 weeks after the initiation of the study drug is not 
expected. (in cases where the subject is not undergoing hemodialysis or peritoneal 
dialysis [patients with severe renal impairment]) 
10. The subject has been undergoing hemodialysis started from at least 6 months prior to 
informed consent and, in the opinion of the investigator or sub-investigator, the 
subject is clinically stable. (in cases where the subject is undergoing hemodialysis 
[patient with end-stage renal failure]) 
11. The subject is male or female and is aged 20 years or older at the time of informed 
consent. 
12. A female subject of childbearing potential who is sexually active with a nonsterilized 
male partner agrees to routinely use adequate contraception from signing of informed 
consent until 1 month after the end of the study. 
Definitions and acceptable methods of contraception are defined in Section 9.1.10 
Contraception and Pregnancy Avoidance Procedure and reporting responsibilities 
are defined in Section 9.1.11 Pregnancy. 
13. In the opinion of the investigator or sub-investigator, the subject is capable of 
understanding and complying with protocol requirements. 
14. The subject signs and dates a written, informed consent form prior to the initiation of 
any study procedures. 
<Justification of Inclusion Criteria> 
1. 
The criterion was set as the target disease of the study. 
2. 
In order to select subjects who maintain capacity for secreting intrinsic insulin, 
the lower limit of the fasting C-peptide value was set at 0.6 ng/mL based on 
Training Guidebook for Board Certified Diabetologists (the revised 6th 
edition)[6]. 
3. 
The criterion was set to require a blood hemoglobin value of 10.0 g/dL or 
higher in reference to the therapeutic target for renal anemia provided in the 
“Clinical Practice Guidebook for Diagnosis and Treatment of Chronic Kidney 
Disease 2012” [7] and “Evidence-based Clinical Practice Guideline for CKD 
2013” [8] because a low blood hemoglobin level may affect HbA1c, which is 
defined as an efficacy endpoint. 


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4. 
The criterion was set to define a lower limit of 7.0% because The 
Evidence-based Practice Guideline for the Treatment for Diabetes in Japan 
2013 [9] recommends that the target value of HbA1c should be less than 7.0% 
from the perspective of prevention of complications. However, since subjects 
on hemodialysis (patients with end-stage renal failure) may have a low HbA1c 
level because of factors such as increased immature erythrocytes and shorter 
erythrocyte lifespan [8], it was decided to take glycoalbumin value 
additionally into consideration in evaluating subjects with the lower limit of 
HbA1c level of less than 7.0%. The acceptable glycoalbumin level for such 
subjects was set at 20% or higher in reference to Best Practice for Diabetic 
Patients on Hemodialysis 2012 [10]. In addition, the upper limit of HbA1c 
level was set at 10.0% to exclude subjects with very poor glycemic control 
with respect to the safety of the subjects. 
5. 
The criterion was set to select subjects with stable glycemic control. 
6. 
The Evidence-based Practice Guideline for the Treatment of Diabetes 2013 
[9] recommends to change treatment for patients who cannot achieve the 
target glucose level despite continuous diet and exercise therapy for 2 to 3 
months; therefore, patients who have been on a fixed diet and/or exercise 
therapy (if any) from at least 6 weeks prior to the start of the screening period 
(Week -6), i.e., at least 12 weeks prior to the start of Treatment Period I, will 
be included in this study. 
7. 
The Guideline for Clinical Evaluation of Hypoglycemic Agents (Revised 
Draft)” [4] stipulates that subjects for phase 3 confirmatory and long-term 
studies should be “adults patients with type 2 diabetes mellitus who are stable 
and are not treated with any hypoglycemic drugs,” while subjects for 
long-term combination therapy studies should be “adult patients with type 2 
diabetes mellitus refractory to 1 of commercially available hypoglycemic 
drugs treated over a certain period.” Therefore, patients who are not using 
antidiabetic drugs (including insulin preparations) from at least 6 weeks prior 
to the start of the screening period (Week -6) (i.e., at least 12 weeks prior to 
the start of Treatment Period I) or those who are using 1 antidiabetic drug 
(including insulin preparations) at a fixed dose and regimen will be included 
in this study. 
With respect to the safety of the subjects, the antidiabetic drug should be any 1 
of mitiglinide calcium hydrate, repaglinide, acarbose, miglitol, voglibose, or 
insulin preparations, which can be used for patients with severe renal 
impairment or end-stage renal failure according to the package insert. Similar 
DPP-4 inhibitors and GLP-1 receptor agonists are excluded with respect to the 
safety of the subjects and possible influence on the evaluation of efficacy and 
safety. 
8. 
The criterion was set to exclude patients with moderate or milder renal 
impairment in reference to the “Clinical Practice Guidebook for Diagnosis 
and Treatment of Chronic Kidney Disease 2012” [7]. In addition, 
hemodialysis was set as the only dialysis method permitted for patients with 


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end-stage renal failure with respect to the possible influence on the evaluation 
of efficacy and safety in the study. 
9. 
The criterion was set to select subjects who are not receiving hemodialysis 
and do not have the possibility of starting hemodialysis during Treatment 
Period I with respect to the safety of the subjects and possible influence on the 
evaluation of efficacy and safety in the study. 
10. 
The criterion was set to select subjects showing stable effects of hemodialysis 
with respect to the possible influence on the evaluation of efficacy and safety 
in the study. 
11 
The criterion was set to define a minimum of 20 years of age at which subjects 
can voluntarily consent to participation in the study. An upper limit of age was 
not set in order to collect results in elderly patients as much as possible. 
12. to 14. These criteria were set as basic matters to conduct clinical studies. 
7.2 
Exclusion Criteria 
Any subject who meets any of the following criteria will not qualify for entry into the 
study: 
1. The subject has clinically evident hepatic impairment (e.g., AST or ALT >=2.5 times 
the upper limit of normal or total bilirubin of >=2.0 mg/dL at the start of the screening 
period [Week -6] or at Week -2 of the screening period). 
2. The subject has any serious cardiac diseases, cerebrovascular disorders, or serious 
pancreatic or hematological diseases (e.g., subjects who require inpatient treatment or 
had been hospitalized for treatment within 24 weeks prior to the start of the screening 
period). 
3. The subject has severe ketosis, diabetic coma or pre coma, type 1 diabetes, severe 
infection, or severe external injury, or immediately before or after surgery. 
4. The subject has hemoglobinopathy (sickle cell disease, thalassemia, etc.). 
5. The subject experienced hypoglycemia (subjects with a blood glucose value of 
≤70 mg/dL or hypoglycemic symptoms) within 6 weeks prior to the start of the 
screening period or during the screening period (at least twice per week). 
6. The subject has inadequately controlled hypertension. 
7. For subjects who are being treated with 1 antidiabetic agent, the subject had been 
treated with at least 2 antidiabetic agentss on the day before 6 weeks prior to the start 
of the screening period (Week -6) (43 days prior to the start of the screening period). 
8. The subject has malignancies. 
9. The subject has a history of hypersensitivity or allergies to dipeptidyl peptidase-4 
(DPP-4) inhibitors. 
10. The subject has a history of gastrectomy or small intestinal resection. 
11. The subject is a habitual drinker and consumes a daily average of more than 100 mL 
of alcohol. 


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12. The subject has a history of drug abuse (defined as any illicit drug use) or a history of 
alcohol abuse. 
13. The subject is required to take excluded medications during the study period. 
14. The subject has received SYR-472 in a previous clinical study. 
15. The subject received any investigational products (including investigational drugs in 
a post-marketing clinical study) within 12 weeks prior to the start of the screening 
period. 
16. The subject is participating in other clinical studies at the time of informed consent. 
17. If female, the subject is pregnant or lactating or intending to become pregnant from 
the time of informed consent to within 1 month after the end of the study; or intending 
to donate ova during such time period. 
18. The subject is an immediate family member, study site employee, or is in a dependant 
relationship with a study site employee who is involved in conduct of this study (e.g., 
spouse, parent, child, sibling) or may consent under duress. 
19. The subject is hospitalized during the screening period or is deemed as requiring 
hospitalization during the study period by the investigator or sub-investigator, unless 
the hospitalization is for short-term evaluations including complete health checkups 
or for short-term admission for shunt operation (including shunt maintenance). 
20. The subject is deemed ineligible for the study for any other reason by the investigator 
or sub-investigator. 
Reference) Alcohol Conversion Chart 
Type 
Type 
Alcohol Content 
Volume Equivalent to 100 mL of Alcohol 
Brewages 
Sake 
15% 
670 mL (approximately 3 gou) 
Beer 
5% 
2000 mL (approximately 3 beer bottles in large 
size) 
Low-malt beer 
5% 
2000 mL 
Wine 
12% 
830 mL 
Shaoxing rice wine 
18% 
560 mL 
Distilled liquors 
Distilled spirit 
(Kou-type shouchu) 
35% 
290 mL 
Distilled spirit 
(Otsu-type shouchu) 
25% 
400 mL 
Whiskey 
40% 
250 mL (approximately 3 double shots) 
Brandy 
40% 
250 mL (approximately 3 double shots) 
Vodka 
40% 
250 mL (approximately 3 double shots) 
Mixed liquors 
Plum wine 
13% 
770 mL 
Synthetic sake 
16% 
630 mL 
 
<Justification of Exclusion Criteria> 
1., 2., 6., 8., and 9. 
These criteria were set with respect to the safety of the subjects. 


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3. 
The criterion was set with respect to the safety of the subjects and possible 
influence on the evaluation of efficacy in the study. 
4., 10. to 12., and 14. 
These criteria were set because they could influence the evaluation of efficacy 
and safety in the study. 
5. 
The criterion was set with respect to the safety of the subjects and possible 
influence on the evaluation of safety in the study. 
7. 
The criterion was set because if excluded antidiabetic drugs are discontinued 
in order to participate in the study under informed consent, the discontinuation 
of 2 or more drugs may jeopardize the safety of the subject. 
13. 
The criterion was set with respect to the safety of the subjects and possible 
influence on the evaluation of efficacy and safety in the study. 
15. to 18. and 20. 
These criteria were set as basic requirements to conduct clinical studies. 
19. 
The criterion was set because intervention in lifestyles due to hospitalization 
is likely to influence the glucose metabolism of subjects. 
7.3 
Excluded Medications and Treatments 
Subjects must be instructed not to take any medications including over-the-counter 
products, without first consulting with the investigator or sub-investigator. 
1. Excluded Medications 
Use of the following medications is prohibited in each period: 
(1) Screening Period and Treatment Period I 
• New antidiabetic drugs* 
• Other DPP-4 inhibitors and GLP-1 receptor agonists 
• Sulfonylureas, biguanides, thiazolidinediones, nateglinide, and SGLT-2 inhibitors 
*: Except for antidiabetic drugs that are being used at the start of the screening period (Week -6) and 
will be concomitantly used during the study period 
(2) Treatment Period II and Follow-up Period 
• New insulin preparations* 
• Other DPP-4 inhibitors and GLP-1 receptor agonists 
• Sulfonylureas, biguanides, thiazolidinediones, nateglinide, and SGLT-2 inhibitors 
*: Except for insulin preparations that are being used at the start of the screening period (Week -6) and 
will be concomitantly used during the study period 


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<Justification for Excluded Medications> 
In the screening period and Treatment Period I, changes in the basic treatment are 
prohibited with respect to the possible influence on the efficacy and safety evaluation of 
SYR-472. However, the addition of new insulin preparations is only prohibited in 
Treatment Period II and thereafter with respect to the safety of the subjects. In addition, 
the use of antidiabetic drugs that are contraindicated in patients with serious renal 
impairment and SGLT-2 inhibitors that cannot be used over a long period as of the start of 
the study is prohibited with respect to the safety of the subjects. Furthermore, the use of 
similar DPP-4 inhibitors and GLP-1 receptor agonists is prohibited with respect to the 
safety of the subjects and possible influence on the evaluation of efficacy and safety. 
2. Restricted Medications 
(1) Oral Hypoglycemic Agents 
1) Screening Period and Treatment Period I 
Changes in the dose/regimen or discontinuations/interruptions of oral hypoglycemic 
drugs that are being used at the start of the screening period (Week -6) and will be 
concomitantly used in the study period are prohibited. 
2) Treatment Period II and Follow-up Period 
• Changes in the dose/regimen or discontinuations/interruptions of oral hypoglycemic 
drugs that are being used at the start of the screening period (Week -6) and will be 
concomitantly used in the study period are allowed. 
• For subjects who are not using any other antidiabetic drug in Treatment Period I 
(those who are only treated with the study drug), the use of 1 new oral 
hypoglycemic drug* is allowed at Week 16 of the treatment period and thereafter. 
*: Any 1 of the following medications: mitiglinide calcium hydrate, repaglinide, acarbose, miglitol, or 
voglibose 
(2) Insulin Preparations 
For subjects who are receiving insulin preparations at the start of the screening period 
(Week -6) and continue to receive in the study period, insulin preparations should be 
administered as specified below. 
• Type of Insulin Preparation 
Any 1 of the mixed (rapid-acting or ultrarapid insulin containing no more than 30% of 
volume), intermediate-acting, or long-acting soluble insulin preparations should be used 
alone, and should not be changed throughout the study period. 
• Daily Dose (Unit) of Insulin Preparation 
1) Screening Period 
The daily dose (unit) of insulin preparation should be 40 units/day or less at the start of 
the screening period (Week -6), and the dose and regimen should not be changed during 
the screening period (for subjects on hemodialysis who receive different daily doses 
[unit] of insulin preparation on days of hemodialysis and on other days, each dose and 
regimen of insulin preparation should not be changed). 


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2) Treatment Period I 
The dose and regimen of insulin preparations at the start of the screening period 
(Week -6) should be maintained and no changes will allowed, in principle. 
However, the investigator or sub-investigator should consider reduction or increase in the 
daily dose (unit) of insulin preparation if the criteria described below are met. After dose 
reduction or increase, the unit after reduction or increase should be continued. 
Even if reduction in the daily dose (unit) of insulin preparation results in the 
discontinuation of insulin use, the study may be continued. If increase in the daily dose 
(unit) of insulin preparation results in a dose exceeding 40 units/day on a continuing basis, 
the investigator or sub-investigator should determine whether the study should be 
continued or discontinued, with respect to the safety of the subject. 
Criteria for dose reduction: If either criterion (i) or (ii) described below is met, the daily 
dose (unit) of insulin preparation may be reduced from the unit administered at the start of 
the screening period (Week -6) by up to 4 units (regardless of the number of changes). 
If it is necessary to reduce the dose from the unit administered at the start of the screening 
period (Week -6) by more than 4 units/day, the study should be discontinued and 
appropriate measures should be taken. 
i) 
A subject shows hypoglycemic symptoms, and the investigator or sub-investigator 
considers that the dose reduction of insulin preparation is necessary in view of the 
safety of the subjects. 
ii) Hypoglycemia is suspected since a subject has had 2 or more consecutive 
self-monitoring blood glucose values of ≤70 mg/dL, and the investigator or 
sub-investigator considers that the risk of developing hypoglycemia is high. 
Criteria for dose increase: If a subject has had 2 or more consecutive self-monitoring 
blood glucose values of >240 mg/dL and the investigator or sub-investigator considers 
that the increase of insulin preparation is necessary in view of the safety of the subjects, 
the daily dose (units) of insulin preparation at the start of the screening period (Week -6) 
can be increased by up to 4 units (regardless of the number of dose changes). 
If dose increase greater than 4 units/day from the unit administered at the start of the 
screening period (Week -6) is required, the subject will be withdrawn from the study and 
receive appropriate treatment. 
3) Treatment Period II and Follow-up Period 
The investigator or sub-investigator should consider reduction or increase in the daily 
dose (unit) of insulin preparation if the criteria described below are met. After dose 
reduction or increase, the unit after reduction or increase should be continued. 
Even if reduction in the daily dose (unit) of insulin preparation results in the 
discontinuation of insulin use, the study may be continued. If increase in the daily dose 
(unit) of insulin preparation results in a dose exceeding 40 units/day on a continuing basis, 
the investigator or sub-investigator should determine whether the study should be 
continued or discontinued, with respect to the safety of the subject. 
Criteria for dose reduction: If either criterion (i) or (ii) described below is met, reduction 
in the daily dose (unit) of insulin preparation should be considered. 


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i) 
A subject shows hypoglycemic symptoms, and the investigator or sub-investigator 
considers that the dose reduction of insulin preparation is necessary in view of the 
safety of the subjects. 
ii) Hypoglycemia is suspected since the subject has had 2 or more consecutive 
self-monitoring blood glucose values of ≤70 mg/dL, and the investigator or 
sub-investigator considers that the risk of developing hypoglycemia is high. 
Criteria for dose increase: If a subject has had 2 or more consecutive self-monitoring 
blood glucose values of >200 mg/dL and the investigator or sub-investigator considers 
that the increase of insulin preparation is necessary in view of the safety of the subjects, 
whether or not to increase the daily dose (units) of insulin preparation should be 
considered. 
<Justification of Restricted Medications> 
For oral hypoglycemic drugs, changes in the basic treatment are prohibited in the 
screening period and Treatment Period I with respect to the possible influence on the 
efficacy and safety evaluation of SYR-472. In Treatment Period II and the follow-up 
period, changes in the dose or regimen as well as discontinuations and interruptions are 
allowed due to ethical considerations on the state of glycemic control for patients with 
type 2 diabetes mellitus complicated by renal impairment during the 54-week study 
period. In addition, for subjects who do not receive any other antidiabetic drug in 
Treatment Period I and still show inadequate glycemic control after 4 weeks following 
entry into Treatment Period II (Week 16 of the treatment period or thereafter), 1 oral 
hypoglycemic drug only may be additionally administered at the discretion of the 
investigator and sub-investigator. 
For insulin preparations, changes in the daily dose (unit) are permitted according to the 
fixed criteria for dose reduction or increase, if the investigator or sub-investigator 
considers it necessary from the perspective of the safety of the subject. 
3. Other medications 
For medications other than those specified in 1 and 2 above, the daily dose administered 
at the start of the screening period (Week -6) should not be changed in Treatment Period I, 
in principle. However, if deemed necessary for treatment by the investigators due to the 
occurrence of an AE or other reasons, changes in the daily dose and administration of a 
new medication are permitted. It should be confirmed that the medication can 
administered to individuals with renal impairment. Caution should be exercised for 
medications that require careful use with the study drug and/or antidiabetic drug that is 
used at the start of the screening period (Week -6) and continued during the study period 
as recommended in the package insert. 
<Justification for Medications Other Than Excluded Medications and Restricted 
Medications> 
The use of other medications is permitted because they are unlikely to influence the 
evaluation of drug effects unless the daily dose is changed. The daily dose of such 
medications should not be changed in principle; however, changes in the daily dose and 
administration of a new medication due to the onset of an AE or other reasons are 
permitted for ethical considerations. 


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4. Other prohibitions 
Hospitalization is prohibited during the study period, excluding short-term 
hospitalization for medical evaluations including complete health checkups or for 
short-term admission for shunt operation (including shunt maintenance). 
<Justification for Other prohibitions> 
Hospitalization during the study period is prohibited because intervention in lifestyle due 
to hospitalization is likely to influence glucose metabolism (for example, continued 
hospitalization for 1 week or longer), possibly affecting the evaluation of drug effects. 
7.4 
Diet, Fluid, Activity Control 
The investigator, sub-investigator, and study coordinator will pay attention to the 
following requirements and provide necessary instructions to subjects: 
1. For diet and/or exercise therapy (if any), the investigator or sub-investigator should 
provide fixed instructions on diet and/or exercise therapy throughout the study period. 
In addition, subjects should be instructed to follow instructions on diet and/or exercise 
therapy. 
2. Subjects are required to comply with the prescribed dose and regimen of the study 
drug. Subjects are required to bring study drug sheet to the study site at each visit. 
Study drug administration should be started after all procedures scheduled for the end 
of the screening period (Week 0) are completed (the day when study drug 
administration is started is defined as the first day of dosing). The SYR-472 25 mg or 
placebo tablets should be taken once weekly (on the same day of the week as the day 
of the first dose). If a dose is missed, just 1 tablet for the last missed dose should be 
taken immediately after the subject notices it. Subjects should not take more than 1 
SYR-472 25 mg or placebo tablet for several missed doses prior to the next scheduled 
dosing day. 
3. Subjects should be instructed to ingest glucose or sucrose (sugar) in case any 
hypoglycemic symptom (e.g., unusual hunger, weakness, finger tremor, cold sweat, 
or palpitations) appears, and to visit the study site immediately if the symptom does 
not improve despite glucose or sucrose ingestion. 
4. For subjects using insulin preparations, the investigator or sub-investigator should 
provide explanations and instructions about the method and timing of self-monitoring 
of blood glucose at the end of the screening period (Week 0). Subjects should also be 
instructed to report the results of self-monitoring of blood glucose to the investigator 
or sub-investigator at each visit. In particular, they should be instructed to report to 
the investigator or sub-investigator whether or not they have experienced a blood 
glucose value exceeding 240 mg/dL (Treatment Period I) or 200 mg/dL (Treatment 
Period II and follow-up period), or a blood glucose value of 70 mg/dL or less as 
measured by self-monitoring, and whether or not they have experienced any 
hypoglycemic symptoms. 
For the time points of self-monitoring of blood glucose, refer to Section 9.1.21. 
5. If a subject plans to use any drugs (including over-the-counter [OCT] drugs) other 
than those prescribed by the investigator or sub-investigator, he/she should consult 


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with the investigator or sub-investigator in advance, whenever possible. In case these 
drugs have already been used, immediate notification is required. 
6. If a subject plans to visit another physician, prior notification to the investigator or 
sub-investigator is required. If a subject has already been treated by another physician, 
immediate notification is required. 
7. Subjects are required to be punctual for visit appointments and undergo physical 
examinations and prescribed tests as scheduled. If a subject cannot visit the study site 
on the scheduled day, immediate contact to the study site is required. 
8. Subjects should be instructed to avoid excessive drinking and eating, extreme 
changes in diet (e.g. ingestion of a high-fat diet), or excessive exercises and live as 
usual on the days before the study visit. 
9. On the day of the visit, subjects should visit the site under fasted conditions (at least 
10 hours of fasting). Subjects using oral hypoglycemic drugs or insulin preparations 
should visit the site without taking them on the day of the visit. 
10. Subjects are required to undergo routine ophthalmologic examination and pay 
attention to complications including diabetic retinopathy. 
7.5 
Criteria for Discontinuation or Withdrawal of a Subject 
The primary reason for discontinuation or withdrawal of the subject from the study 
should be recorded in the case report form (eCRF) using the following categories. For 
screen failure subjects, refer to Section 9.1.25. 
1. Pretreatment event (PTE) or AE 
The subject has experienced a PTE or 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 PTE or AE. 
Liver Function Test (LFT) Abnormalities 
Study drug should be discontinued immediately with appropriate clinical follow-up 
(including repeat laboratory tests, until a subject’s laboratory profile has returned to 
normal/baseline status [value at immediately after the inforned consent for PTEs and 
at immediately before the initiation of the study drug for AEs], see Section 9.1.9), if 
the following circumstances occur at any time during study drug treatment: 
– alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >8 × upper 
limit of normal (ULN), or 
– ALT or AST >5 × ULN and persists for more than 2 weeks, or 
– ALT or AST >3 × ULN in conjunction with elevated total bilirubin >2 × ULN 
or international normalized ratio (INR) >1.5, or 
– ALT or AST >3 × ULN with appearance of fatigue, nausea, vomiting, right 
upper quadrant pain or tenderness, fever, rash and/or eosinophilia (>5%). 
• Renal Function Test Abnormalities 
For subjects not on hemodialysis at the start of the screening period (Week -6) 
(patients with severe renal impairment), the study drug should be discontinued with 


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appropriate clinical follow-up until a subject’s laboratory profile has returned to 
normal/baseline status for subjects not on hemodialysis at the start of the screening 
period (Week -6) (patients with severe renal impairment) if the subject shows 
worsening of renal function that may necessitate hemodialysis in Treatment Period I 
and is considered inappropriate to continue the study in the opinion of the investigator 
or sub-investigator, or if the subject shows rapid worsening of Ccr (e.g., reduction of 
30% or more) on 2 consecutive post dose measurements, as compared with the value 
at the end of the screening period (Week 0), and is considered inappropriate to 
continue the study in the opinion of the investigator or sub-investigator. 
• Serious hypoglycemia 
A serious hypoglycemic symptom (coma, depressed consciousness, etc.; severe 
enough to require active sugar or glucagon administration or other resuscitation by 
other people) appears. For reporting in the event of serious hypoglycemia, refer to 
Section 10.2.1.3 and Section 10.2.2. 
• Serious hyperglycemia 
A serious hyperglycemic symptom (coma, ketosis, ketoacidosis, etc.; severe enough 
to require assistance by other people) appears. For reporting in the event of serious 
hyperglycemia, refer to Section 10.2.2. 
• Acute pancreatitis 
Acute pancreatitis is conclusively diagnosed. For reporting in the event of acute 
pancreatitis, refer to Section 10.2.1.3. 
• Abnormal QT/QTc interval 
Serious arrhythmia or significant QT interval prolongation (e.g., an absolute QTcF 
interval of >500 msec or a change of >60 msec from the end of the screening period 
[Week 0]) is observed, and the investigator or sub-investigator considers it 
inappropriate for the subject to continue the study. For reporting in the event of 
abnormal QT/QTc interval, refer to Section 10.2.1.3. 
2. Significant protocol deviation. 
The discovery postrandomization 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 study site and attempts to contact the subject were 
unsuccessful. Attempts to contact the subject must be documented. 
4. Voluntary withdrawal. 
The subject wishes to withdraw from the study. The reason for withdrawal, if 
provided, should be recorded in the eCRF. 
NOTE: All attempts should be made to determine the underlying reason for the 
withdrawal and, where possible, the primary underlying reason should be 
recorded (i.e., withdrawal due to an AE or lack of efficacy should not be 
recorded in the “voluntary withdrawal” category). 


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5. Study termination. 
The sponsor, IRB, or regulatory agency terminates the study. 
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 9.1.11. 
7. Lack of efficacy. 
The investigator or sub-investigator has determined that the subject is not benefiting 
from the study drug treatment; and, continued participation would pose an 
unacceptable risk to the subject. 
8. Other. 
NOTE: The specific reasons should be recorded in the “specify” field of the eCRF. 
7.6 
Procedures for Discontinuation or Withdrawal of a Subject 
The investigator or sub-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 
or sub-investigator. In addition, efforts should be made to perform all procedures 
scheduled for the Early Termination Visit. 


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8.0 
CLINICAL TRIAL MATERIAL MANAGEMENT 
8.1 
Study Drug 
8.1.1 Dosage Form, Manufacturing, Packaging, and Labeling 
8.1.1.1 Study drug 
The study drug refers to SYR-472DB tablets (SYR-472 25 mg tablets or placebo tablets) 
for Treatment Period I and SYR-472 25 mg tablets for Treatment Period II. 
1. Dosage Form 
(i) SYR-472DB tablets (for Treatment Period I) 
Genetic name: Trelagliptin Succinate (JAN) 
Chemical name: 2-({6-[(3R)-3-aminopiperidin-1-yl]-3-methyl-2,4-dioxo-3,4-
 
dihydropyrimidin-1(2H)-yl}methyl)-4-fluorobenzonitrile monosuccinate 
Dose: 
• SYR-472 25 mg tablets: 1 tablet contains 25 mg of SYR-472 (as free base). 
• SYR-472 placebo tablets: the placebo tablet does not contain SYR-472. 
Dosage form: Yellow-red film-coated tablets 
The appearance of SYR-472 25 mg tablets and SYR-472 placebo tablets is mutually 
indistinguishable. 
(ii) SYR-472 25 mg tablets (for Treatment Period II) 
Genetic name: Trelagliptin Succinate (JAN) 
Chemical name: 2-({6-[(3R)-3-aminopiperidin-1-yl]-3-methyl-2,4-dioxo-3,4-
 
dihydropyrimidin-1(2H)-yl}methyl)-4-fluorobenzonitrile monosuccinate 
Dose: 
• SYR-472 25 mg tablets: 1 tablet contains 25 mg of SYR-472 (as free base). 
Dosage form: Yellow-red film-coated tablets 
2. Manufacturing 
SYR-472 25 mg and placebo tablets were manufactured by Takeda Pharmaceutical 
Company Limited. 
3. Packaging and Labeling 
For Treatment Period I, 2 AL-AL blister sheets each containing 8 tablets (12 tablets 
for 12 weeks and 4 spare tablets for 4 weeks) are packed in a carton for 1 subject. For 
Treatment Period II, 16 AL-AL blister sheets each containing 8 tablets (128 tablets) 
are packed in a carton. The study drug for Treatment Period II can be used in 
common among all subjects in each study site. 


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The outer carton is labeled with a statement that it is for clinical study use, and with 
information such as the name of the study drug, quantity, sponsor’s name and address, 
manufacturing number, and storage conditions. 
8.1.2 Storage 
The study drug will be stored at room temperature (1 to 30°C). 
Study drug must be kept in an appropriate, limited-access, secure place until it is used or 
returned to the sponsor or designee for destruction. All drugs provided by the sponsor 
must be stored under the conditions specified on the label, and remain in the original 
container until dispensed. A daily temperature log of the drug storage area must be 
maintained every working day. 
8.1.3 Dose and Regimen 
In Treatment Period I, 1 tablet of SYR-472 25 mg or placebo will be orally administered 
once weekly before breakfast. In Treatment Period II, 1 tablet of SYR-472 25 mg tablet 
will be orally administered once weekly before breakfast. 
Subjects will start study drug administration after all procedures scheduled for the end of 
the screening period (Week 0) are completed. At subsequent visits when the study drug is 
administered, all specified procedures should be performed prior to study drug 
administration. 
Table 8.a describes the dose and regimen that will be provided to each group in Treatment 
Period I. 
Table 8.a 
Dose and Regimen (Treatment Period I) 
Treatment Group 
Dose 
Treatment Description 
SYR-472 25 mg tablet 
SYR-472 placebo 
tablet 
SYR-472 25 mg group 
SYR-472 25 mg tablet 
once weekly 
×1 
×0 
Placebo group 
SYR-472 placebo tablet 
once weekly 
×0 
×1 
8.1.4 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 study protocol. 
All cases of overdose (with or without associated AEs) will be documented on an 
Overdose page of the eCRF, in order to capture this important safety information 
consistently in the database. AEs associated with an overdose will be documented on AE 
CRFs according to Section 10.0, PRETREATMENT EVENTS AND ADVERSE 
EVENTS. 
Serious adverse events (SAEs) associated with overdose should be reported according to 
the procedure outlined in Section 10.2.2, Collection and Reporting of SAEs. 
In the event of drug overdose, the subject should be treated symptomatically. 


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8.2 
Study drug Assignment and Dispensing Procedures 
After judging and confirming eligibility of a subject, the investigator or sub-investigator 
will assign the subject to receive the study drugs for Treatment Period I which have been 
allocated to each study site (SYR-472DB tablets) in consecutive order of medication ID 
number. The investigator or investigator’s designee will record the medication ID 
number in the eCRF. 
In Treatment Period II, the investigator or sub-investigator will start administration of the 
study drug for Treatment Period II (SYR-472 25 mg tablet) after performing all physical 
examinations/examinations/assessments scheduled for Week 12 in the treatment period. 
8.3 
Randomization Code Creation and Storage 
Randomization personnel of the sponsor or designee will generate the randomization 
schedule. All randomization information will be stored in a secured area, accessible only 
by authorized personnel. 
8.4 
Study Drug Blind Maintenance 
Emergency Key Code Administration Center will maintain the subject's study drug blind 
information until emergency key code breaking or data lock of all subjects. 
Since the measured values of study drug concentration and DPP-4 may hinder study drug 
blind maintenance in this study, the central laboratory institute should retain the final 
results of these parameters until the key code breaking without disclosing them 
externally; the final results will be reported to the investigator via the sponsor after the 
code breaking. 
The study blind in Treatment Period I will be maintained until the end of the study. 
8.5 
Unblinding Procedure 
The study drug blind shall not be broken by the investigator or sub-investigator unless 
information concerning the study drug is necessary for the medical treatment of the 
subject. 
For unblinding a subject, the study drug blind can be obtained by contacting the 
Emergency Key Code Administration Center (Annex 1). 
If the study drug blind is broken, the date, time, and reason the blind is broken must be 
recorded in the document called Record of Early Blind-Breaking and submitted to the 
sponsor. The same information (except the time) must be recorded on the eCRF. 
If any site personnel are unblinded, study drug must be discontinued immediately and the 
subject must be withdrawn from the study. 
8.6 
Accountability and Destruction of Sponsor-Supplied Drugs 
The site designee will receive the procedures for handling, storage and management of 
study drugs created by the sponsor, according to which the site designee will 
appropriately manage the sponsor-supplied drug. The investigator will also receive those 
procedures from the sponsor. The procedures include those for ensuring appropriate 
receipt, handling, storage, management, dispensation of the sponsor-supplied drug, and 


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collection of unused medications from the subject as well as return of them to the sponsor 
or destruction of them. 
The site designee will immediately return unused medications to the sponsor after the 
study is closed at the site. 


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9.0 
STUDY PLAN 
9.1 
Study Procedures 
The following sections describe the study procedures and data to be collected. For each 
procedure, subjects are to be assessed by the same investigator or sub-investigator 
whenever possible. The Schedule of Study Procedures is located in Appendix A. 
If a subject undergoing hemodialysis (patients with end-stage renal failure) receive 
hemodialysis on the day of study site visit, all procedures should be performed before 
hemodialysis. 
9.1.1 Informed Consent Procedure 
The requirements of the informed consent are described in Section 15.2. 
Informed consent must be obtained prior to the subject entering into the study, and before 
any protocol-directed procedures are performed. 
A unique subject identification number (subject number) will be assigned to each subject 
at the time that informed consent is explained; this subject number will be used 
throughout the study. 
PGx Informed Consent Procedure 
A separate informed consent form pertaining to storage of the sample must be obtained 
prior to collecting a blood sample for PGx Research for this study. The provision of 
consent to collect and analyze the PGx sample is independent of consent to the other 
aspects of the study. 
9.1.2 Demographics, Medical History, and Medication History Procedure 
Demographic information to be obtained will include date of birth, sex, height, weight, 
body mass index (BMI), alcohol use, smoking status, onset time of type 2 diabetes, 
presence or absence of hemodialysis and diet and/or exercise therapy. 
The BMI will be calculated by the sponsor using the formula provided below: 
Metric: BMI = weight (kg)/[height (m)]2 
Height should be measured in centimeters without decimal places (rounding off the first 
decimal place). For measurement of weight, refer to Section 9.1.5. 
Medical history to be obtained will include determining whether the subject has any 
significant conditions or diseases relevant to the disease under study that stopped within 1 
year prior to signing of informed consent. Ongoing conditions are considered concurrent 
medical conditions (see Section 9.1.8). 
Medication history information to be obtained includes drug name, route of 
administration, daily dose, and end date of any antidiabetic drug stopped between 24 
weeks prior to the end of the screening period (Week 0) and the start of the screening 
period (Week -6). 
9.1.3 Antidiabetic Drugs Administered During the Study 
1. Screening Period 


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For antidiabetic drugs administered at the start of the screening period (Week -6) and 
concomitantly used during the study period, the drug name, type (for insulin 
preparations), and daily dose of antidiabetic drugs used at the start of the screening period 
(Week -6) and concomitantly used during the study will be recorded in the eCRF. 
2. Treatment Period I 
For antidiabetic drugs administered at the start of the screening period (Week -6) and 
concomitantly used during the study period, the drug name, type (for insulin 
preparations), and daily dose of antidiabetic drugs used at the start of the screening period 
(Week -6) and concomitantly used during the study period will be recorded in the eCRF. 
In case concomitant use of other antidiabetic drugs in addition to an antidiabetic drug 
used at the start of the screening period (Week -6) is judged to be appropriate, the 
investigator or sub-investigator should record the reason for the judgment in the eCRF 
according to the following categories: 
• Combination therapy is expected to be more effective. 
• Development of AEs due to dose increase is concerned. 
• The maximum dose has already been administered. 
• Others 
3. Treatment Period II 
For subjects who do not receive 1 antidiabetic drug other than the study drug in Treatment 
Period I and start the administration of 1 new oral hypoglycemic drug from Week 16 of 
the Treatment Period II (or thereafter), the drug name, daily dose, date of the start and end 
of administration, will be recorded in the eCRF. 
9.1.4 Physical Examination Procedure 
A baseline physical examination (defined as the assessment prior to first dose of study 
drug) will consist of the following body systems: (1) eyes; (2) ears, nose, throat; (3) 
cardiovascular system; (4) respiratory system; (5) gastrointestinal system; (6) 
dermatologic system; (7) extremities; (8) musculoskeletal system; (9) nervous system; 
(10) lymph nodes; and (11) other. 
All subsequent physical examinations should assess clinically significant changes from 
the assessment prior to the first dose examination. 
9.1.5 Weight 
Weight should be measured in kilograms to one decimal place (rounding off the second 
decimal place) under fasting conditions (at least 10 hours of fasting) to avoid the effect of 
meal. For subjects receiving hemodialysis (patients with end-stage renal failure), dry 
weight should be used. 
9.1.6 Vital Sign Procedure 
Vital signs will include sitting or supine blood pressure (resting more than 5 minutes) 
(systolic and diastolic) and pulse. 


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9.1.7 Documentation of Concomitant Medications 
Concomitant medication is any drug given in addition to the study drug and antidiabetic 
drugs. These may be prescribed by a physician or obtained by the subject over the counter. 
Concomitant medication is not provided by Takeda. At each study visit, subjects will be 
asked whether they have taken any medication other than the study drug (including 
vitamin supplements, over-the-counter medications, and herbal preparations) used from 
the start of the screening period (Week -6) through the end of the study, and the drug 
name, route of administration, dates of the start and end of administration, and purpose of 
use must be recorded in the eCRF. 
9.1.8 Documentation of Concurrent Medical Conditions 
Concurrent medical conditions are those significant ongoing conditions or diseases that 
are present at signing of informed consent. This includes clinically significant laboratory, 
ECG, or physical examination abnormalities noted at baseline examination. The 
condition (i.e., diagnosis) should be described. 
9.1.9  Procedures for Clinical Laboratory Samples 
Clinical laboratory tests that will be performed in this study are shown in Table 9.a. 
All samples will be collected in accordance with acceptable laboratory procedures. The 
maximum volume of blood at any single visit is approximately 27 mL, and the 
approximate total volume of blood for the study is 322 mL. 


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Table 9.a 
Clinical Laboratory Tests 
Hematology 
Serum Chemistry 
Red blood cells 
Reticulocytes 
White blood cells 
Hemoglobin 
Hematocrit 
Platelets 
White blood cells with differential 
(neutrophils, lymphocytes, monocytes, 
eosinophils, basophils) 
Erythrocyte indices (MCV, MCH, MCHC) 
Alanine aminotransferase 
Aspartate aminotransferase 
γ-Glutamyl transferase 
Alkaline phosphatase 
Total bilirubin 
Total protein 
Albumin 
Creatinine 
Amylase 
Lipase 
Blood urea nitrogen 
Uric acid 
Creatine kinase 
Lactate dehydrogenase 
Total cholesterol 
Triglyceride (fasting) 
Low-density lipoprotein (LDL) cholesterol (direct 
measurement) 
High-density lipoprotein (HDL) cholesterol 
high-sensitivity CRP 
Potassium 
Sodium 
Calcium 
Chloride 
Phosphate 
Ferrum 
Other: 
Pregnancy test (serum or urine human chorionic gonadotropin [hCG]) (female subjects of childbearing 
potential) 
 
The central laboratory (Annex 1) will perform laboratory tests listed above except for the 
pregnancy test. Creatinine clearance (Ccr) will be calculated by the sponsor using the 
Cockcroft-Gault equation. 
Cockcroft-Gault equation 
Male: Ccr = {(140 - age) × weight (kg)} / {72 × serum creatinine (mg/dL)} 
Female: Ccr = 0.85 × {(140 - age) × weight (kg)} / {72 × serum creatinine (mg/dL)} 
If subjects experience ALT or AST >3 × ULN, follow-up laboratory tests (at a minimum, 
serum alkaline phosphatase, ALT, AST, total bilirubin, GGT, and INR) should be 
performed within a maximum of 7 days and preferably within 48-72 hours after the 
abnormality was noted. (Refer to Section 7.5 and Section 10.2.3) 
The results of laboratory tests will be returned to the investigator or sub-investigator, who 
is responsible for reviewing and filing these results. The investigator will also maintain a 
copy of the reference ranges including their amendment for the laboratory used. 
9.1.10 Contraception and Pregnancy Avoidance Procedure 
From signing of informed consent and throughout the duration of the study and for 1 
month after the end of the study, female subjects of childbearing potential (i.e., 


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nonsterilized, premenopausal female subjects) who are sexually active must use 
acceptable methods of contraception. Such subjects will be provided with information on 
acceptable methods of contraception as part of the subject informed consent process, and 
will be asked to sign a consent form stating that they understand the requirements for 
avoidance of pregnancy during the course of the study. During the course of the study, 
regular serum/urine hCG pregnancy tests will be performed, and subjects will receive 
continued guidance with respect to avoiding pregnancy as part of the study procedures 
(Appendix A). 
In addition to a negative serum/urine hCG pregnancy test at the start of the screening 
period (Week -6), subjects also must have a negative serum/urine hCG pregnancy test 
immediately before randomization. Subjects must also have a negative serum or urine 
hCG pregnancy test at Week 24 and Week 52 of the treatment period or early termination. 
9.1.11 Pregnancy 
If any subject is found to be pregnant during the study she should be withdrawn and any 
sponsor-supplied drug should be immediately discontinued. 
If the pregnancy occurs during the study period or within 1 month after the end of the 
study, the pregnancy should be reported immediately, using a pregnancy notification 
form, to the contact listed in Annex 1. 
Should the pregnancy occur during or after administration of blinded drug, the 
investigator or sub-investigator must inform the subject of their right to receive treatment 
information. If the subject chooses to receive unblinded treatment information, the 
individual blind should be broken by the investigator or sub-investigator. Subjects 
randomized to placebo who discontinued in Treatment Period I without proceeding to 
Treatment Period II need not be followed. 
If the female subject agrees to the primary care physician being informed, the investigator 
or sub-investigator should notify the primary care physician that the subject was 
participating in a clinical study at the time she became pregnant and provide details of 
treatment the subject received (blinded or unblinded, as applicable). 
All reported pregnancies will be followed up to final outcome under the agreement from 
the female subject, using the pregnancy form. The outcome, including any premature 
termination, must be reported to the sponsor. An evaluation after the birth of the child will 
also be conducted. 
9.1.12 ECG Procedure 
A standard 12-lead ECG will be recorded after a rest of at least 5 minutes. The 
investigator or sub-investigator will interpret the ECG using 1 of the following 
categories: within normal limits, abnormal but not clinically significant, or abnormal and 
clinically significant. 
The following parameters will be recorded on the eCRF from the subject’s ECG trace: 
heart rate, RR interval, PR interval, QRS interval, QT interval, and QTcF interval. 


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9.1.13 Fasting C-peptide 
Fasting C-peptide will be measured in the central laboratory. Blood samples will be 
collected under fasting condition (after at least 10-hour fasting). 
9.1.14 HbA1c (NGSP Value) 
HbA1c will be measured in the central laboratory. 
9.1.15 Fasting Blood Glucose, Fasting Glucagon 
Fasting blood glucose and fasting glucagon will be measured in the central laboratory. 
Blood samples will be collected under fasting condition (after at least 10-hour fasting). 
9.1.16 Glycoalbumin 
Glycoalbumin will be measured in the central laboratory. 
9.1.17 DPP-4 Activity 
DPP-4 activity will be measured in the central laboratory. For study drug blind 
maintenance, refer to Section 8.4. 
9.1.18 Blood Transfusion 
Whether or not the subject has received a blood transfusion from the start of the screening 
period (Week -6) through the end of the study (if yes, the date and type of blood 
transfusion [whole blood, red blood cells, plasma, or platelets]) will be recorded in the 
eCRF. 
9.1.19 Introduction of Hemodialysis 
For subjects not receiving hemodialysis (patients with severe renal impairment), whether 
or not hemodialysis has been introduced between the start of the study drug 
administration (Day 1 of administration of the study drug for Period I) through the end of 
the study (if yes, the date of introduction) will be recorded in the eCRF. 
9.1.20 Presence or Absence of Changes and Compliance of Diet and/or Exercise 
Therapy 
Presence or absence of changes in diet and/or exercise therapy should be recorded in the 
eCRFs. If any instruction for diet and/or exercise therapy has to be changed, the date, 
contents, and reason for the change should be recorded in the source document. 
Instructions for diet and/or exercise therapy (if any) given to subjects by the investigator 
or sub-investigator should be consistent throughout the study. 
Compliance with diet and/or exercise therapy (if any) will be monitored and rated on the 
4-grade scale shown below: 
1. Fully complied (90% or more) 
2. Almost complied (70% or more) 
3. Occasionally complied (50% or more) 


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CONFIDENTIAL 
hypoglycemia and treatment is required, the contents of treatment should also be recorded 
in the eCRF (refer to Section 9.1.21). 
If any hypoglycemic symptoms are observed and no blood glucose values have been 
obtained at appropriate time points, whether or not the symptoms was caused by 
decreased blood glucose (≤ 70 mg/dL) should be assessed and recorded in the eCRF. 
Hypoglycemia will be classified according to the following definitions in reference to the 
“The Guideline for Clinical Evaluation of Hypoglycemic Agents (Revised draft)” [4]. 
• Significant hypoglycemia: an event requiring assistance of another person to 
actively administer carbohydrate, glucagon, or other resuscitative actions. 
• Symptomatic hypoglycemia: an event accompanied by typical symptoms of 
hypoglycemia with a measured plasma glucose concentration of ≤70 mg/dL 
(including self-monitoring of blood glucose values). 
• Asymptomatic hypoglycemia: an event not accompanied by typical symptoms of 
hypoglycemia but with a measured plasma glucose concentration of ≤70 mg/dL 
(including sself-monitoring of blood glucose values). 
• Probable symptomatic hypoglycemia: an event accompanied by symptoms of 
hypoglycemia without a plasma glucose determination but that was presumably 
caused by a plasma glucose concentration of ≤70 mg/dL (including self-monitoring 
of blood glucose values). 
• Relative hypoglycemia: an event accompanied by the typical symptoms of 
hypoglycemia observed in patients with diabetes mellitus is assumed, but with a 
measured plasma glucose concentration >70 mg/dL (including self-monitoring of 
blood glucose values). 
9.1.23 PGx Sample Collection 
One 5-mL whole blood sample for PGx should be collected at the end of the screening 
period (Week 0) from the subject who signed PGx informed consent after the study drug 
was assigned for possible exploratory investigation of markers enabling the prediction of 
drug response. 
PGx sample should not be collected from any subject who has received bone marrow 
transplant or whole blood transfusion within 6 months of any sample collection. 
See the separately created procedure for directions on collecting, handling, and storage of 
PGx samples. 
9.1.24 Pharmacokinetic Sample Collection and Analysis 
9.1.24.1 Collection of Plasma for Pharmacokinetic Sampling 
Blood samples (5 mL/sample) for pharmacokinetic analysis of SYR-472Z will be 
collected in blood sampling tubes containing anticoagulant according to the schedule 
shown in Appendix A, and plasma will be taken. 
Instructions for sample processing and shipment are provided in the separately prepared 
Procedures for Handling of Biological Samples for Drug Concentration Measurement. 


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9.1.27 Hospitalization 
If a subject is hospitalized for 1 week or longer during the study period due to a SAE or 
other reasons, the investigator or sub-investigator will record the hospitalization in the 
eCRF. 
9.2 
Monitoring Subject Treatment Compliance 
Subjects will be required to bring unused study drugs and antidiabetic drugs (if any) to the 
study site at each visit. 
For the SYR-472DB tablets (for use in Treatment Period I) and the SYR-472 25 mg 
tablets (for use in Treatment Period II), the date of dosing will be recorded in the eCRFs. 
For antidiabetic drugs (if any), treatment compliance during the study will be assessed 
and rated on the 4-point scale shown below at each visit: 
1. Fully Complied (90% or more) 
2. Almost complied (70% or more) 
3. Occasionally complied (50% or more) 
4. Rarely complied (less than 50%) 
If a subject is persistently noncompliant with the study drug (e.g., 70% of the allocated 
medication for the period since the last visit), it may be appropriate to withdraw the 
subject from the study. The authorized study personnel conducting the re-education must 
document the process in the subject source records. 
9.3 
Schedule of Observations and Procedures 
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 Screening (Week -6 to Week 0) 
At the start of the screening period (Week -6), subjects will be screened within 49 to 35 
days prior to study drug administration. 
Subjects will be screened in accordance with predefined inclusion and exclusion criteria 
as described in Section 7.0. 
Subjects will be randomized at the end of the screening period (Week 0). 
See Section 9.1.25 for procedures for documenting screening failures. 
9.3.2 Randomization 
If the subject has satisfied all of the inclusion criteria and none of the exclusion criteria for 
randomization, the subject should be randomized as described in Section 8.2. 
Subjects will be instructed on when to take the first dose of study drug as described in 
Section 6.1. 


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9.3.3 Treatment Period 
All specified procedures will be performed at each visit. 
9.3.4 Week 52 in the Treatment Period or Early Termination 
All procedures scheduled for the final visit will be performed at Week 52 of the treatment 
period. 
For subjects prematurely withdrawn from the study during the treatment period, all 
procedures scheduled for Week 52 will be performed within 7 days after the final dose of 
the study drug (reckoned from the day after the final dose) whenever possible. 
For all subjects receiving study drug, the investigator or sub-investigator must complete 
the End of Study eCRF page. 
9.3.5 Follow-up 
All procedures scheduled for the end of the follow-up period will be performed at the 21st 
day after the final dose of the study drug (reckoned from the day after the final dose). 
For subjects who discontinued study treatment, all procedures scheduled for the end of 
the follow-up period should be performed wherever possible. 
9.3.6 Post Study Care 
The study drug will not be available upon completion of the subject’s participation in the 
study. 
9.4 
Biological Sample Retention and Destruction 
Samples of 5-mL whole blood collected for PGx will be stored frozen at the storage site 
for PGx samples (Annex 1). 
The collected samples will be retained for 20 years from the day when a first PGx sample 
was collected during the study. 
When subjects request disposal of a stored sample during the retention period, the site 
will ask the storage site for PGx samples (Annex 1) to destroy the sample via the sponsor 
according to the procedure. The storage site for PGx samples (Annex 1) will destroy the 
sample in accordance with the procedure, and notify the site and sponsor. However, any 
samples should not be destroyed if all the documents (including medical records) have 
been destroyed which could identify the subject and it is impossible to link the sample to 
the subject. 
Even if the sample can be linked to the subject, when PGx investigation has been 
conducted, the remaining samples will be destroyed and the results of PGx investigation 
of anonymized subject will be retained by the sponsor. 
The sponsor will build a management system required for protection of the subject’s 
personal information, define standards for collecting store and destruction of samples, 
and prepare appropriate procedures. 


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10.0 
PRETREATMENT EVENTS AND ADVERSE EVENTS 
10.1 
Definitions 
10.1.1 PTEs 
A PTE is defined as any untoward medical occurrence in a clinical investigation subject 
who has signed informed consent to participate in a study but prior to administration of 
any study drug; it does not necessarily have to have a causal relationship with study 
participation. 
10.1.2 AEs 
An AE is defined as any untoward medical occurrence in a clinical investigation subject 
administered a drug; it does not necessarily have to have a causal relationship with this 
treatment. 
An AE can therefore be any unfavorable and unintended sign (e.g., a clinically significant 
abnormal laboratory finding), symptom, or disease temporally associated with the use of 
a drug whether or not it is considered related to the drug. 
10.1.3 Additional Points to Consider for PTEs and AEs 
An untoward finding generally may: 
• 
Indicate a new diagnosis or unexpected worsening of a pre-existing condition. 
(Intermittent events for pre-existing conditions underlying disease should not be 
considered PTEs or AEs.) 
• 
Necessitate therapeutic intervention. 
• 
Require an invasive diagnostic procedure. 
• 
Require discontinuation or a change in dose of study drug or a concomitant 
medication. 
• 
Be considered unfavorable by the investigator for any reason. 
Diagnoses 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 a PTE(s) or as an AE(s). 
Laboratory values and ECG findings: 
Changes in laboratory values or ECG parameters are only considered to be PTEs or AEs 
if they are judged to be clinically significant (i.e., if some action or intervention is 
required or if the investigator or sub-investigator judges the change to be beyond the 
range of normal physiologic fluctuation). A laboratory re-test and/or continued 
monitoring of an abnormal value 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. 


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If abnormal laboratory values or ECG findings are the result of pathology for which there 
is an overall diagnosis (e.g., increased creatinine in renal failure), the diagnosis only 
should be reported appropriately as a PTE or as an AE. 
Pre-existing conditions: 
Pre-existing conditions (present at the time of signing of informed consent) are 
considered concurrent medical conditions and should NOT be recorded as PTEs or AEs. 
Baseline evaluations (e.g., laboratory tests, ECG, X-rays) should NOT be recorded as 
PTEs unless related to study procedures. However, any abnormal finding related to study 
procedures (e.g., bruise after blood draw) should be recorded as a PTE. If the subject 
experiences a worsening or complication of a concurrent condition, the worsening or 
complication should be recorded appropriately as a PTE (worsening or complication 
occurs before start of study drug) or an AE (worsening or complication occurs after start 
of study drug). Investigators or sub-investigator should ensure that the event term 
recorded captures the change in the condition from baseline (e.g., “worsening of 
hypertension”). 
If a subject has a pre-existing episodic condition (e.g., asthma, epilepsy) any occurrence 
of an episode should only be captured as a PTE/AE if the episodes become more frequent, 
serious or severe in nature. If a subject has a degenerative concurrent condition (e.g., 
cataracts, rheumatoid arthritis), worsening of the condition should only be captured as a 
PTE/AE if occurring to a greater extent to that which would be expected. The investigator 
or sub-investigator should ensure that the AE term recorded captures the change in the 
condition (e.g., “worsening of…”). 
Worsening of PTEs or AEs: 
If the subject experiences a worsening or complication of a PTE after starting 
administration of the study drug, the worsening or complication should be recorded 
appropriately as an AE. The investigator or sub-investigator should ensure that the AE 
term recorded captures the change in the condition (e.g., “worsening of…”). 
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. The investigator or 
sub-investigator should ensure that the AE term recorded captures the change in the 
condition (e.g., “worsening of…”). 
Changes in intensity of AEs /Serious PTEs: 
If the subject experiences changes in intensity of an AE/serious PTE, the event should be 
captured once with the maximum intensity recorded. 
Preplanned surgeries or procedures: 
Preplanned procedures (surgeries or therapies) that were scheduled prior to signing of 
informed consent are not considered PTEs or AEs. However, if a preplanned procedure is 
performed early (e.g., as an emergency) due to a worsening of the pre-existing condition, 
the worsening of the condition should be captured appropriately as a PTE or an AE. 
Complications resulting from any planned surgery should be reported as AEs. 


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Elective surgeries or procedures: 
Elective procedures performed where there is no change in the subject’s medical 
condition (e.g., cosmetic surgery) should not be recorded as PTEs or 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 or sub-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 PTEs or AEs, but instead will be documented on an Overdose page of the 
eCRF. Any manifested side effects will be considered PTEs or AEs and will be recorded 
on the AE page of the eCRF. 
10.1.4 SAEs 
An SAE is defined as any untoward medical occurrence that at any dose: 
1. Results in DEATH. 
2. Is LIFE THREATENING* 
* 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. 
3. Requires inpatient HOSPITALIZATION or prolongation of existing hospitalization. 
4. Results in persistent or significant DISABILITY/INCAPACITY. 
5. Leads to a CONGENITAL ANOMALY/BIRTH DEFECT. 
6. Is an IMPORTANT MEDICAL EVENT that satisfies any of the following: 
• 
May require intervention to prevent items 1 through 5 above. 
• 
May expose the subject to danger, even though the event is not immediately life 
threatening or fatal or does not result in hospitalization. 
• 
Includes any event or synonym described in the Takeda Medically Significant AE 
List (Table 10.a). 


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Table 10.a 
Takeda Medically Significant AE List 
Acute respiratory failure/acute respiratory 
distress syndrome 
Torsade de pointes / ventricular fibrillation / 
ventricular tachycardia 
Malignant hypertension 
Convulsive seizure 
Agranulocytosis 
Aplastic anemia 
Toxic epidermal necrolysis/Stevens-Johnson 
syndrome 
Hepatic necrosis 
Acute liver failure 
Anaphylactic shock 
Acute renal failure 
Pulmonary hypertension 
Pulmonary fibrosis 
Neuroleptic malignant syndrome / malignant 
hyperthermia 
Spontaneous abortion / stillbirth and fetal death 
Confirmed or suspected transmission of infectious 
agent by a medicinal product 
Confirmed or suspected endotoxin shock 
PTEs that fulfill 1 or more of the serious criteria above are also to be considered SAEs 
and should be reported and followed up in the same manner (see Sections 10.2.2 and 
10.3). 
10.1.5 Adverse Events of Special Interest 
An AE of Special Interest (AESI) (serious or non-serious) is 1 of scientific and medical 
concern specific to the compound or program, for which ongoing monitoring and rapid 
communication by the investigator to Takeda may be appropriate. Such events may 
require further investigation in order to characterize and understand them and would be 
described in protocols and instructions provided for investigators as to how and when 
they should be reported to the sponsor (refer to Section 10.2.1.3). 
• AESIs: hypoglycemia-related AEs, intestinal obstruction-related AEs, acute 
pancreatitis-related AEs, and QT/QTc interval prolongation-related AEs 
<Hypoglycemia-related AEs> 
Hypoglycemia-related AEs are defined as AESIs since special attention is generally paid 
to these events in patients with diabetes mellitus using antidiabetic drugs and severe 
hypoglycemia has been reported in combination therapy with other DPP-4 inhibitors and 
insulin preparations. 
<Intestinal obstruction-related AEs> 
Intestinal obstruction-related AEs are defined as AESIs since adverse reaction reports on 
intestinal obstruction with the use of incretin-related drugs (GLP-1 receptor agonists and 
other DPP-4 inhibitors) in the same class as SYR-472 have been accumulated. 
<Acute pancreatitis-related AEs> 
Acute pancreatitis-related AEs are defined as AESIs since adverse reaction reports on 
acute pancreatitis with the use of incretin-related drugs in the same class as SYR-472 
have been accumulated. 
<QT/QTc interval prolongation-related AEs> 
In thorough QT/QTc study (Study CPH-005), QT/QTc interval prolongation was 
reported in the SYR-472 800 mg group, although it was not reported in the SYR-472 


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200 mg group; therefore, QT/QTc interval prolongation-related AEs are defined as 
AESIs. 
10.1.6 Intensity of PTEs and 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 causes the subject discomfort and interrupts the subject’s usual activities. 
Severe: 
The event causes considerable interference with the subject’s usual activities. 
10.1.7 Causality of AEs 
The relationship of each AE to study drugs will be assessed using the following 
categories: 
Related: 
An AE that follows a reasonable temporal sequence from administration of a drug 
(including the course after withdrawal of the drug), or for which possible involvement of the 
drug cannot be ruled out, although factors other than the drug, such as underlying diseases, 
complications, concomitant drugs and concurrent treatments, may also be responsible. 
Not Related: 
An AE that does not follow a reasonable temporal sequence from administration of a drug 
and/or that can reasonably be explained by other factors, such as underlying diseases, 
complications, concomitant drugs and concurrent treatments. 
10.1.8 Relationship to Study Procedures 
Relationship (causality) to study procedures should be determined for all PTEs and AEs. 
The relationship should be assessed as Related if the investigator or sub-investigator 
considers that there is a reasonable possibility that an event is due to a study procedure. 
Otherwise, the relationship should be assessed as Not Related. 
10.1.9 Start Date 
The start date of AEs/PTEs is determined based on the following criteria: 
AE/PTE 
Start Date 
Signs, symptoms, and diseases 
(diagnosis) 
Date when the subject and/or the investigator or sub-investigator first 
notices the sign or symptom of the AE. 
Asymptomatic disease 
Date when a definite diagnosis is determined based on the results of 
diagnostic testing: 
Even if obsolete findings are indicated based on the test findings or the 
approximate time of onset can be estimated, the date when a definite 
diagnosis is made should be recorded. 
Worsening of concurrent medical 
conditions or PTE 
Date when the subject or the investigator or sub-investigator first 
notices worsening of the disease or symptom. 
Normal in the initial assessment 
after signing informed consent 
but abnormal in the subsequent 
assessment (for PTEs) 
Abnormal in the assessment after 
the start of study drug (for AEs) 
Date when the test is performed in which a clinically significant 
abnormal test value is observed. 


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Abnormal in the initial 
assessment after signing 
informed consent and has 
worsened at the subsequent 
assessment (in case of PTEs) 
Abnormal in the assessment at 
the start of study drug and has 
worsened in the subsequent 
assessment (in case of AEs) 
Date when the test is performed in which a medically significant 
elevation, reduction, increase, or decrease in clinical test values is 
observed. 
10.1.10 Stop Date 
The stop date of the AE/PTE is the date at which the subject recovered, the event resolved 
but with sequelae or the subject died. The event not has resolved at the end of the study 
will be assessed as ongoing. 
10.1.11 Frequency 
Episodic AEs/PTEs (e.g., constipation, diarrhea, or vomiting) or those which occur 
repeatedly over a period of consecutive days are intermittent. All other events are 
continuous. 
10.1.12 Action Concerning Study Drug 
Action taken for the study drug is classified and defined as follows: 
Drug withdrawn 
A study drug is stopped due to the particular AE (including withdrawal at the 
discretion of subjects). 
Dose not changed 
The dose is not changed even after the occurrence of the particular AE. 
This shall apply in case the study drug is stopped or the dose is reduced or increased 
due to another AE. 
This shall also apply, for example, in case the study drug is stopped or the dose is 
reduced for any reason other than intervention for the particular AE, such as the 
subject’s negligence. 
Unknown 
For example, attempts to contact the subject are unsuccessful and the course of the 
particular AE after the start day cannot be followed. 
Not Applicable 
For example, the study drug has already been completed or stopped before the onset 
of the particular AE. 
Dose interrupted 
The study drug is stopped (suspended) due to the particular AE and resumed 
afterwards (including temporary withdrawal at the discretion of subjects). 
10.1.13 Outcome 
The outcome of AEs/PTEs is classified as follows: 
Classification 
Assessment criteria 
Recovered/resolved 
•The diagnosis or signs/symptoms has disappeared or resolved. 
•The abnormal laboratory value has improved to the normal range or the value 
at baseline (AEs), or at the first assessment after signing of informed consent 
(PTEs). 
•The event was recorded as another AE in the eCRF due to increased intensity. 


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Classification 
Assessment criteria 
Recovering/resolving 
•The intensity is lowered by 1 or more stages. 
•The diagnosis or sign/symptom has almost disappeared. 
•The abnormal laboratory value improved, but has not returned to the normal 
range or to baseline (AEs) or to the first assessment after signing of informed 
consent (PTEs). 
•The subject died from a cause other than the particular AE/PTE with the 
condition remaining “recovering/resolving” (in this case, no need to record the 
date of death). 
Not recovered/not 
resolved 
•There is no change in the diagnosis or signs/symptoms, or laboratory values. 
•The intensity of the diagnosis or signs/symptoms, or laboratory value on the 
last day of the observed study period has got worse than when it started. 
•An irreversible congenital anomaly. 
•The subject died from another cause with the particular AE/PTE state 
remaining “Not recovered/not resolved” (in this case, no need to record the 
date of death). 
Resolved with sequelae 
•Dysfunction that interferes with the subject's daily life is observed. 
Fatal 
•There is a direct relationship between the death and the AE/PTE. 
A “direct relationship” means that the AE/PTE caused or apparently 
contributed to the death. 
•The outcome of another AE/PTE reported in the same subject that is not 
determined (considered or estimated) to cause the death is not assessed as 
“fatal.” 
•If the outcome is “fatal,” the date of death should be recorded. 
Unknown 
•The course the AE/PTE after the start day cannot be followed up as specified 
in the protocol due to hospital change or residence change. 
10.2 
Procedures 
10.2.1 Collection and Reporting of AEs 
10.2.1.1 PTE and AE Collection Period 
Collection of PTEs will commence from the time the subject signs the informed consent 
to participate in the study and continue until the subject is first administered study drug 
(Visit 3). For subjects who discontinue prior to study drug administration, PTEs are 
collected until the subject discontinues study participation. 
Collection of AEs will commence from the time that the subject is first administered 
study drug (Visit 3). Routine collection of AEs will continue until Visit 18. 
10.2.1.2 PTE and AE Reporting 
At each study visit, the investigator or sub-investigator will assess whether any subjective 
AEs have occurred. A neutral question, such as “How have you been feeling since your 
last visit?” may be asked. Subjects may report AEs occurring at any other time during the 
study. 
Subjects experiencing a serious PTE must be monitored until the symptoms subside and 
any clinically relevant changes in laboratory values have returned to baseline or there is a 
satisfactory explanation for the change (permanent or irreversible PTEs). Non-serious 


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PTEs, related or unrelated to the study procedure, need not to be followed-up for the 
purposes of the protocol. 
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 (permanent or irreversible AEs). All PTEs and AEs 
will be documented in the PTE/AE page of the eCRF, whether or not the investigator or 
sub-investigator concludes that the event is related to the drug treatment. The following 
information will be documented for each event: 
• Event term. 
• Start and stop date. 
• Frequency. 
• Intensity. 
• Causal relationship between the event and administration of study drug(s) (related or 
not related). 
• Action concerning study drug. 
• Outcome of event. 
• Causal relationship to study procedure(s) (if related, include the details of the 
suspected procedure). 
• Seriousness. 
AEs and serious PTEs should be followed up until the AEs/PTEs have resolved or 
follow-up is no longer necessary in the opinion of the investigator or sub-investigator. 
10.2.1.3 AESI Reporting 
If any AESI, which occurs during the treatment period or the follow-up period, is 
considered to be clinically significant based on the criteria below, it should be reported to 
the sponsor (Annex 1) immediately or within 1 business day of first onset or subject’s 
notification of the event. In addition, AESI Form should be completed by the investigator, 
and reported to the Safety Information Emergency Call Center (Annex 1) within 10 
business days. 
The original AESI Form should be submitted to the sponsor. 
The criteria for AESIs (hypoglycemia-related AEs, intestinal obstruction-related AEs, 
acute pancreatitis-related AEs, and QT/QTc interval prolongation-related AEs) are as 
described below. If any AE considered to be related to these condition occurs, whether or 
not to handle it as an AESI should be considered. 
<Hypoglycemia-related AEs> 
AEs related to hypoglycemia 
<Intestinal obstruction-related AEs> 


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Intestinal obstruction, ileus, subileus, gastrointestinal obstruction, 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, disturbance of consciousness, convulsion, ECG QT prolonged, and 
AEs related to these conditions. 
The AESIs have to be recorded as AEs in the eCRF. An evaluation form along with all 
other required documentation must be submitted to the sponsor. 
10.2.2 Collection and Reporting of SAEs 
When an SAE occurs through the AE collection period it should be reported according to 
the following procedure. Any PTE which meets the SAE criteria described in Section 
10.1.4 should be reported in the same manner as SAEs: 
An SAE should be reported to the sponsor (Annex 1) within 1 business day of first onset 
or subject’s notification of the event. The investigator should submit the completed SAE 
form within 10 calendar days. 
The information to be reported within 1 business day should be completed as fully as 
possible but contain, at a minimum: 
• A short description of the event and the reason why the event is categorized as 
serious. 
• Subject identification number. 
• Investigator’s or sub-investigator’s name. 
• Name of the study drug(s) 
• Causality assessment. 
Any SAE spontaneously reported to the investigator or sub-investigator’s following the 
AE collection period should be reported to the sponsor. 
10.2.3 Reporting of Abnormal Liver Function Tests 
If a subject is noted to have ALT or AST >3 × ULN and total bilirubin > 2 × ULN for 
which an alternative etiology has not been identified, the event should be recorded as an 
SAE and reported as per Section 10.2.2. The investigator or sub-investigator must contact 
sponsor, and investigate the details of the subject and possible alternative etiologies 
immediately, such as acute viral hepatitis A or B or other acute liver disease or medical 
history/concurrent medical conditions. Follow-up laboratory tests as described in Section 
9.1.9 must also be performed. 


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10.3 
Follow-up of SAEs 
If information not available at the time of the detailed report becomes available at a later 
date, the investigator or sub-investigator should complete a follow-up SAE form or 
provide other written documentation and submit it to the sponsor (Annex 1) immediately. 
Copies of any relevant data from the hospital notes (e.g., ECGs, laboratory tests, 
discharge summary, postmortem results) should be sent to the addressee, if requested by 
the sponsor or IRB. 
All SAEs should be followed up until resolution or permanent outcome of the event. 
10.3.1 Safety Reporting to Investigators, IRBs, and Regulatory Authorities 
The sponsor will be responsible for reporting all suspected unexpected serious adverse 
reactions (SUSARs) and any other applicable SAEs to regulatory authorities, 
investigators and IRBs/the head of the study site, as applicable, in accordance with 
national regulations in the countries where the study is conducted. Relative to the first 
awareness of the event by/or further provision to the sponsor or sponsor’s designee 
(contract research organization [CRO]), SUSARs will be submitted to the regulatory 
authorities as expedited report within 7 days for fatal and life-threatening events and 15 
days for other serious events. The sponsor will also prepare an expedited report for other 
safety issues where these might materially alter the current benefit-risk assessment of a 
study drug or that would be sufficient to consider changes in the study drug 
administration or in the overall conduct of the trial. The study site also will forward a 
copy of all expedited reports to his or her IRB. 


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11.0 
STUDY-SPECIFIC COMMITTEES 
No steering committee, data safety monitoring committee, or clinical endpoint committee 
will be used in this study. 


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12.0 
DATA HANDLING AND RECORDKEEPING 
The full details of procedures for data handling will be documented in the Data 
Management Plan. AEs, PTEs, medical history, and concurrent conditions will be coded 
using the Medical Dictionary for Regulatory Activities (MedDRA). Drugs will be coded 
using the World Health Organization Drug Dictionary. 
12.1 
CRFs 
Completed eCRFs are required for each subject who signs an informed consent. 
The sponsor or its designee will supply investigative sites with access to eCRFs. The 
sponsor will make arrangements to train appropriate site staff in the use of the eCRF. 
These forms are used to transmit the information collected in the performance of this 
study to the sponsor and regulatory authorities. eCRFs must be completed in Japanese. 
Data are transcribed directly onto eCRFs. 
The investigator or sub-investigator should complete assessments scheduled for 
Treatment Period I prior to starting study drug administration in Treatment Period II; the 
schedule of assessments should not be changed unless there is an appropriate reason. 
Corrections to eCRFs are recorded in an audit trail that captures the old information, new 
information, identification of the person making the correction, date the correction was 
made, and the reason for change. 
The investigator must review the eCRFs for completeness and accuracy and must sign 
and date the appropriate eCRFs as indicated. Furthermore, the investigator must retain 
full responsibility for the accuracy and authenticity of all data entered on the eCRFs. 
The following data will not be recorded directly into the eCRFs: 
• Laboratory parameters measured in the central clinical laboratory 
After the lock of the clinical study database, any change of, modification of or addition to 
the data on the eCRFs should be made by the investigator or sub-investigator with use of 
change and modification records of the eCRFs (Data Clarification Form) provided by the 
sponsor. The principal investigator must review the data change for completeness and 
accuracy, and must sign, or sign and seal, and date. 
eCRFs will be reviewed for completeness and acceptability at the study site during 
periodic visits by study monitors. The sponsor or its designee will be permitted to review 
the subject’s medical and hospital records pertinent to the study to ensure accuracy of the 
eCRFs. The completed (e)CRFs are the sole property of the sponsor and should not be 
made available in any form to third parties, except for authorized representatives of 
appropriate governmental health or regulatory authorities, without written permission of 
the sponsor. 
12.2 
Record Retention 
The investigator and the head of the institution agree to keep the records stipulated in 
Section 12.1 and documents include the study-specific documents, identification log of 
all participating subjects, medical records, source worksheets, all original signed and 
dated informed consent forms, electronic copy of eCRFs including the audit trail, and 
detailed records of drug disposition to enable evaluations or audits from regulatory 


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authorities, the sponsor or its designees. The investigator and the head of the institution 
are required to retain essential relevant documents until the day specified as 1) or 2) 
below, whichever comes later. However, if the sponsor requests a longer time period for 
retention, the head of the institution should discuss how long and how to retain those 
documents with the sponsor. 
1) The day on which marketing approval of the study drug is obtained (or the day 
3 years after the date of notification in the case that the investigation is discontinued.) 
2) The day 3 years after the date of early termination or completion of the clinical study. 
In addition, the investigator and the head of the institution should retain the essential 
relevant documents until the receipt of a sponsor-issued notification to state the retention 
is no longer required. 


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13.0 
STATISTICAL METHODS 
13.1 
Statistical and Analytical Plans 
A statistical analysis plan (SAP) will be prepared and finalized prior to unblinding of 
subject’s treatment assignment. This document will provide further details regarding the 
definition of analysis variables and analysis methodology to address all study objectives. 
A blinded data review will be conducted prior to unblinding of subject’s treatment 
assignment. This review will assess the accuracy and completeness of the study database, 
subject evaluability, and appropriateness of the planned statistical methods. 
13.1.1 Analysis Sets 
In this study, 3 kinds of analysis sets are defined: full analysis set (FAS), per protocol set 
(PPS), and safety analysis set. The FAS, the main analysis set used for efficacy analysis, 
is defined as all subjects who were randomized and received at least 1 dose of the study 
drug. The safety analysis set, is defined as all subjects who received at least 1 dose of the 
study drug. The definition of each analysis set will be described in the Handling Rules for 
Analysis Data. 
The sponsor will verify the validity of the definitions of the analysis sets as well as the 
rules for handling data and supplement descriptions about handling of the unspecified 
issues, consulting a medical expert as needed. The Handling Rules for Analysis Data 
must be finalized prior to database lock. 
13.1.2 Analysis of Demographics and Other Baseline Characteristics 
Key demographics and other baseline characteristics will be summarized for each 
treatment group and for overall treatment groups using the all randomized subjects. 
13.1.3 Efficacy Analysis 
(1) Primary endpoint and analytical methods 
[Primary endpoint] 
Change in HbA1c at the end of Treatment Period I from the end of the screening period 
(Week 0) 
[Primary analysis] 
The following analyses will be performed in the FAS. 
The population mean change in HbA1c at the end of Treatment Period I from the end of 
the screening period (Week 0) will be compared between SYR-472 25 mg group and 
placebo group based on an analysis of covariance (ANCOVA) model for the change in 
HbA1c at the end of Treatment Period I from the end of the screening period (Week 0) 
with factors of treatment group and HbA1c at the end of the screening period (Week 0). 
The same ANCOVA model will be used to calculate the least square (LS) mean and the 
two-sided 95% confidence interval (CI) for each treatment group, as well as the 
intergroup difference in the LS mean between the treatment groups (SYR-472 25 mg 
group - placebo group) and the two-sided 95% CI. 


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[Secondary analysis] 
For the change in HbA1c at the end of Treatment Period I from the end of the screening 
period (Week 0), summary statistics (number of subjects, mean, standard deviation, 
maximum, minimum, and quartiles; hereinafter the same) and two-sided 95% CI for the 
mean will be calculated for each treatment group, as well as the intergroup difference in 
the mean between treatment groups (SYR-472 25 mg group - placebo group) and the 
two-sided 95% CI. 
In addition, the same analyses as the primary analysis and the secondary analysis 
described above will be performed using the PPS to evaluate the robustness of the results 
in terms of a sensitivity analysis. 
[Adjustment for covariates] 
The following analyses will be performed in the FAS. 
The treatment effect of SYR-472 25 mg will be assessed in consideration of the effects of 
baseline characteristics based on the ANCOVA model for the change in HbA1c at the end 
of Treatment Period I from the end of the screening period (Week 0) with factors of 
treatment group, HbA1c at the end of the screening period (Week 0) and baseline 
characteristics that may affect the primary endpoint at the blind data review. 
(2) Secondary Endpoints and Analysis Methods 
[Secondary endpoints] 
HbA1c, fasting blood glucose, glycoalbumin 
[Analytical methods] 
The following analyses will be performed in the FAS. 
For each endpoint, summary statistics and two-sided 95% CI for the mean will be 
calculated for each treatment group at each time point. In addition, summary statistics for 
the change from the end of the screening period (Week 0) and two-sided 95% CI for the 
mean will be calculated for each treatment group at each time point, and the intergroup 
difference in the mean between treatment groups (SYR-472 25 mg group - placebo 
group) and the two-sided 95% CI will be calculated at each time point in Treatment 
Period I. 
For the proportions of subjects who achieved an HbA1c less than 6.0%, 7.0%, or 8.0% at 
the end of Treatment Period I and Treatment Period II, the proportions and the two-sided 
95% CIs will be calculated for each treatment group, and the intergroup difference in the 
proportions between treatment groups (SYR-472 25 mg group - placebo group) and the 
two-sided 95% CIs will be calculated at the end of Treatment Period I. In the analysis of 
each proportion, subjects who did not achieve the relevant target HbA1c at the end of the 
screening period (Week 0) will be included in the analysis. 
(3) Additional efficacy endpoints 
See Section 5.2. 
(4) Method of data conversion and handling of missing data 
Details will be specified separately in the Handling Rules for Analysis Data and the SAP. 


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(5) Significance level and confidence coefficient 
• Significance level: 5% (two-sided tests) 
• Confidence coefficient: 95% (two-sided) 
13.1.4 Safety Analysis 
The following analyses will be performed in the Safety Analysis Set. 
(1) Primary endpoint and analytical methods 
[Primary endpoint] 
AEs 
[Analytical methods] 
A treatment-emergent adverse event (TEAE) is defined as an AE whose date of onset 
occurs on or after the start of study drug administration. 
The following analyses will be performed for each treatment group for TEAEs that occur 
before the start of the study drug for Treatment Period II, and for those that occur after the 
start of SYR-472 25 mg tablet. In the analysis of TEAEs occurring after the start of 
SYR-472 25 mg tablet, subjects who received SYR-472 25 mg tablet will be included in 
the analyses. 
TEAEs will be coded using MedDRA dictionary. Frequency distributions will be 
provided using System Organ Class and Preferred Term for each treatment group as 
follows: 
• All TEAEs 
• Drug-related TEAEs 
• Intensity of TEAEs 
• Intensity of drug-related TEAEs 
• TEAEs leading to study drug discontinuation 
• Serious TEAEs 
• TEAEs over time 
(2) Secondary endpoints and analytical methods 
[Secondary endpoints] 
Vital signs, 12-lead ECGs, clinical laboratory tests 
[Analytical methods] 
For continuous variables, the observed values and change from the end of the screening 
period (Week 0) will be summarized using descriptive statistics for each treatment group 
at each time point. In addition, case plots over time for observed values will be presented 
for each treatment group. 
For 12-lead ECG findings and laboratory tests classified as "Low", "Normal" or "High" 
based on the normal reference ranges, shift tables showing the number of subjects in each 


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category at the end of the screening period (Week 0) and each post-baseline time point 
will be presented for each treatment group. 
(3) Additional endpoint and analysis methods 
[Additional endpoint] 
Hypoglycemia 
[Analytical methods] 
The following analyses will be performed for hypoglycemia that occur prior to the start of 
the study drug for Treatment Period II by treatment group, and for those occurring after 
the start of SYR-472 25 mg tablet. Subjects who concomitantly receive insulin 
preparation will be included in these analyses of hypoglycemia, while subjects who 
concomitantly receive insulin preparation and SYR-472 25 mg tablet will be included in 
the analysis of hypoglycemia occurring after the start of SYR-472 25 mg tablet. 
• Severe hypoglycemia 
• Documented symptomatic hypoglycemia 
• Asymptomatic hypoglycemia 
• Probable symptomatic hypoglycemia 
• Relative hypoglycemia 
13.2 
Interim Analysis and Criteria for Early Termination 
No interim analysis is planned. 
13.3 
Determination of Sample Size 
Randomized subjects: 53 subject per group, 106 in total 
(Changed as of 12 September 2016) 
<Justification of sample size> 
In Study CCT-002, the intergroup difference (two-sided 95% CI) in the mean change in 
HbA1c (JDS value) at the end of the treatment period (value at the end of the treatment 
period - value at the end of the screening period) between the SYR-472 100 mg group and 
placebo group was -0.56 ([-0.753, -0.367])%. In the same study, the standard deviation of 
the change in HbA1c (JDS value) at the end of the treatment period (value at the end of 
the treatment period - value at the end of the screening period) for each treatment group 
ranged from 0.523% to 0.628%. 
In this study, which will administer SYR-472 at a dose of 25 mg once weekly to patients 
with type 2 diabetes mellitus complicated by severe renal impairment or end-stage renal 
failure, the intergroup difference in the mean change in HbA1c at the end of Treatment 
Period I from the end of the screening period (Week 0) between the SYR-472 25 mg 
group and placebo group is assumed to be -0.40%, given that the efficacy of SYR-472 25 
mg in this study is similar to that of SYR-472 100 mg administered once weekly to 
patients with type 2 diabetes mellitus not complicated by renal impairment. The common 
standard deviation in each treatment group is assumed to be 0.80%. 


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Based on these assumptions, 86 subjects per group will be required to provide a 90% 
power in a two-sample t-test with a significance level of 5% (two-sided). Therefore, the 
sample size was set at 90 as randomized subjects per group at the start of the study 
allowing for the possibility that there exit some subjects whose primary endpoint cannot 
be evaluated. 
However, achievement of the sample size as originally planned at the start of the study 
was found difficult because there were more than expected numbers of candidate subjects 
who did not provide consent and who dropped out during screening after providing 
consent for the study. It was therefore decided to change some of the inclusion and 
exclusion criteria for this study. After these changes, the ultimate number of subjects 
randomized and evaluable for the primary endpoints are expected to be around 53 and 51, 
respectively, per group. 
Assuming the number of subjects per group as 51 under these assumptions, the study will 
provide a 70.6% power in a two-sample t-test with a significance level of 5% (two-sided). 


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14.0 
QUALITY CONTROL AND QUALITY ASSURANCE 
14.1 
Study-Site Monitoring Visits 
Monitoring visits to the study site will be made periodically during the study to ensure 
that all aspects of the protocol are followed. Source documents will be reviewed for 
verification of data recorded on the eCRFs. Source documents are defined as original 
documents, data, and records. The investigator and the head of the institution guarantee 
access to source documents by the sponsor or its designee and by the IRB. 
All aspects of the study and its documentation will be subject to review by the sponsor or 
designee, including but not limited to the Investigator’s Binder, study drug, subject 
medical records, informed consent documentation, and review of eCRFs and associated 
source documents. It is important that the investigator or sub-investigator and other study 
personnel are available during the monitoring visits and that sufficient time is devoted to 
the process. 
14.2 
Protocol Deviations 
The investigator or sub-investigator can deviate and change from the protocol for any 
medically unavoidable reason, for example, to eliminate an immediate hazard to study 
subjects, without a prior written agreement with the sponsor or a prior approval from IRB. 
In the event of a deviation or change, the principal investigator should notify the sponsor 
and the head of the site of the deviation or change as well as its reason in a written form, 
and then retain a copy of the written form. When necessary, the principal investigator 
may consult and agree with the sponsor on a protocol amendment. If the protocol 
amendment is appropriate, the amendment proposal should be submitted to the head of 
the site as soon as possible and an approval from IRB should be obtained. 
The investigator or sub-investigator should document all protocol deviations. 
14.3 
Quality Assurance Audits and Regulatory Agency Inspections 
The study site also may be subject to quality assurance audits by the sponsor or designees. 
In this circumstance, the sponsor-designated auditor will contact the site in advance to 
arrange an auditing visit. The auditor may ask to visit the facilities where laboratory 
samples are collected, where the medication is stored and prepared, and any other facility 
used during the study. In addition, there is the possibility that this study may be inspected 
by regulatory agencies, including those of foreign governments (e.g., the FDA, the United 
Kingdom Medicines and Healthcare products Regulatory Agency). If the study site is 
contacted for an inspection by a regulatory body, the sponsor should be notified 
immediately. The investigator and the head of the institution guarantee access for quality 
assurance auditors to all study documents as described in Section 14.1. 


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15.0 
ETHICAL ASPECTS OF THE STUDY 
This study will 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 ICH Harmonised Tripartite Guideline for GCP. Each 
investigator will conduct the study according to applicable regulatory requirements and 
align his or her conduct in accordance with the “Responsibilities of the Investigator” that 
are listed in Appendix B. 
15.1 
IRB Approval 
IRBs must be constituted according to the applicable requirements of each participating 
region. The sponsor or designee will require documentation noting all names and titles of 
members who make up the respective IRB. If any member of the IRB has direct 
participation in this study, written notification regarding his or her abstinence from 
reviewing and voting must also be obtained. 
The sponsor or designee will supply relevant documents for submission to the respective 
IRB for the protocol’s review and approval. This protocol, the Investigator’s Brochure, a 
copy of the informed consent form, and, if applicable, subject recruitment materials 
and/or advertisements and other documents required by all applicable laws and 
regulations, must be submitted to a central or local IRB for approval. The IRB’s written 
approval of the protocol and subject informed consent must be obtained and submitted to 
the sponsor or designee before commencement of the study (i.e., before conclusion of 
study contract). The IRB approval must refer to the study by exact protocol title, number, 
and version date; identify versions of other documents (e.g., informed consent form) 
reviewed; and state the approval date. The sponsor will notify site once the sponsor has 
confirmed the adequacy of site regulatory documentation. Until the site receives 
notification, no protocol activities, including the informed consent procedure, may occur. 
Sites must adhere to all requirements stipulated by their respective IRB. This may include 
notification to the IRB regarding protocol amendments, updates to the informed consent 
form, recruitment materials intended for viewing by subjects, local safety reporting 
requirements, reports and updates regarding the ongoing review of the study at intervals 
specified by the respective IRB, and submission of the investigator’s final status report to 
IRB. All IRB approvals and relevant documentation for these items must be provided to 
the sponsor or its designee. 
Subject incentives should not exert undue influence for participation. Payments to 
subjects must be approved by the IRB and sponsor. 
Regarding PGx investigation using collected and stored specimens, analysis will be 
carried out at the time when detail is determined. The sponsor will create a research 
protocol for PGx investigations and a research protocol will require prior approval of the 
company IRB in Japan. 
15.2 
Subject Information, Informed Consent, and Subject Authorization 
Written consent documents will embody the elements of informed consent as described in 
the Declaration of Helsinki and the ICH Guidelines for GCP and will be in accordance 
with all applicable laws and regulations. The informed consent form describes the 


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planned and permitted uses, transfers, and disclosures of the subject’s personal and 
personal health information for purposes of conducting the study. The informed consent 
form further explains 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 he or she is free to withdraw at any time without giving a reason and without 
prejudice to his or her further medical care. 
The investigator is responsible for the preparation, content, and IRB approval of the 
informed consent form. The informed consent form must be approved by the IRB prior to 
use. 
The informed consent form must be written in a language fully comprehensible to the 
prospective subject. It is the responsibility of the investigator or sub-investigator to 
explain the detailed elements of the informed consent form to the subject. Information 
should be given in both oral and written form whenever possible and in the manner 
deemed appropriate by the IRB. 
The subject must be given ample opportunity to: (1) inquire about details of the study and 
(2) decide whether or not to participate in the study. If the subject determines he or she 
will participate in the study, then the informed consent form must be signed or signed and 
sealed, and dated by the subject at the time of consent and prior to the subject entering 
into the study. The subject should be instructed to sign using their legal name, not 
nickname, using blue or black ballpoint ink. The investigator or sub-investigator must 
also sign or sign and seal and date the informed consent form at the time of consent and 
prior to the subject entering into the study. 
Once signed or signed and sealed, the original informed consent form will be stored in the 
investigator’s site file. The investigator or sub-investigator must document the date the 
subject signs or signs and seals the informed consent in the subject’s medical record. 
Copies of the signed or signed and sealed informed consent form shall be given to the 
subject. 
All revised informed consent forms must be reviewed and signed by relevant subjects in 
the same manner as the original informed consent. The date the revised consent was 
obtained should be recorded in the subject’s medical record, and the subject should 
receive a copy of the revised informed consent form. 
The informed consent form for PGx research in the clinical study of SYR-472 will be 
used to explain the PGx research to subjects after the study itself is explained with the 
informed consent form for the study. PGx samples will be collected from subjects who 
have consented to both the study and the PGx research. 
If a subject requests disposal of stored sample, the procedures described in Section 9.4 
should be followed. 
15.3 
Subject Confidentiality 
The sponsor and designees affirm and uphold the principle of the subject’s right to 
protection against invasion of privacy. Throughout this study, a subject’s source data will 
only be linked to the sponsor’s clinical study database or documentation via a unique 
identification number. As permitted by all applicable laws and regulations, limited 


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subject attributes, such as sex, age, or date of birth may be used to verify the subject and 
accuracy of the subject’s unique identification number. 
To comply with ICH Guidelines for GCP and to verify compliance with this protocol, the 
sponsor requires the investigator to permit its monitor or designee’s monitor, 
representatives from any regulatory authority (e.g., Food and Drug Administration, 
Medicines and Healthcare products Regulatory Agency, Pharmaceuticals and Medical 
Devices Agency), the sponsor’s designated auditors, and the appropriate IRBs to review 
the subject’s original medical records (source data or documents), including, but not 
limited to, laboratory test result reports, ECG reports, admission and discharge 
summaries for hospital admissions occurring during a subject’s study participation, and 
autopsy reports. Access to a subject’s original medical records requires the specific 
authorization of the subject as part of the informed consent process (see Section 15.2). 
Copies of any subject source documents that are provided to the sponsor must have 
certain personally identifiable information removed (i.e., subject name, address, and 
other identifier fields not collected on the subject’s eCRF). 
15.4 
Publication, Disclosure, and Clinical Trial Registration Policy 
15.4.1 Publication and Disclosure 
The investigator is obliged to provide the sponsor with complete test results and all data 
derived by the investigator from the study. During the study, only the sponsor may make 
study information available to other study investigators, sub-investigators or to regulatory 
agencies, except as required by law or regulation. Except as otherwise allowable in the 
clinical study site agreement, any public disclosure (including publicly accessible 
websites) related to the protocol or study results is the sole responsibility of the sponsor. 
The sponsor may publish any data and information from the study (including data and 
information generated by the investigator) without the consent of the investigator. 
The investigator or sub-investigator needs to obtain a prior written approval from the 
sponsor to publish any information from the study externally such as to a professional 
association. 
15.4.2 Clinical Trial 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 interventional clinical trials it sponsors anywhere in the world on the publicly 
accessible website (ClinicalTrials.gov and Japan Pharmaceutical Information Center- 
Clinical Trials Information) before start of study, as defined in Takeda Policy/Standard. 
15.4.3 Clinical Trial Results Disclosure 
Takeda will post the results of clinical trials on publicly accessible websites, as required 
by Takeda Policy/Standard, applicable laws and/or regulations. 


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15.5 
Insurance and Compensation for Injury 
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 clinical study subjects. 
Refer to the Clinical Study Site Agreement regarding the sponsor’s policy on subject 
compensation and treatment for injury. If the investigator or sub-investigator has 
questions regarding this policy, he or she should contact the sponsor or sponsor’s 
designee. 


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SAP_001.pdf: 
 
 
Title: A Phase 3, Multicenter, Randomized, Double-Blind, Placebo-Controlled, 
Parallel-Group, Comparative Study and a Phase 3, Multicenter, Open-Label, Long-term 
Study to Evaluate the Efficacy and Safety of SYR-472 When Orally Administered at a 
Dose of 25 mg Once Weekly in Patients with Type 2 Diabetes Mellitus Complicated by 
Severe Renal Impairment or End-Stage Renal Failure 
 
NCT Number: NCT02512068 
Statistical analysis plan Approve Date: 19-Jun-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. 


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Protocol No. SYR-472-3003 
 
1 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ......................................................... 3 
HANDLING OF TIME WINDOW ...................................................................................................... 4 
OTHER HANDLING ......................................................................................................................... 11 
1 STUDY SUBJECTS, DEMOGRAPHICS, AND OTHER BASELINE CHARACTERISTICS .... 12 
1.1 Disposition of Subjects ................................................................................................................. 12 
1.1.1 Study Information .................................................................................................................. 12 
1.1.2 Disposition of All Subjects Who Were Not Randomized ...................................................... 12 
1.1.3 Subject Eligibility .................................................................................................................. 12 
1.1.4 Number of Subjects Who Were Randomized by Site ............................................................ 13 
1.1.5 Disposition of Subjects .......................................................................................................... 13 
1.1.6 Study Drug Completion Status .............................................................................................. 15 
1.1.7 Protocol Deviations and Analysis Sets .................................................................................. 15 
1.2 Demographic and Other Baseline Characteristics ......................................................................... 16 
1.2.1 Distribution of Baseline Demographics ................................................................................. 16 
1.2.2 Medical History and Concurrent Medical Conditions ........................................................... 18 
1.2.3 Medication History and Concomitant Medications ............................................................... 18 
1.2.4 Concomitant Antidiabetic Drugs Permitted in the Study ....................................................... 19 
1.3 Measurement of Compliance Status for Treatment ...................................................................... 20 
1.3.1 Study Drug Exposure and Compliance in the Treatment Period ........................................... 20 
1.3.2 Compliance of Antidiabetic Drugs ........................................................................................ 21 
1.3.3 Compliance of Diet and/or Exercise Therapy ........................................................................ 21 
2 EFFICACY ANALYSIS ................................................................................................................. 22 
2.1 Primary Endpoints and Analysis Methodology ............................................................................ 22 
2.1.1 Primary Analysis .................................................................................................................... 22 
2.1.2 Secondary Analysis ................................................................................................................ 22 
2.2 Secondary Endpoints and Analysis Methodology ........................................................................ 23 
2.2.1 HbA1c, Fasting Blood Glucose, Glycoalbumin ..................................................................... 23 
2.3 Other Endpoints and Analysis Methodology ................................................................................ 24 
2.3.1 Fasting C-peptide, Fasting Glucagon, DPP-4 Activity, Weight ............................................ 24 
2.4 Statistical and Analytical Issues .................................................................................................... 25 
2.4.1 Adjustments for Covariates .................................................................................................... 25 
2.4.2 Handling of Dropouts or Missing Data .................................................................................. 25 
2.4.3 Interim Analysis and Data Monitoring .................................................................................. 25 
2.4.4 Multicenter Studies ................................................................................................................ 25 
2.4.5 Multiple Comparisons/Multiplicity ........................................................................................ 25 
2.4.6 Use of an “Efficacy Subset of Subjects” ................................................................................ 25 


Protocol No. SYR-472-3003 
 
2 
2.4.7 Active-Control Studies Intended to Show Equivalence or Non-inferiority ........................... 26 
2.4.8 Examination of Subgroups ..................................................................................................... 26 
2.5 Plasma Concentration of SYR-472Z ............................................................................................. 27 
3 SAFETY ANALYSIS ...................................................................................................................... 28 
3.1 Treatment-Emergent Adverse Event ............................................................................................. 28 
3.1.1 Overview of Treatment-Emergent Adverse Events ............................................................... 28 
3.1.2 Displays of Treatment-Emergent Adverse Events ................................................................. 29 
3.1.3 Subgroup Analysis of Treatment-Emergent Adverse Events ................................................ 31 
3.2 Pretreatment Event ........................................................................................................................ 32 
3.2.1 Display of Pretreatment Events.............................................................................................. 32 
3.3 Clinical Laboratory Evaluations and Other Safety Endpoints ...................................................... 33 
3.3.1 Clinical Laboratory Evaluations ............................................................................................ 33 
3.3.2 Vital Signs, Physical Examination, and Other Observation Items Related to Safety ............ 34 
4 SIGNIFICANCE LEVEL AND CONFIDENCE COEFFICIENT .................................................. 37 
History of Revision (version management) ........................................................................................ 38 
[Appendix 1] SYR-472-3003 Comparison Table for Changes ............................................................. 1 
 


Protocol No. SYR-472-3003 
 
3 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
• 
Study Day: The day before the start of the study drug administration will be defined as Day -1 
and the day of the start of the study drug administration will be defined as Day 1. 
• 
Follow-up Day for Treatment Period I: The day after the last administration of the study drug 
for Treatment Period I will be defined as Follow-up Day 1 for Treatment Period I. 
• 
Study Day for Treatment Period II: The day before the start of the study drug administration for 
Treatment Period II will be defined as Day -1 for Treatment Period II and the day of the start of 
the study drug administration for Treatment Period II will be defined as Day 1 for Treatment 
Period II. 
• 
Study Day for SYR-472 25 mg tablet: The day before the start of SYR-472 25 mg tablet will be 
defined as Day -1 for SYR-472 25 mg tablet and the day of the start of SYR-472 25 mg tablet 
will be defined as Day 1 for SYR-472 25 mg tablet. 
• 
Follow-up Day for SYR-472 25 mg tablet: The day after the last administration of SYR-472 
25 mg tablet will be defined as Follow-up Day 1 for SYR-472 25 mg tablet. 
• 
Treatment groups: SYR-472 25 mg group (subjects who received SYR-472 25 mg in both 
Treatment Periods I and II), placebo group (subjects who received placebo in Treatment Period 
I and SYR-472 25 mg in Treatment Period II). 
In this statistical analysis plan (hereinafter referred to as SAP), the treatment groups will be 
presented as the SYR-472 25 mg/SYR-472 25 mg group and the placebo/SYR-472 25 mg 
group. 
• 
Summary statistics: number of subjects, mean, standard deviation, maximum, minimum, and 
quartiles 
• 
Reason for not being treated with the study drug for Treatment Period II: If the subject is “Not 
treated” with the study drug for Treatment Period II, the reason why the administration of study 
drug was discontinued will be analyzed as the reason for not being treated with the study drug 
for Treatment Period II. 
• 
Treatment-emergent adverse event (TEAE): An adverse event whose date of onset occurs on or 
after the start of the study drug administration. Since there is a possibility that the evaluation 
result of an adverse event may differ before and after the start of the study drug administration 
for Treatment Period II, the evaluation result of adverse event to be used for analysis will be 
defined according to the rules below: 
 
TEAEs that occur before the start of the study drug for Treatment Period II: The analysis 
will be performed based on the evaluation result entered in the CRF under “Pretreatment 
Event/Adverse Event (Period 1).” 
 
TEAEs that occur after the start of SYR-472 25 mg tablet: The analysis will be performed 
based on the evaluation results entered in the CRFs under “Pretreatment Event/Adverse 
Event (Period 1)” and “Pretreatment Event/Adverse Event (Period 2 and thereafter).” If the 


Protocol No. SYR-472-3003 
 
4 
evaluation results differ between “Pretreatment Event/Adverse Event (Period 1)” and 
“Pretreatment Event/Adverse Event (Period 2 and thereafter),” the evaluation result of 
“Pretreatment Event/Adverse Event (Period 2 and thereafter)” will be preferentially used. 
• 
Time of onset: In the analysis of TEAEs that occur before the start of the study drug for 
Treatment Period II, the time of onset will be calculated by defining the day of the start of the 
study drug administration as day 1. In the analysis of TEAEs that occur after the start of 
SYR-472 25 mg tablet, it will be calculated by defining the day of the start of SYR-472 25 mg 
tablet as day 1. 
• 
Number of days from the immediate study drug administration: To be calculated by defining 
the day of the immediate study drug administration as Day 1. If the study drug administration 
and TEAE occur on the same day, the number of days from the immediate study drug 
administration will be defined as 1 day. 
• 
Complications of hepatobiliary disorders: Concurrent medical conditions summarized as 
hepatobiliary disorders by SOC. 
• 
MAV: An abbreviation for markedly abnormal value. 
• 
Overall hypoglycemia: Hypoglycemia reported as “Yes” for hypoglycemic symptoms and 
asymptomatic hypoglycemia. 
• 
Asymptomatic hypoglycemia: Hypoglycemia with an evaluable self-monitoring blood glucose 
value (i.e., non-missing and determined to be eligible based on “Handling Rules for Analysis 
Data”) and a measured concentration of ≤70 mg/dL but determined to be not accompanied by 
symptoms of hypoglycemia at the measurement of that blood glucose value. The presence or 
absence of asymptomatic hypoglycemia will be determined for each blood glucose value 
measured. 
 
HANDLING OF TIME WINDOW 
For each test, observation, and evaluation items, evaluable data (i.e., non-missing data and data 
determined to be eligible based on “Handling Rules for Analysis Data”) will be handled according 
to the following rules. 
The evaluable data within the acceptable window will be used. If more than one evaluable datum 
lies within the same acceptable window, the data whose test/observation/evaluation date is closest to 
the scheduled date will be used and, if there are two data equidistant to the scheduled date, the data 
obtained earlier will be used for efficacy endpoints and the data obtained later will be used for safety 
endpoints. 
 
 


Protocol No. SYR-472-3003 
 
5 
HbA1c 
Visit 
Scheduled Study Day 
Acceptable Window 
Study Day 
Follow-up Day 
for Treatment 
Period I 
Study Day for 
Treatment 
Period II 
Follow-up Day 
for SYR-472 
25 mg Tablet 
Week -6 
Study Day: -42 
-49 to -29 
 
 
 
Week -2 
Study Day: -14 
-28 to -8 
 
 
 
Week 0 
Study Day: 1 
-7 to 1 
 
 
 
Week 2 
Study Day: 15 
2 to 22 
~ 20 
~ 1 
 
Week 4 
Study Day: 29 
23 to 42 
~ 20 
~ 1 
 
Week 8 
Study Day: 57 
43 to 70 
~ 20 
~ 1 
 
Week 12 
Study Day: 85 
71 to 98 
~ 20 
~ 1 
 
Week 16 
Study Day: 113 
99 to 126 
 
2 ~  
~ 20 
Week 20 
Study Day: 141 
127 to 154 
 
2 ~  
~ 20 
Week 24 
Study Day: 169 
155 to 182 
 
2 ~  
~ 20 
Week 28 
Study Day: 197 
183 to 210 
 
2 ~  
~ 20 
Week 32 
Study Day: 225 
211 to 238 
 
2 ~  
~ 20 
Week 36 
Study Day: 253 
239 to 266 
 
2 ~  
~ 20 
Week 40 
Study Day: 281 
267 to 294 
 
2 ~  
~ 20 
Week 44 
Study Day: 309 
295 to 322 
 
2 ~  
~ 20 
Week 48 
Study Day: 337 
323 to 350 
 
2 ~  
~ 20 
Week 52 
Study Day: 365 
351 to 378 
 
2 ~  
~ 20 
At the End of 
Treatment Period I 
Follow-up Day for  
Treatment Period I: 7 
2 ~  
~ 20 
~ 1 
 
At the End of 
Treatment Period II 
Follow-up Day for  
SYR-472 25 mg Tablet: 7 
 
 
2 ~ * 
~ 20 
*: At the end of Treatment Period II, “Study Day for Treatment Period II” will be assumed to be “Study Day for SYR-472 25 mg 
tablet.” 
 
Fasting blood glucose 
Visit 
Scheduled Study Day 
Acceptable Window 
Study Day 
Follow-up Day 
for Treatment 
Period I 
Study Day for 
Treatment 
Period II 
Follow-up Day 
for SYR-472 
25 mg Tablet 
Week -6 
Study Day: -42 
-49 to -22 
 
 
 
Week 0 
Study Day: 1 
-21 to 1 
 
 
 
Week 2 
Study Day: 15 
2 to 22 
~ 20 
~ 1 
 
Week 4 
Study Day: 29 
23 to 42 
~ 20 
~ 1 
 


Protocol No. SYR-472-3003 
 
6 
Visit 
Scheduled Study Day 
Acceptable Window 
Study Day 
Follow-up Day 
for Treatment 
Period I 
Study Day for 
Treatment 
Period II 
Follow-up Day 
for SYR-472 
25 mg Tablet 
Week 8 
Study Day: 57 
43 to 70 
~ 20 
~ 1 
 
Week 12 
Study Day: 85 
71 to 98 
~ 20 
~ 1 
 
Week 16 
Study Day: 113 
99 to 126 
 
2 ~  
~ 20 
Week 20 
Study Day: 141 
127 to 154 
 
2 ~  
~ 20 
Week 24 
Study Day: 169 
155 to 182 
 
2 ~  
~ 20 
Week 28 
Study Day: 197 
183 to 210 
 
2 ~  
~ 20 
Week 32 
Study Day: 225 
211 to 238 
 
2 ~  
~ 20 
Week 36 
Study Day: 253 
239 to 266 
 
2 ~  
~ 20 
Week 40 
Study Day: 281 
267 to 294 
 
2 ~  
~ 20 
Week 44 
Study Day: 309 
295 to 322 
 
2 ~  
~ 20 
Week 48 
Study Day: 337 
323 to 350 
 
2 ~  
~ 20 
Week 52 
Study Day: 365 
351 to 378 
 
2 ~  
~ 20 
Week 54 
Follow-up Day for  
SYR-472 25 mg Tablet: 21 
 
 
 
21 to 28 
At the End of 
Treatment Period I 
Follow-up Day for  
Treatment Period I: 7 
2 ~  
~ 20 
~ 1 
 
At the End of 
Treatment Period II 
Follow-up Day for  
SYR-472 25 mg Tablet: 7 
 
 
2 ~ * 
~ 20 
*: At the end of Treatment Period II, “Study Day for Treatment Period II” will be assumed to be “Study Day for SYR-472 25 mg 
tablet.” 
 
Glycoalbumin 
Visit 
Scheduled Study Day 
Acceptable Window 
Study Day 
Follow-up Day 
for Treatment 
Period I 
Study Day for 
Treatment 
Period II 
Follow-up Day 
for SYR-472 
25 mg Tablet 
Week -6 
Study Day: -42 
-49 to -29 
 
 
 
Week -2 
Study Day: -14 
-28 to -8 
 
 
 
Week 0 
Study Day: 1 
-7 to 1 
 
 
 
Week 2 
Study Day: 15 
2 to 22 
~ 20 
~ 1 
 
Week 4 
Study Day: 29 
23 to 42 
~ 20 
~ 1 
 
Week 8 
Study Day: 57 
43 to 70 
~ 20 
~ 1 
 
Week 12 
Study Day: 85 
71 to 98 
~ 20 
~ 1 
 
Week 16 
Study Day: 113 
99 to 126 
 
2 ~  
~ 20 


Protocol No. SYR-472-3003 
 
7 
Visit 
Scheduled Study Day 
Acceptable Window 
Study Day 
Follow-up Day 
for Treatment 
Period I 
Study Day for 
Treatment 
Period II 
Follow-up Day 
for SYR-472 
25 mg Tablet 
Week 20 
Study Day: 141 
127 to 154 
 
2 ~  
~ 20 
Week 24 
Study Day: 169 
155 to 182 
 
2 ~  
~ 20 
Week 28 
Study Day: 197 
183 to 210 
 
2 ~  
~ 20 
Week 32 
Study Day: 225 
211 to 238 
 
2 ~  
~ 20 
Week 36 
Study Day: 253 
239 to 266 
 
2 ~  
~ 20 
Week 40 
Study Day: 281 
267 to 294 
 
2 ~  
~ 20 
Week 44 
Study Day: 309 
295 to 322 
 
2 ~  
~ 20 
Week 48 
Study Day: 337 
323 to 350 
 
2 ~  
~ 20 
Week 52 
Study Day: 365 
351 to 378 
 
2 ~  
~ 20 
Week 54 
Follow-up Day for  
SYR-472 25 mg Tablet: 21 
 
 
 
21 to 28 
At the End of 
Treatment Period I 
Follow-up Day for  
Treatment Period I: 7 
2 ~  
~ 20 
~ 1 
 
At the End of 
Treatment Period II 
Follow-up Day for  
SYR-472 25 mg Tablet: 7 
 
 
2 ~ * 
~ 20 
*: At the end of Treatment Period II, “Study Day for Treatment Period II” will be assumed to be “Study Day for SYR-472 25 mg 
tablet.” 
 
Fasting C-peptide 
Visit 
Scheduled Study Day 
Acceptable Window 
Study Day 
Follow-up Day 
for Treatment 
Period I 
Study Day for 
Treatment 
Period II 
Follow-up Day 
for SYR-472 
25 mg Tablet 
Week -6 
Study Day: -42 
-49 to -29 
 
 
 
Week -2 
Study Day: -14 
-28 to -8 
 
 
 
Week 0 
Study Day: 1 
-7 to 1 
 
 
 
Week 2 
Study Day: 15 
2 to 22 
~ 20 
~ 1 
 
Week 4 
Study Day: 29 
23 to 42 
~ 20 
~ 1 
 
Week 8 
Study Day: 57 
43 to 70 
~ 20 
~ 1 
 
Week 12 
Study Day: 85 
71 to 98 
~ 20 
~ 1 
 
Week 24 
Study Day: 169 
99 to 210 
 
2 ~  
~ 20 
Week 36 
Study Day: 253 
211 to 308 
 
2 ~  
~ 20 
Week 52 
Study Day: 365 
309 to 378 
 
2 ~  
~ 20 
Week 54 
Follow-up Day for  
SYR-472 25 mg Tablet: 21 
 
 
 
21 to 28 


Protocol No. SYR-472-3003 
 
8 
Visit 
Scheduled Study Day 
Acceptable Window 
Study Day 
Follow-up Day 
for Treatment 
Period I 
Study Day for 
Treatment 
Period II 
Follow-up Day 
for SYR-472 
25 mg Tablet 
At the End of 
Treatment Period I 
Follow-up Day for  
Treatment Period I: 7 
2 ~  
~ 20 
~ 1 
 
At the End of 
Treatment Period II 
Follow-up Day for  
SYR-472 25 mg Tablet: 7 
 
 
2 ~ * 
~ 20 
*: At the end of Treatment Period II, “Study Day for Treatment Period II” will be assumed to be “Study Day for SYR-472 25 mg 
tablet.” 
 
Fasting glucagon, DPP-4 activity 
Visit 
Scheduled Study Day 
Acceptable Window 
Study Day 
Follow-up Day 
for Treatment 
Period I 
Study Day for 
Treatment 
Period II 
Follow-up Day 
for SYR-472 
25 mg Tablet 
Week 0 
Study Day: 1 
-49 to 1 
 
 
 
Week 2 
Study Day: 15 
2 to 22 
~ 20 
~ 1 
 
Week 4 
Study Day: 29 
23 to 42 
~ 20 
~ 1 
 
Week 8 
Study Day: 57 
43 to 70 
~ 20 
~ 1 
 
Week 12 
Study Day: 85 
71 to 98 
~ 20 
~ 1 
 
Week 24 
Study Day: 169 
99 to 210 
 
2 ~  
~ 20 
Week 36 
Study Day: 253 
211 to 308 
 
2 ~  
~ 20 
Week 52 
Study Day: 365 
309 to 378 
 
2 ~  
~ 20 
Week 54 
Follow-up Day for  
SYR-472 25 mg Tablet: 21 
 
 
 
21 to 28 
At the End of 
Treatment Period I 
Follow-up Day for  
Treatment Period I: 7 
2 ~  
~ 20 
~ 1 
 
At the End of 
Treatment Period II 
Follow-up Day for  
SYR-472 25 mg Tablet: 7 
 
 
2 ~ * 
~ 20 
*: At the end of Treatment Period II, “Study Day for Treatment Period II” will be assumed to be “Study Day for SYR-472 25 mg 
tablet.” 
 
Weight, BMI 
Visit 
Scheduled Study Day 
Acceptable Window 
Study Day 
Follow-up Day 
for Treatment 
Period I 
Study Day for 
Treatment 
Period II 
Follow-up Day 
for SYR-472 
25 mg Tablet 
Week -6 
Study Day: -42 
-49 to -29 
 
 
 
Week -2 
Study Day: -14 
-28 to -8 
 
 
 
Week 0 
Study Day: 1 
-7 to 1 
 
 
 
Week 2 
Study Day: 15 
2 to 22 
~ 20 
~ 1 
 


Protocol No. SYR-472-3003 
 
9 
Visit 
Scheduled Study Day 
Acceptable Window 
Study Day 
Follow-up Day 
for Treatment 
Period I 
Study Day for 
Treatment 
Period II 
Follow-up Day 
for SYR-472 
25 mg Tablet 
Week 4 
Study Day: 29 
23 to 42 
~ 20 
~ 1 
 
Week 8 
Study Day: 57 
43 to 70 
~ 20 
~ 1 
 
Week 12 
Study Day: 85 
71 to 98 
~ 20 
~ 1 
 
Week 16 
Study Day: 113 
99 to 126 
 
2 ~  
~ 20 
Week 20 
Study Day: 141 
127 to 154 
 
2 ~  
~ 20 
Week 24 
Study Day: 169 
155 to 182 
 
2 ~  
~ 20 
Week 28 
Study Day: 197 
183 to 210 
 
2 ~  
~ 20 
Week 32 
Study Day: 225 
211 to 238 
 
2 ~  
~ 20 
Week 36 
Study Day: 253 
239 to 266 
 
2 ~  
~ 20 
Week 40 
Study Day: 281 
267 to 294 
 
2 ~  
~ 20 
Week 44 
Study Day: 309 
295 to 322 
 
2 ~  
~ 20 
Week 48 
Study Day: 337 
323 to 350 
 
2 ~  
~ 20 
Week 52 
Study Day: 365 
351 to 378 
 
2 ~  
~ 20 
Week 54 
Follow-up Day for  
SYR-472 25 mg Tablet: 21 
 
 
 
21 to 28 
At the End of 
Treatment Period I 
Follow-up Day for  
Treatment Period I: 7 
2 ~  
~ 20 
~ 1 
 
At the End of 
Treatment Period II 
Follow-up Day for  
SYR-472 25 mg Tablet: 7 
 
 
2 ~ * 
~ 20 
*: At the end of Treatment Period II, “Study Day for Treatment Period II” will be assumed to be “Study Day for SYR-472 25 mg 
tablet.” 
 
Vital signs, laboratory test, creatinine clearance, eGFR 
Visit 
Scheduled Study Day 
Acceptable Window 
Study Day 
Follow-up Day 
for Treatment 
Period I 
Study Day for 
Treatment 
Period II 
Follow-up Day 
for SYR-472 
25 mg Tablet 
Week -6 
Study Day: -42 
-49 to -29 
 
 
 
Week -2 
Study Day: -14 
-28 to -8 
 
 
 
Week 0 
Study Day: 1 
-7 to 1 
 
 
 
Week 2 
Study Day: 15 
2 to 22 
~ 20 
~ 1 
 
Week 4 
Study Day: 29 
23 to 42 
~ 20 
~ 1 
 
Week 8 
Study Day: 57 
43 to 70 
~ 20 
~ 1 
 
Week 12 
Study Day: 85 
71 to 98 
~ 20 
~ 1 
 


Protocol No. SYR-472-3003 
 
10 
Visit 
Scheduled Study Day 
Acceptable Window 
Study Day 
Follow-up Day 
for Treatment 
Period I 
Study Day for 
Treatment 
Period II 
Follow-up Day 
for SYR-472 
25 mg Tablet 
Week 16 
Study Day: 113 
99 to 126 
 
2 ~  
~ 20 
Week 20 
Study Day: 141 
127 to 154 
 
2 ~  
~ 20 
Week 24 
Study Day: 169 
155 to 182 
 
2 ~  
~ 20 
Week 28 
Study Day: 197 
183 to 210 
 
2 ~  
~ 20 
Week 32 
Study Day: 225 
211 to 238 
 
2 ~  
~ 20 
Week 36 
Study Day: 253 
239 to 266 
 
2 ~  
~ 20 
Week 40 
Study Day: 281 
267 to 294 
 
2 ~  
~ 20 
Week 44 
Study Day: 309 
295 to 322 
 
2 ~  
~ 20 
Week 48 
Study Day: 337 
323 to 350 
 
2 ~  
~ 20 
Week 52 
Study Day: 365 
351 to 378 
 
2 ~  
~ 20 
Week 54 
Follow-up Day for  
SYR-472 25 mg Tablet: 21 
 
 
 
21 to 28 
 
12-lead ECG 
Visit 
Scheduled Study Day 
Acceptable Window 
Study Day 
Follow-up Day 
for Treatment 
Period I 
Study Day for 
Treatment 
Period II 
Follow-up Day 
for SYR-472 
25 mg Tablet 
Week -6 
Study Day: -42 
-49 to -22 
 
 
 
Week 0 
Study Day: 1 
-21 to 1 
 
 
 
Week 4 
Study Day: 29 
2 to 56 
~ 20 
~ 1 
 
Week 12 
Study Day: 85 
57 to 98 
~ 20 
~ 1 
 
Week 24 
Study Day: 169 
99 to 210 
 
2 ~  
~ 20 
Week 36 
Study Day: 253 
211 to 308 
 
2 ~  
~ 20 
Week 52 
Study Day: 365 
309 to 378 
 
2 ~  
~ 20 
Week 54 
Follow-up Day for  
SYR-472 25 mg Tablet: 21 
 
 
 
21 to 28 
 
Plasma concentration of SYR-472Z 
Visit 
Scheduled Study Day 
Acceptable Window 
Study Day 
Follow-up Day 
for Treatment 
Period I 
Study Day for 
Treatment 
Period II 
Follow-up Day 
for SYR-472 
25 mg Tablet 
Week 4 
Study Day: 29 
23 to 42 
~ 20 
~ 1 
 
Week 12 
Study Day: 85 
71 to 98 
~ 20 
~ 1 
 


Protocol No. SYR-472-3003 
 
11 
 
OTHER HANDLING 
• 
Creatinine clearance (mL/min): To be calculated using the following Cockcroft-Gault equation 
(rounded off to the nearest integer in both cases). 
Male: ([140 − Age] × Weight [kg]) / (72 × Serum creatinine [mg/dL]) 
Female: 0.85 × ([140 − Age] × Weight [kg]) / (72 × Serum creatinine [mg/dL]) 
Creatinine clearance will be calculated when the variables to be used for calculation are all 
evaluable and measured on the same day. The age will be calculated from the test dates of 
variables to be used for calculation and the date of birth. 
• 
eGFR (mL/min/1.73 m2): To be calculated using the following equation (rounded off to the 
nearest integer in both cases). 
Male: 194 × Serum creatinine (mg/dL)-1.094 × Age-0.287 
Female: 194 × Serum creatinine (mg/dL)-1.094 × Age-0.287 × 0.739 
The age will be calculated from the test dates of variables to be used for calculation and the date 
of birth. 
• 
Duration of disease (months): Period from the onset time of type 2 diabetes until the time of 
informed consent. 
• 
Duration of study drug exposure for Treatment Period I: Date of the last administration of the 
study drug for Treatment Period I − Date of the start of the study drug administration for 
Treatment Period I + 1 
• 
Compliance with study drug for Treatment Period I: Number of study drug administrations for 
Treatment Period I / (Smallest integer of ≥ [(Date of the last administration of the study drug 
for Treatment Period I − Date of the start of the study drug administration for Treatment Period 
I + 7) / 7]) × 100 (rounded off to the first decimal place) 
• 
Duration of exposure to SYR-472 25 mg tablet: Date of the last administration of SYR-472 
25 mg tablet − Date of the start of SYR-472 25 mg tablet + 1 
• 
Compliance with SYR-472 25 mg tablet: Number of administrations of SYR-472 25 mg tablet / 
(Smallest integer of ≥ [(Date of the last administration of SYR-472 25 mg tablet − Date of the 
start of SYR-472 25 mg tablet + 7) / 7]) × 100 (rounded off to the first decimal place) 


Protocol No. SYR-472-3003 
 
12 
1 STUDY SUBJECTS, DEMOGRAPHICS, AND OTHER BASELINE CHARACTERISTICS 
1.1 Disposition of Subjects 
1.1.1 Study Information 
Analysis set: 
All subjects who signed the informed consent form 
Analysis variables: 
Date first subject signed the informed consent form 
 
Date of last visit or contact, whichever comes later 
 
MedDRA version 
 
WHO Drug version 
 
SAS version used for creating the datasets 
Analysis methodology: The following analysis will be performed for the above analysis 
variables. 
 
(1) Display of the analysis variables 
 
1.1.2 Disposition of All Subjects Who Were Not Randomized 
Analysis set: 
All subjects who were not randomized 
Analysis variables: 
Categories in brackets [  ] (hereinafter the same) 
 
Age (years) 
[Min≤ - <65, 65≤ - ≤Max] 
 
Sex 
[Male, Female] 
Analysis methodology: The following analysis will be performed for the above analysis 
variables. 
(1) Frequency distributions for categorical variables and summary 
statistics for continuous variables 
 
1.1.3 Subject Eligibility 
Analysis set: 
All subjects who signed the informed consent form 
Analysis variables: 
Eligibility for randomization 
[Eligible, Not eligible] 
 
Reason for not being randomized 
[Pretreatment event/Adverse 
event, Significant protocol 
deviation, Lost to follow-up, 
Voluntary withdrawal, Study 
termination, Pregnancy, Did 
not meet inclusion criteria or 
did meet exclusion criteria, 
Other] 
Analysis methodology: The following analysis will be performed for the above analysis 
variables. 
When calculating percentages for the reasons for not being 


Protocol No. SYR-472-3003 
 
13 
randomized, the number of subjects who were not randomized will 
be used as the denominator. 
 
(1) 
Frequency distribution 
 
1.1.4 Number of Subjects Who Were Randomized by Site 
Analysis set: 
All subjects who were randomized 
Analysis variables: 
Eligibility for randomization 
[Eligible] 
Stratum: 
Study site 
[Site numbers will be used as 
categories] 
 
Analysis methodology: The following analysis will be performed for the above analysis 
variables for each stratum by each treatment group and in the 
consolidated treatment groups. 
 
(1) 
Frequency distribution 
 
1.1.5 Disposition of Subjects 
1.1.5.1 
Disposition of Subjects in Treatment Period I 
Analysis set: 
All subjects who were randomized 
Analysis variables: 
Study drug administration status 
[Not treated] 
 
Reason for not being treated 
[Pretreatment event/Adverse 
event, Significant protocol 
deviation, Lost to follow-up, 
Voluntary withdrawal, Study 
termination, Pregnancy, Lack 
of efficacy, Other] 
 
Study drug administration status for 
Treatment Period II 
[Treated, Not treated] 
 
Reason for not being treated 
[Pretreatment event/Adverse 
event, Significant protocol 
deviation, Lost to follow-up, 
Voluntary withdrawal, Study 
termination, Pregnancy, Lack 
of efficacy, Other] 
Analysis methodology: The following analysis will be performed for the above analysis 
variables by each treatment group and in the consolidated treatment 
groups. When calculating percentages of the reasons for not being 
treated, the number of subjects who did not receive with the study 


Protocol No. SYR-472-3003 
 
14 
drug will be used as the denominator. 
 
(1) 
Frequency distribution 
 
1.1.5.2 
Disposition of Subjects in the Entire Study 
Analysis set: 
All subjects who were randomized 
Analysis variables: 
Study drug administration status 
[Not treated] 
 
Reason for not being treated 
[Pretreatment event/Adverse 
event, Significant protocol 
deviation, Lost to follow-up, 
Voluntary withdrawal, Study 
termination, Pregnancy, Lack 
of efficacy, Other] 
 
Study drug completion status 
[Completed, Incompleted] 
 
Reason for not being completed 
[Pretreatment event/Adverse 
event, Significant protocol 
deviation, Lost to follow-up, 
Voluntary withdrawal, Study 
termination, Pregnancy, Lack 
of efficacy, Other] 
 
Completion status of the follow-up 
period 
[Completed, Incompleted] 
 
Reason for not being completed 
[Pretreatment event/Adverse 
event, Significant protocol 
deviation, Lost to follow-up, 
Voluntary withdrawal, Study 
termination, Pregnancy, Lack 
of efficacy, Other] 
Analysis methodology: The following analysis will be performed for the above analysis 
variables by each treatment group and in the consolidated treatment 
groups. When calculating percentages of the reasons for not being 
treated, the number of subjects who did not receive the study drug 
will be used as the denominator. When calculating percentages of 
the reasons for not being completed, the number of subjects who did 
not complete the study drug/follow-up period will be used as the 
denominator. 
 
(1) 
Frequency distribution 
 


Protocol No. SYR-472-3003 
 
15 
1.1.6 Study Drug Completion Status 
Analysis set: 
All subjects who were randomized 
Analysis variables: 
Study drug completion status 
[Completed, Incompleted] 
 
Reason for not being completed 
[Pretreatment event/Adverse 
event, Significant protocol 
deviation, Lost to follow-up, 
Voluntary withdrawal, Study 
termination, Pregnancy, Lack 
of efficacy, Other] 
Categories: 
Number of study drug 
administrations 
[0, 1-4, 5-8, 9-12, 13-24, 
25-36, 37-48, 49-52, 
53-Max] 
Analysis methodology: The following analysis will be performed for the above analysis 
variables by each treatment group and in the consolidated treatment 
groups. 
 
(1) 
Frequency distribution by number of study drug 
administrations 
 
1.1.7 Protocol Deviations and Analysis Sets 
1.1.7.1 
Protocol Deviations 
Analysis set: 
All subjects who were randomized 
Analysis variables: 
Protocol deviations 
[Major GCP violations, Deviations of 
protocol entry criteria, Deviations of 
discontinuation criteria, Deviations 
related to treatment procedure or 
dose, Deviations concerning excluded 
medication or therapy, Deviations to 
avoid emergency risk, Other] 
Analysis methodology: The following analysis will be performed for the above analysis 
variables by each treatment group and in the consolidated treatment 
groups. 
Frequency distribution of subjects with protocol deviations will be 
provided for each deviation category above. A subject who has 
several deviations that can be classified into the same category will 
be counted once in each appropriate category (overlapped counting). 
(1) 
Frequency distribution 
 


Protocol No. SYR-472-3003 
 
16 
1.1.7.2 
Analysis Sets 
Analysis set: 
All subjects who were randomized 
Analysis variables: 
Handling of subjects and subject 
data in analysis sets 
 
Inclusion/Exclusion of analysis sets 
Full analysis set 
Per protocol set 
Safety analysis set 
[Categories are based on the 
specifications in “Handling 
Rules for Analysis Data”] 
 
[Included] 
[Included] 
[Included] 
Analysis methodology: The following analyses of (1) and (2) will be performed for the 
above analysis variables by treatment group and the following 
analysis of (3) will be performed by each treatment group and in the 
consolidated treatment groups. 
A subject who corresponds to several categories in (1) and (2) will 
be counted once in each appropriate category (overlapped counting). 
 
(1) 
Frequency distributions concerning the handling of subjects in 
each analysis set 
(2) 
Frequency distributions concerning the handling of subject 
data in each analysis set 
(3) 
Frequency distributions concerning the number of subjects 
included in each analysis set 
 
1.2 Demographic and Other Baseline Characteristics 
1.2.1 Distribution of Baseline Demographics 
Analysis set: 
All subjects who were randomized 
Analysis variables: 
Age (years) 
[Min≤ - <65, 65≤ - ≤Max] 
[Min≤ - <75, 75≤ - ≤Max] 
 
Sex 
[Male, Female] 
 
Height (cm) 
 
 
Weight (kg) (Week 0) 
 
 
BMI (kg/m2) (Week 0) 
[Min≤ - <18.5, 18.5≤ - <25.0, 
25.0≤ - <30.0, 30.0≤ - ≤Max] 
 
Duration of disease (months) 
[Min≤ - ≤24, 24< - ≤60,  
60< - ≤120, 120< - ≤Max] 
 
Smoking status 
[Never smoked, Current 
smoker, Ex-smoker] 
 
Alcohol use 
[Yes, No] 


Protocol No. SYR-472-3003 
 
17 
 
Exercise therapy 
[Yes, No] 
 
Hemodialysis 
[Yes (end-stage renal 
failure), No (severe renal 
impairment)] 
 
Use of antidiabetic drugs (Week -6) 
[Yes, No] 
 
Rapid-acting insulin 
secretagogues 
Details of rapid-acting insulin 
secretagogues 
Mitiglinide calcium hydrate 
Repaglinide 
[Yes, No] 
 
 
 
[Yes] 
[Yes] 
 
α-glucosidase inhibitors 
Details of α-glucosidase inhibitors 
Acarbose 
Miglitol 
Voglibose 
[Yes, No] 
 
[Yes] 
[Yes] 
[Yes] 
 
Insulin preparations 
Types of insulin preparations 
[Yes, No] 
[Mixed, intermediate-acting, 
Long-acting soluble] 
 
 
Reason for concomitant use of 
antidiabetic drugs being judged to 
be appropriate 
[Combination therapy is 
expected to be more 
effective, Development of 
AEs due to dose increase is 
concerned, Maximum dose 
has already been 
administered, Other] 
 
Creatinine (mg/dL) (Week 0) 
Male 
Female 
Male 
[Min≤ - ≤2.4, 2.4< - ≤Max] 
Female 
[Min≤ - ≤2.0, 2.0< - ≤Max] 
 
Creatinine clearance (mL/min) 
(Week 0) 
 
 
eGFR (mL/min/1.73 m2) (Week 0) 
[Min≤ - <15, 15≤ - <30,  
30≤ - ≤Max] 
 
HbA1c (%) (Week 0) 
[Min≤ - <7.0, 7.0≤ - ≤Max] 
[Min≤ - <8.0, 8.0≤ - ≤Max] 


Protocol No. SYR-472-3003 
 
18 
 
Fasting blood glucose (mg/dL) 
(Week 0) 
[Min≤ - <130, 130≤ - <160, 
160≤ - ≤Max] 
 
Glycoalbumin (%) (Week 0) 
[Min≤ - <24, 24≤ - ≤Max] 
 
Fasting C-peptide (ng/mL) (Week 0) [Min≤ - <1.0, 1.0≤ - <2.0, 
2.0≤ - ≤Max] 
 
Fasting glucagon (pg/mL) (Week 0) 
 
 
DPP-4 activity (nmol/min/mL) 
(Week 0) 
 
Analysis methodology: The following analysis will be performed for the above analysis 
variables by each treatment group and in the consolidated treatment 
groups. (1) Frequency distributions for categorical variables and 
summary statistics for continuous variables 
 
1.2.2 Medical History and Concurrent Medical Conditions 
Analysis set: 
Safety analysis set 
Analysis variables: 
Medical history 
 
 
Concurrent medical conditions 
 
Analysis methodology: The following analysis will be performed for the above analysis 
variables by each treatment group and in the consolidated treatment 
groups. 
The analysis variables will be coded using MedDRA dictionary and 
will be summarized based on the SOC and PT. SOC will be sorted 
alphabetically and PT will be sorted in decreasing frequency.  
(1) 
Frequency distributions for medical history (by SOC and PT) 
(2) 
Frequency distributions for concurrent medical conditions (by 
SOC and PT) 
 
The frequency distributions will be provided according to the rules 
below: 
[Number of subjects] 
A subject with multiple occurrences of medical history or 
concurrent medical condition within a SOC will be counted only 
once in that SOC. A subject with multiple occurrences of medical 
history or concurrent medical condition within a PT will be 
counted only once in that PT. 
 
1.2.3 Medication History and Concomitant Medications 
Analysis set: 
Safety analysis set 


Protocol No. SYR-472-3003 
 
19 
Analysis variables: 
Medication history 
 
 
Concomitant medications 
 
Analysis methodology: The following analysis will be performed for the above analysis 
variables by each treatment group and in the consolidated treatment 
groups. 
The analysis variables will be coded by use of WHO Drug and 
summarized based on Preferred Name, which will be sorted in 
decreasing frequency.  
A subject who has been administered several medications with the 
same Preferred Name will be counted only once for that Preferred 
Name. 
(1) Frequency distributions for medication history 
(2) Frequency distributions for concomitant medications that were 
discontinued prior to the first dose of the study drug 
(3) Frequency distributions for concomitant medications that were 
ongoing at the first dose of the study drug and continued in the 
treatment period 
(4) Frequency distributions for concomitant medications that 
started after the first dose of the study drug 
(5) Frequency distributions for concomitant medications that were 
ongoing at the first dose of the study drug and continued in the 
treatment period, and concomitant medications that started after 
the first dose of the study drug 
 
1.2.4 Concomitant Antidiabetic Drugs Permitted in the Study 
Analysis set: 
Full analysis set 
Analysis variables: 
Newly added oral hypoglycemic drug 
in Treatment Period II (at Week 16 
and thereafter) 
[Yes, No] 
 
Any change in antidiabetic drugs that 
are being used at Week -6 and will be 
concomitantly used during the study 
period in Treatment Period II 
[Yes, No] 
Stratum: 
Types of antidiabetic drugs 
[Rapid-acting insulin 
secretagogues, 
α-glucosidase inhibitors, 
Insulin preparations] 


Protocol No. SYR-472-3003 
 
20 
Analysis methodology: The following analysis will be performed for the newly added oral 
hypoglycemic drug in Treatment Period II (at Week 16 and 
thereafter) in subjects who are not using any antidiabetic drug at 
Week -16 among the full analysis set by treatment group. 
Also, the following analysis will be performed for any change in 
antidiabetic drugs that are being used at Week -6 and will be 
concomitantly used during the study period in Treatment Period II in 
subjects who are using antidiabetic drugs at Week -16 among the 
full analysis set by treatment group. 
Treatment Period II is the period from the start of the study drug 
administration for Treatment Period II until 20 days after the last 
administration of the study drug for Treatment Period II. 
 
(1) Frequency distribution 
 
1.3 Measurement of Compliance Status for Treatment 
1.3.1 Study Drug Exposure and Compliance in the Treatment Period 
Analysis set: 
Safety analysis set 
Analysis variables: 
Number of study drug 
administrations 
[1-12, 13-24, 25-36, 37-48, 
49-52, 53-Max] 
 
Number of study drug 
administrations in Treatment Period 
I 
[1-4, 5-8, 9-12, 13-Max] 
 
Duration of study drug exposure in 
Treatment Period I (days) 
[1-28, 29-56, 57-84, 85-Max] 
 
Compliance with study drug for 
Treatment Period I (%) 
[Min≤ - ≤50.0, 50.0< - ≤70.0, 
70.0< - ≤90.0, 90.0< - ≤Max] 
 
Number of administrations of 
SYR-472 25 mg tablet 
[1-12, 13-24, 25-36, 37-48, 
49-52, 53-Max] 
 
Duration of exposure to SYR-472 
25 mg tablet (days) 
[1-84, 85-168, 169-252, 
253-336, 337-364, 365-Max] 
 
Compliance with SYR-472 25 mg 
tablet (%) 
[Min≤ - ≤50.0, 50.0< - ≤70.0, 
70.0< - ≤90.0, 90.0< - ≤Max] 
Analysis methodology: 
 
The following analysis will be performed for the above analysis 
variables by each treatment group and in the consolidated treatment 
groups. 
(1) Frequency distributions for categorical variables and summary 
statistics for continuous variables 


Protocol No. SYR-472-3003 
 
21 
 
1.3.2 Compliance of Antidiabetic Drugs 
Analysis set: 
Full analysis set 
Analysis variables: 
Compliance with antidiabetic drugs 
[Fully complied (90% or 
more), Almost complied 
(70% or more), Occasionally 
complied (50% or more), 
Rarely complied (less than 
50%)] 
Visits: 
Weeks -2, 0, 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52 or at 
discontinuation, and 54 
Analysis methodology: 
 
The following analysis will be performed for the above analysis 
variables in subjects who are using antidiabetic drugs at Week -16 
among the full analysis set by each treatment group and in the 
consolidated treatment groups. 
(1) Frequency distributions at each visit 
 
1.3.3 Compliance of Diet and/or Exercise Therapy 
Analysis set: 
Full analysis set 
Analysis variables: 
Compliance with diet 
[Fully complied (90% or 
more), Almost complied 
(70% or more), Occasionally 
complied (50% or more), 
Rarely complied (less than 
50%)] 
 
Compliance with exercise therapy 
[Fully complied (90% or 
more), Almost complied 
(70% or more), Occasionally 
complied (50% or more), 
Rarely complied (less than 
50%)] 
Visits: 
Weeks -2, 0, 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52 or at 
discontinuation, and 54 
Analysis methodology: 
 
The following analysis will be performed for the above analysis 
variables by each treatment group and in the consolidated treatment 
groups. 
(1) Frequency distributions at each visit 


Protocol No. SYR-472-3003 
 
22 
2 EFFICACY ANALYSIS 
The “full analysis set” based on the specifications in the protocol and the “Handling Rules for 
Analysis Data” will be the main analysis set. For the sensitivity point of view, the “per protocol 
set” will be used for an analysis performed secondarily on the primary endpoint in order to 
examine the robustness of the results. 
 
2.1 Primary Endpoints and Analysis Methodology 
2.1.1 Primary Analysis 
Analysis set: 
Full analysis set 
Analysis variables: 
Change in HbA1c at the end of Treatment Period I from Week 0 
Analysis methodology: The population mean change in HbA1c at the end of Treatment 
Period I from Week 0 will be compared between the SYR-472 
25 mg/SYR-472 25 mg group and placebo/SYR-472 25 mg group 
based on an analysis of covariance (ANCOVA) model for the 
change in HbA1c at the end of Treatment Period I from Week 0 with 
factors of treatment group and HbA1c at Week 0. 
The same ANCOVA model will be used to calculate the least square 
(LS) mean and the two-sided 95% confidence interval (CI) for each 
treatment group, as well as the intergroup difference in the LS mean 
between the treatment groups (SYR-472 25 mg/SYR-472 25 mg 
group − placebo/SYR-472 25 mg group) and the two-sided 95% CI. 
 
2.1.2 Secondary Analysis 
Analysis set: 
Full analysis set 
Per protocol set 
Analysis variables: 
Change in HbA1c at the end of Treatment Period I from Week 0 
Analysis methodology: The analysis (1) will be performed in the “full analysis set” and (2) 
in the “per protocol set” for the above analysis variables. 
 
(1) 
Summary statistics and the two-sided 95% CI for the mean 
will be calculated for each treatment group, as well as the 
intergroup difference in the mean between treatment groups 
(SYR-472 25 mg/SYR-472 25 mg group − placebo/SYR-472 
25 mg group) and the two-sided 95% CI. 
 
(2) 
In addition, the same analyses as 2.1.1 Primary Analysis and 
2.1.2 Secondary Analysis (1) will be performed to evaluate 
the robustness of the results in terms of a sensitivity analysis. 
 


Protocol No. SYR-472-3003 
 
23 
2.2 Secondary Endpoints and Analysis Methodology 
2.2.1 HbA1c, Fasting Blood Glucose, Glycoalbumin 
Analysis set: 
Full analysis set 
Analysis variables: 
HbA1c 
 
 
Fasting blood glucose 
 
 
Glycoalbumin 
 
Visits: 
HbA1c 
Weeks -6, -2, 0, 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 
at the end of Treatment Period I, and at the end of Treatment 
Period II 
Fasting blood glucose 
Weeks -6, 0, 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 54, 
at the end of Treatment Period I, and at the end of Treatment 
Period II 
Glycoalbumin 
Weeks -6, -2, 0, 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 
54, at the end of Treatment Period I, and at the end of Treatment 
Period II 
Analysis methodology: The following analyses (1) and (2) will be performed for the above 
analysis variables. Also, the following analysis (3) will be 
performed for HbA1c. 
For the mean and standard deviation plot, a plot until Treatment 
Period I and a plot for the entire study will be created, respectively, 
but the plot for the entire period will not be output at Week 54 or at 
the end of Treatment Period I. 
 
(1) Summary statistics and the two-sided 95% CI for the mean will 
be calculated for each visit and the mean and standard 
deviation plot by treatment group will be prepared. Also, the 
intergroup difference in the mean between treatment groups 
(SYR-472 25 mg/SYR-472 25 mg group − placebo/SYR-472 
25 mg group) and the two-sided 95% CI will be calculated for 
each visit during the Screening and Treatment Period I. 
 
(2) The same analysis as the above (1) will be performed for 
changes from Week 0 at each visit after Treatment Period I. 
 
(3) For the proportions of subjects who achieved an HbA1c less 
than 6.0%, 7.0%, or 8.0% at the end of Treatment Period I and 
Treatment Period II, the proportions and the two-sided 95% 


Protocol No. SYR-472-3003 
 
24 
CIs will be calculated for each treatment group, and the 
intergroup difference in the proportions between treatment 
groups (SYR-472 25 mg/SYR-472 25 mg group − 
placebo/SYR-472 25 mg group) and the two-sided 95% CIs 
will be calculated at the end of Treatment Period I. In the 
analysis of each proportion, subjects who did not achieve the 
relevant target HbA1c at Week 0 will be included in the 
analysis. 
 
2.3 Other Endpoints and Analysis Methodology 
2.3.1 Fasting C-peptide, Fasting Glucagon, DPP-4 Activity, Weight 
Analysis set: 
Full analysis set 
Analysis variables: 
Fasting C-peptide 
 
Fasting glucagon 
 
DPP-4 activity 
 
Weight 
Visits: 
Fasting C-peptide 
Weeks -6, -2, 0, 2, 4, 8, 12, 24, 36, 52, 54, at the end of Treatment 
Period I, and at the end of Treatment Period II 
Fasting glucagon, DPP-4 activity 
Weeks 0, 2, 4, 8, 12, 24, 36, 52, 54, at the end of Treatment 
Period I, and at the end of Treatment Period II 
Weight 
Weeks -6, -2, 0, 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 
54, at the end of Treatment Period I, and at the end of Treatment 
Period II 
Analysis methodology: The following analyses (1) and (2) will be performed for the above 
analysis variables. 
For the mean and standard deviation plot, a plot until Treatment 
Period I and a plot for the entire study will be created respectively 
and the plot for the entire period will not be output at Week 54 and 
at the end of Treatment Period I. 
 
(1) 
Summary statistics and the two-sided 95% CI for the mean 
will be calculated for each visit and the mean and standard 
deviation plot by treatment group will be prepared. Also, the 
intergroup difference in the mean between treatment groups 
(SYR-472 25 mg/SYR-472 25 mg group − placebo/SYR-472 


Protocol No. SYR-472-3003 
 
25 
25 mg group) and the two-sided 95% CI will be calculated for 
each visit during the Screening and Treatment Period I. 
 
(2) 
The same analysis as the above (1) will be performed for 
changes from Week 0 at each visit after Treatment Period I 
(for DPP-4 activity, inhibition rate [100 × (Week 0 − each 
visit after Treatment Period I) / Week 0, rounded off to the 
first decimal place]). 
 
2.4 Statistical and Analytical Issues 
2.4.1 Adjustments for Covariates 
See 2.1.1 Primary Analysis. 
 
2.4.2 Handling of Dropouts or Missing Data 
Missing test results and ineligible data according to the “Handling Rules for Analysis Data” 
or the SAP will be excluded from statistical analyses and estimations. 
 
2.4.3 Interim Analysis and Data Monitoring 
No interim analysis is planned. 
 
2.4.4 Multicenter Studies 
Although this is a multicenter study, interactions between treatment and the study site will 
not be investigated since the target number of subjects per study site is not sufficiently large 
for meaningful analyses of the interactions. 
 
2.4.5 Multiple Comparisons/Multiplicity 
The main focuses will be placed on the results of the primary analysis performed for the 
primary endpoint defined as “change in HbA1c at the end of Treatment Period I from Week 
0” in the “full analysis set.” Other analytical results will be interpreted to support the results 
of the primary endpoint or to explore the characteristics of efficacy of the study drug. These 
results will be considered one measure suggesting the trends or characteristics of efficacy. 
Thus, no adjustment for multiplicity will be performed. 
 
2.4.6 Use of an “Efficacy Subset of Subjects” 
To confirm the robustness of the primary analysis results for the primary endpoint for the 
sensitivity point of view, the same analysis as for the “full analysis set” will be performed 
secondarily in the “per protocol set.” 
 


Protocol No. SYR-472-3003 
 
26 
2.4.7 Active-Control Studies Intended to Show Equivalence or Non-inferiority 
Not applicable. 
 
2.4.8 Examination of Subgroups 
Analysis set: 
Full analysis set 
Analysis variables: 
Change in HbA1c at the end of Treatment Period I from Week 0 
Stratum: 
Age (years) 
[Min≤ - <65, 65≤ - ≤Max]  
 
Sex 
[Male, Female] 
 
BMI (kg/m2) (Week 0) 
[Min≤ - <25.0, 25.0≤ - 
<30.0, 30.0≤ - ≤Max] 
 
Duration of disease (months) 
[Min≤ - ≤120, 120< - ≤Max] 
 
Medication history 
[Yes, No] 
 
Hemodialysis 
[Yes (end-stage renal 
failure), No (severe renal 
impairment)] 
 
Use of antidiabetic drugs (Week -6) 
[Yes, No] 
 
Rapid-acting insulin secretagogues [Yes, No] 
 
α-glucosidase inhibitors 
[Yes, No] 
 
Insulin preparations 
[Yes, No] 
 
eGFR (mL/min/1.73 m2) (Week 0) 
[Min≤ - <15, 15≤ - ≤Max] 
 
HbA1c (%) (Week 0) 
[Min≤ - <7.0, 7.0≤ - ≤Max] 
[Min≤ - <8.0, 8.0≤ - ≤Max] 
 
Fasting blood glucose (mg/dL) 
(Week 0) 
[Min≤ - <160, 160≤ - =Max] 
 
Glycoalbumin (%) (Week 0) 
[Min≤ - <24, 24≤ - ≤Max] 
 
Fasting C-peptide (ng/mL) 
(Week 0) 
[Min≤ - <2.0, 2.0≤ - ≤Max] 
Analysis methodology: The following analyses will be performed for the above analysis 
variables. 
 
(1) 
Summary statistics and the two-sided 95% CI for the mean 
will be calculated for each stratum by treatment group, as well 
as the intergroup difference in the mean between treatment 
groups (SYR-472 25 mg/SYR-472 25 mg group − 
placebo/SYR-472 25 mg group) and the two-sided 95% CI. 
 
(2) 
The ANCOVA will be performed for each stratum with the 
change in HbA1c at the end of Treatment Period I from Week 
0 as the response and with treatment group, stratum, and 


Protocol No. SYR-472-3003 
 
27 
interactions of treatment group and stratum as factors. The 
stratum will be included in the ANCOVA model as category 
variables based on the above category and analyzed. 
 
2.5 Plasma Concentration of SYR-472Z 
Analysis set: 
Full analysis set 
Analysis variables: 
Plasma concentration of SYR-472Z 
 
Stratum: 
Hemodialysis 
[Yes (end-stage renal 
failure), No (severe renal 
impairment)] 
Visits: 
Weeks 4 and 12 
Analysis methodology: Summary statistics will be calculated for the above analysis 
variables for each visit in the SYR-472 25 mg/SYR-472 25 mg 
group among the full analysis set. 
The same analysis as the above will be performed for each stratum. 


Protocol No. SYR-472-3003 
 
28 
3 SAFETY ANALYSIS 
3.1 Treatment-Emergent Adverse Event 
3.1.1 Overview of Treatment-Emergent Adverse Events 
Analysis set: 
Safety analysis set 
Analysis variables: 
TEAEs that occur before the start of the study drug for Treatment 
Period II 
TEAEs that occur after the start of SYR-472 25 mg tablet 
Categories: 
Causality 
[Related, Not related] 
 
Intensity 
[Mild, Moderate, Severe] 
Analysis methodology: The following summaries will be provided for the above analysis 
variables by treatment group. 
In the analysis of TEAEs occurring after the start of SYR-472 25 mg 
tablet, subjects who received SYR-472 25 mg tablet in the safety 
analysis set will be included in the analyses and the summaries in 
the consolidated treatment groups will be also provided. 
 
(1) 
Overview of TEAEs 
 
 
1) All TEAEs (number of events, number and percentage of 
subjects) 
 
 
2) Causal relationship between all TEAEs and study drug 
(number of events, number and percentage of subjects) 
 
 
3) Intensity of all TEAEs (number of events, number and 
percentage of subjects) 
 
 
4) TEAEs leading to study drug discontinuation (number of 
events, number and percentage of subjects) 
 
 
5) Serious TEAEs (number of events, number and 
percentage of subjects) 
 
 
6) Causal relationship between serious TEAEs and study 
drug (number of events, number and percentage of 
subjects) 
 
 
7) Serious TEAEs leading to study drug discontinuation 
(number of events, number and percentage of subjects) 
 
 
8) TEAEs leading to death (number of events, number and 
percentage of subjects) 
 
TEAEs will be counted according to the rules below: 
[Number of subjects] 
• In the case of “summaries by causality” 
A subject with occurrences of TEAE in both categories (i.e., 


Protocol No. SYR-472-3003 
 
29 
“Related” and “Not related”) will be counted once in the 
“Related” category. 
• In the case of “summaries by intensity” 
A subject with multiple occurrences of TEAE will be counted 
once for the TEAE with the maximum intensity. 
• In the case of summaries other than the above 
A subject with multiple occurrences of TEAE will be counted 
only once. 
[Number of events] 
For each summary, the total number of events will be calculated. 
 
3.1.2 Displays of Treatment-Emergent Adverse Events 
Analysis set: 
Safety analysis set 
Analysis variables: 
TEAEs that occur before the start of the study drug for Treatment 
Period II 
TEAEs that occur after the start of SYR-472 25 mg tablet 
Categories: 
Intensity 
[Mild, Moderate, Severe] 
 
Time of onset (day) 
TEAEs that occur before the 
start of the study drug for 
Treatment Period II 
[1-28, 29-56, 57-Max] 
[1-14, 15-28, 29-Max] 
TEAEs that occur after the 
start of SYR-472 25 mg 
tablet 
[1-84, 85-168, 169-252, 
253-336, 337-Max] 
[1-14, 15-28, 29-Max] 
 
Number of days from the immediate 
study drug administration (days) 
[1, 2, 3, 4, 5, 6, 7, 8-Max] 
Analysis methodology: The following summaries will be provided for the above analysis 
variables using frequency distributions by treatment group. 
In the analysis of TEAEs occurring after the start of SYR-472 25 mg 
tablet, subjects who received SYR-472 25 mg tablet in the safety 
analysis set will be included in the analyses and the summaries in 
the consolidated treatment groups will be also provided concerning 
(1) and (4). 


Protocol No. SYR-472-3003 
 
30 
TEAEs will be coded using MedDRA dictionary and will be 
summarized based on SOC and PT. SOC will be sorted 
alphabetically and PT will be sorted in decreasing frequency for 
tables provided by SOC and PT. SOC and PT will be sorted in 
decreasing frequency for tables provided by SOC only or PT only.  
 
(1) All TEAEs by SOC and PT 
 
(2) All TEAEs by SOC 
 
(3) All TEAEs by PT 
 
(4) Drug-related TEAEs by SOC and PT 
 
(5) Intensity of all TEAEs by SOC and PT 
 
(6) Intensity of drug-related TEAEs by SOC and PT 
 
(7) TEAEs leading to study drug discontinuation by SOC and PT 
 
(8) Serious TEAEs by SOC and PT 
 
(9) All TEAEs by SOC and PT over time 
 
(10) Number of days from the immediate study drug administration 
for all TEAEs by SOC and PT 
 
(11) TEAEs whose incidence summarized by PT is 2% or higher 
(rounded off to the first decimal place) in either treatment 
group by SOC and PT 
 
(12) Intestinal obstruction-related TEAEs by SOC and PT 
 
(13) Acute pancreatitis-related TEAEs by SOC and PT 
 
(14) QT/QTc interval prolongation-related TEAEs by SOC and PT 
 
(15) Hypersensitivity-related TEAEs by SOC and PT 
 
(16) Cardiovascular TEAEs by SOC and PT 
 
(17) Pemphigoid TEAEs by SOC and PT 
 
(18) Renal impairment TEAEs by SOC and PT 
 
(19) Hypoglycemia-related TEAEs by SOC and PT 
 
The frequency distribution and incidence will be provided according 
to the rules below: 
[Number of subjects] 
• In the case of “summaries by SOC and PT, by SOC, and by PT” 
A subject with multiple occurrences of TEAE within a SOC will 
be counted only once in that SOC. A subject with multiple 
occurrences of TEAE within a PT will be counted only once in 
that PT. Percentages of TEAEs will be based on the number of 
subjects in the analysis set. 
• In the case of “summaries of intensity by SOC and PT” 


Protocol No. SYR-472-3003 
 
31 
A subject with multiple occurrences of TEAE within a SOC or a 
PT will be counted only once for the TEAE with the maximum 
intensity. Percentages of TEAEs will be based on the number of 
subjects in the analysis set. 
• In the case of “summaries by SOC and PT over time” 
A subject with a TEAE that occurs in more than one interval is 
counted in all the intervals that the TEAE occurs. For each time 
interval, a subject with multiple occurrences of TEAE within a 
SOC or a PT will be counted only once in that SOC or PT. 
When calculating percentages of TEAEs for each time interval, 
the number of subjects at risk (i.e., “subjects who either have an 
exposure in the study or have an occurrence of TEAE, during or 
after the corresponding time interval”) will be used as the 
denominator. The number of subjects whose “onset of any one 
of the TEAEs is within the time interval” will be used as the 
numerator. 
• In the case of “summaries of number of days from the 
immediate study drug administration” by SOC and PT 
A subject with a TEAE that occurs in more than one category of 
number of days is counted in all the categories that the TEAE 
occurs. For each category of number of days, a subject with 
multiple occurrences of TEAE within a SOC or a PT will be 
counted only once in that SOC or PT. Percentages of TEAEs 
will be based on the number of subjects in the analysis set. 
 
3.1.3 Subgroup Analysis of Treatment-Emergent Adverse Events 
Analysis set: 
Safety analysis set 
Analysis variables: 
TEAEs that occur before the start of the study drug for Treatment 
Period II  
TEAEs that occur after the start of SYR-472 25 mg tablet 
Stratum: 
Age (years) 
[Min≤ - <65, 65≤ - ≤Max]  
[Min≤ - <75, 75≤ - ≤Max] 
 
Hemodialysis 
[Yes (end-stage renal 
failure), No (severe renal 
impairment)] 
 
Complications of hepatobiliary 
disorders 
[Yes, No] 


Protocol No. SYR-472-3003 
 
32 
 
Use of antidiabetic drugs (Week -6) 
[Yes, No] 
 
Rapid-acting insulin 
secretagogues 
[Yes, No] 
 
α-glucosidase inhibitors 
[Yes, No] 
 
Insulin preparations 
[Yes, No] 
 
eGFR (mL/min/1.73 m2) (Week 0) 
[Min≤ - <15, 15≤ - ≤Max] 
Analysis methodology: The following summaries will be provided for the above analysis 
variables using frequency distributions for each stratum by treatment 
group for TEAEs occurring before the start of the study drug for 
Treatment Period II and in the consolidated treatment groups for 
TEAEs occurring after the start of SYR-472 25 mg tablet. 
In the analysis of TEAEs occurring after the start of SYR-472 25 mg 
tablet, subjects who received SYR-472 25 mg tablet in the safety 
analysis set will be included in the analyses. TEAEs will be coded 
using MedDRA dictionary and will be summarized based on SOC 
and PT. SOC will be sorted alphabetically and PT will be sorted in 
decreasing frequency. 
 
(1) 
All TEAEs by SOC and PT 
 
(2) 
Drug-related TEAEs by SOC and PT 
 
The frequency distributions will be provided according to the rules 
below: 
[Number of subjects] 
A subject with multiple occurrences of TEAE within a SOC will 
be counted only once in that SOC. A subject with multiple 
occurrences of TEAE within a PT will be counted only once in 
that PT. 
 
3.2 Pretreatment Event 
3.2.1 Display of Pretreatment Events 
Analysis set: 
All subjects who signed the informed consent form 
Analysis variables: 
PTE 
Analysis methodology: The following summaries will be provided for the above analysis 
variables using frequency distributions. 
PTEs will be coded using MedDRA dictionary and will be 
summarized based on SOC and PT. SOC will be sorted 
alphabetically and PT will be sorted in decreasing frequency.  
 
(1) 
All PTEs by SOC and PT 


Protocol No. SYR-472-3003 
 
33 
(2) 
Serious PTEs by SOC and PT 
 
The frequency distributions will be provided according to the rules 
below: 
[Number of subjects] 
A subject with multiple occurrences of PTE within a SOC will be 
counted only once in that SOC. A subject with multiple 
occurrences of PTE within a PT will be counted only once in that 
PT. 
 
3.3 Clinical Laboratory Evaluations and Other Safety Endpoints 
3.3.1 Clinical Laboratory Evaluations 
3.3.1.1 Hematology and Serum Chemistry 
Analysis set: 
Safety analysis set 
Analysis variables: 
Hematology 
 
Red blood cells 
Reticulocytes 
White blood cells 
 
Hemoglobin 
Hematocrit 
Platelets 
 
Neutrophils 
Lymphocytes 
Monocytes 
 
Eosinophils 
Basophils 
MCV 
 
MCH 
MCHC 
 
 
Serum chemistry 
 
ALT 
AST 
 
γ-GTP 
ALP 
 
Total bilirubin 
Total protein 
 
Albumin 
Creatinine 
 
Amylase 
Lipase 
 
Blood urea nitrogen 
Uric acid 
 
Creatine kinase 
LDH 
 
Total cholesterol 
Triglyceride 
 
LDL cholesterol 
HDL cholesterol 
 
High-sensitivity CRP 
K 
 
Na 
Ca 
 
Cl 
P 
 
Fe 
Creatinine clearance 
Categories: 
Adjudication results based on the normal reference ranges 
[Low, Normal, High] 
Visits: 
Weeks -6, -2, 0, 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, and 
54 


Protocol No. SYR-472-3003 
 
34 
Analysis methodology: The following analysis will be performed for the above analysis 
variables except for high-sensitivity CRP and creatinine clearance 
by treatment group. The following analyses of (1) to (2) will be 
performed for high-sensitivity CRP and creatinine clearance by 
treatment group. 
When the analysis of MAV is performed, if both “upper” and 
“lower” criteria in the MAV Criteria are applicable to the same test 
item, the analysis will be performed for each criterion separately. 
See Appendix 2 of this SAP for the definitions of test items subject 
to this analysis and the MAV Criteria. 
 
(1) Summary statistics for each visit and summary statistics for 
change from Week 0 at each visit after Treatment Period I 
 
(2) Case plots 
 
(3) Shift tables showing adjudication results based on normal 
reference range at Week 0 and each visit after Treatment 
Period I 
 
(4) Frequency distributions for MAV before the start of the study 
drug administration for Treatment Period II and after the start 
of SYR-472 25 mg tablet 
 
3.3.2 Vital Signs, Physical Examination, and Other Observation Items Related to Safety 
3.3.2.1 
Vital Signs 
Analysis set: 
Safety analysis set 
Analysis variables: 
Systolic blood pressure 
 
 
Diastolic blood pressure 
 
 
Pulse 
 
Visits: 
Weeks -6, -2, 0, 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, and 
54 
Analysis methodology: The following analysis will be provided for the above analysis 
variables by treatment group. 
 
(1) Summary statistics for each visit and summary statistics for 
change from Week 0 at each visit after Treatment Period I 
 
(2) Case plots 
 
3.3.2.2 
12-lead ECG 
Analysis set: 
Safety analysis set 
Analysis variables: 
Heart rate 
 


Protocol No. SYR-472-3003 
 
35 
 
RR interval 
 
 
PR interval 
 
 
QRS interval 
 
 
QT interval 
 
 
QTcF interval 
 
 
Findings of 12-lead ECG 
[Within normal limits, 
Abnormal but not clinically 
significant, Abnormal and 
clinically significant] 
Visits: 
Weeks -6, 0, 4, 12, 24, 36, 52, and 54 
Analysis methodology: The following analyses of (1) to (3) will be performed for the above 
analysis variables except for findings of 12-lead ECG by treatment 
group. 
The following analyses of (4) will be performed for findings of 
12-lead ECG by treatment group. 
When the analysis of MAV is performed, if both “upper” and 
“lower” criteria in the MAV Criteria are applicable to the same test 
item, the analysis will be performed for each criterion separately. 
See Appendix 2 of this SAP for the definitions of test items subject 
to this analysis and the MAV Criteria. 
 
(1) Summary statistics for each visit and summary statistics for 
change from Week 0 at each visit after Treatment Period I 
 
(2) Case plots 
 
(3) Frequency distributions for MAV before the start of the study 
drug administration for Treatment Period II and after the start 
of SYR-472 25 mg tablet 
 
(4) Shift tables showing at Week 0 and each visit after Treatment 
Period I 
 
3.3.2.3 
Hypoglycemia 
Analysis set: 
Safety analysis set 
Analysis variables: 
Hypoglycemia that occurs after the start of the study drug 
administration and before the start of the study drug for Treatment 
Period II 
Hypoglycemia that occurs after the start of SYR-472 25 mg tablet 
Analysis methodology: The following summaries will be provided for the above analysis 
variables using frequency distributions in subjects who 


Protocol No. SYR-472-3003 
 
36 
concomitantly received insulin preparations among the safety 
analysis set by treatment group. 
In the analysis of hypoglycemia occurring after the start of SYR-472 
25 mg tablet, subjects who concomitantly received insulin 
preparation and SYR-472 25 mg tablet in the safety analysis set will 
be included in the analyses. 
 
(1) All hypoglycemia 
 
(2) Severe hypoglycemia 
 
(3) Symptomatic hypoglycemia 
 
(4) Asymptomatic hypoglycemia 
 
(5) Probable symptomatic hypoglycemia 
 
(6) Relative hypoglycemia 
 
The frequency distributions will be provided according to the rules 
below: 
[Number of subjects] 
A subject with multiple occurrences of hypoglycemia within the 
same classification will be counted only once in that classification. 
[Number of events] 
For each summary, the total number of events will be calculated. 


Protocol No. SYR-472-3003 
 
37 
4 SIGNIFICANCE LEVEL AND CONFIDENCE COEFFICIENT 
• 
Significance level: 5% (two-sided tests) 
• 
Confidence coefficient: 95% (two-sided) 
 
 


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Protocol No. SYR-472-3003 
 
1 
[Appendix 1] SYR-472-3003 Comparison Table for Changes 
 
Page 
Existing Text 
Revised Text 
Rationale for Changes  
18 
1.2.1 Distribution of Baseline Demographics 
Rapid-acting insulin secretagogues [Yes] 
… 
α-glucosidase inhibitors [Yes] 
… 
Insulin preparations [Yes] 
Mixed [Yes] 
Intermediate-acting [Yes] 
Long-acting soluble [Yes] 
 
1.2.1 Distribution of Baseline Demographics 
Rapid-acting insulin secretagogues [Yes, No] 
Details of rapid-acting insulin secretagogues 
… 
α-glucosidase inhibitors [Yes, No] 
Details of α-glucosidase inhibitors 
… 
Insulin preparations [Yes, No] 
Types of insulin preparations [Mixed, 
intermediate-acting, Long-acting soluble] 
Adjustment of descriptions and changes in 
the contents of distributions as a result of 
reexamination of contents of distributions 
19 
1.2.1 Distribution of Baseline Demographics 
HbA1c (%) (Week 0) 
[Min≤ - <8.0, 8.0<= - ≤Max] 
1.2.1 Distribution of Baseline Demographics 
HbA1c (%) (Week 0) 
[Min≤ - <7.0, 7.0≤ - ≤Max] 
[Min≤ - <8.0, 8.0≤ - ≤Max] 
Addition of distributions as a result of 
reexamination of contents of distributions 
20 
1.2.4 Concomitant Antidiabetic Drugs 
Permitted in the Study 
Any change in doses of antidiabetic drugs that 
are being used at Week -6 and will be 
concomitantly used during the study period in 
Treatment Period II 
1.2.4 Concomitant Antidiabetic Drugs 
Permitted in the Study 
Any change in antidiabetic drugs that are 
being used at Week -6 and will be 
concomitantly used during the study period in 
Treatment Period II 
Adjustment of descriptions to clarify the 
contents of distribution 


Protocol No. SYR-472-3003 
 
2 
Page 
Existing Text 
Revised Text 
Rationale for Changes  
… 
Also, regarding the presence or absence of 
any change in doses of antidiabetic drugs that 
are being used at Week -6 and will be 
concomitantly used during the study period in 
Treatment Period II, … 
… 
Also, regarding the presence or absence of 
any change in antidiabetic drugs that are 
being used at Week -6 and will be 
concomitantly used during the study period in 
Treatment Period II, … 
27 
2.4.8 Examination of Subgroups 
Duration of disease (months) 
[Min≤ - ≤60, 60< - =Max] 
Fasting C-peptide (ng/mL) 
[Min≤ - <1.0, 1.0≤ - <2.0, 2.0≤ - ≤Max] 
2.4.8 Examination of Subgroups 
Duration of disease (months) 
[Min≤ - ≤120, 120< - =Max] 
Fasting C-peptide (ng/mL) 
[Min≤ - <2.0, 2.0≤ - ≤Max] 
Changes in the contents of distributions as a 
result of reexamination of categories at the 
blinded review 
29 
3.1.2 3.1.2 Displays of Treatment-Emergent 
Adverse Events 
 
3.1.2 3.1.2 Displays of Treatment-Emergent 
Adverse Events 
(19) Hypoglycemia-related TEAEs by SOC 
and PT 
Addition of distributions as a result of 
reexamination of contents of distributions