Conditions: Type 2 Diabetes Mellitus
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 77
Healthy volunteers: no

Brief summary:
This is a study to assess the safety and efficacy of the addition of ipragliflozin to sitagliptin in Japanese participants with Type 2 diabetes mellitus (T2DM) who have inadequate glycemic control on sitagliptin, diet, and exercise therapy.

Detailed description:

Arms:
arm 1: Ipragliflozin one 50 mg tablet co-administered with one 50 mg sitagliptin once daily (QD) for 52 weeks in addition to diet and exercise therapy.

Interventions: intervention 1: Ipragliflozin intervention 2: Sitagliptin
Intervention descriptions: intervention 1: one 50 mg tablet QD intervention 2: one 50 mg tablet QD

Protocol document:
Prot_SAP_000.pdf: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Official Protocol Title: A Phase III, Multicenter, Open-label Long-term Treatment Trial to 
Assess the Safety and Efficacy of Addition of Ipragliflozin in 
Japanese Patients with Type 2 Diabetes Mellitus Who Have 
Inadequate Glycemic Control on Sitagliptin Monotherapy in Addition 
to Diet and Exercise Therapy 
 
NCT number: 
NCT02564211
Document Date: 
05-Aug-2015


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THIS PROTOCOL AND ALL OF THE INFORMATION RELATING TO IT ARE 
CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK SHARP & 
DOHME CORP., A SUBSIDIARY OF MERCK & CO., INC., WHITEHOUSE 
STATION, NJ, U.S.A.
SPONSOR:
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. 
(hereafter referred to as the Sponsor or Merck)
One Merck Drive
P.O. Box 100
Whitehouse Station, New Jersey, 08889-0100, U.S.A.
Protocol-specific Sponsor Contact information can be found in the Investigator Trial File 
Binder (or equivalent).
TITLE:
A Phase III, Multicenter, Open-label Long-term Treatment Trial to Assess the Safety and 
Efficacy of Addition of Ipragliflozin in Japanese Patients with Type 2 Diabetes Mellitus Who
Have Inadequate Glycemic Control on Sitagliptin Monotherapy in Addition to Diet and 
Exercise Therapy
  
EudraCT NUMBER:  Not Applicable


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TABLE OF CONTENTS
1.0
TRIAL SUMMARY.................................................................................................. 10
2.0
TRIAL DESIGN........................................................................................................ 11
Trial Design ........................................................................................................... 11
2.1
Trial Diagram........................................................................................................ 12
2.2
3.0
OBJECTIVE(S) & HYPOTHESIS(ES).................................................................. 13
Primary Objective(s) & Hypothesis(es) .............................................................. 13
3.1
Secondary Objective(s) & Hypothesis(es)........................................................... 13
3.2
Tertiary Objectives ............................................................................................... 13
3.3
4.0
BACKGROUND & RATIONALE.......................................................................... 13
Background ........................................................................................................... 13
4.1
Pharmaceutical and Therapeutic Background..................................................... 13
4.1.1
Rationale................................................................................................................ 15
4.2
Rationale for the Trial and Selected Subject Population .................................... 15
4.2.1
Rationale for Dose Selection/Regimen ............................................................... 16
4.2.2
Rationale for Endpoints ...................................................................................... 16
4.2.3
Safety Endpoints .......................................................................................... 16
4.2.3.1
Efficacy Endpoints....................................................................................... 16
4.2.3.2
Rationale for duration of the treatment period.................................................... 16
4.2.4
Benefit/Risk ........................................................................................................... 17
4.3
5.0
METHODOLOGY ................................................................................................... 17
Entry Criteria........................................................................................................ 17
5.1
Diagnosis/Condition for Entry into the Trial ...................................................... 17
5.1.1
Subject Inclusion Criteria.................................................................................... 17
5.1.2
Subject Exclusion Criteria .................................................................................. 19
5.1.3
Trial Treatment(s) ................................................................................................ 24
5.2
Dose Selection..................................................................................................... 24
5.2.1
Dose Selection (Preparation) ....................................................................... 24
5.2.1.1
Timing of Dose Administration .......................................................................... 24
5.2.2


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From screening period to pre-treatment period (From the day after Visit 
5.2.2.1
1/Screening to the day of Visit 4/Week 0)................................................... 24
Treatment period (From the day after Visit 4/Week 0 to the day before 
5.2.2.2
Visit 15/Week 52 or discontinuation visit).................................................. 24
Handling of Missed Doses........................................................................... 25
5.2.2.3
Timing of Dosing of Study Drug on Days of Study Visits.......................... 25
5.2.2.4
Trial Blinding/Masking....................................................................................... 25
5.2.3
Randomization or Treatment Allocation............................................................ 25
5.3
Stratification.......................................................................................................... 25
5.4
Concomitant Medications/Vaccinations (Allowed & Prohibited).................... 25
5.5
Prohibited medications........................................................................................ 25
5.5.1
Limited Concomitant Medications...................................................................... 26
5.5.2
Rescue Medications & Supportive Care ............................................................. 27
5.6
Timing of Dose Administration .......................................................................... 27
5.6.1
Handling of Missed Doses .................................................................................. 27
5.6.2
Timing of Dosing of Rescue Medication on Days of Study Visits..................... 27
5.6.3
Diet/Activity/Other Considerations..................................................................... 28
5.7
Diet therapy......................................................................................................... 28
5.7.1
Exercise therapy.................................................................................................. 28
5.7.2
Subject Withdrawal/Discontinuation Criteria................................................... 28
5.8
Subject Replacement Strategy............................................................................. 31
5.9
Beginning and End of the Trial ........................................................................... 31
5.10
Clinical Criteria for Early Trial Termination ................................................... 31
5.11
6.0
TRIAL FLOW CHART ........................................................................................... 32
7.0
TRIAL PROCEDURES ........................................................................................... 34
Trial Procedures ................................................................................................... 34
7.1
Administrative Procedures.................................................................................. 34
7.1.1
Informed Consent......................................................................................... 34
7.1.1.1
7.1.1.1.1
General Informed Consent.................................................................... 34
Inclusion/Exclusion Criteria ........................................................................ 35
7.1.1.2
Subject Identification Card .......................................................................... 35
7.1.1.3
Medical History ........................................................................................... 35
7.1.1.4


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Prior and Concomitant Medications Review ............................................... 35
7.1.1.5
7.1.1.5.1
Prior Medications.................................................................................. 35
7.1.1.5.2
Concomitant Medications ..................................................................... 35
Assignment of Screening Number ............................................................... 35
7.1.1.6
Assignment of Treatment/Randomization Number ..................................... 36
7.1.1.7
Trial Compliance (Medication/Diet/Activity/Other) ................................... 36
7.1.1.8
Diet And Exercise Therapy Counseling ...................................................... 36
7.1.1.9
Patient Registration...................................................................................... 37
7.1.1.10
Instruction and Dispensing Recording of Patient’s Log .............................. 37
7.1.1.11
Collection and Review of Patient’s Log ...................................................... 37
7.1.1.12
Self-Monitoring Blood Glucose Procedures................................................ 37
7.1.1.13
Instructions on Hypoglycemic Symptoms, Management, and Recording 
7.1.1.14
of Hypoglycemic Assessment Log .............................................................. 38
Study Medication Dispensing ...................................................................... 38
7.1.1.15
Clinical Procedures/Assessments........................................................................ 39
7.1.2
Collection and Review of HAL ................................................................... 39
7.1.2.1
Adverse Experience Monitoring.................................................................. 39
7.1.2.2
7.1.2.2.1
Hyperglycemia...................................................................................... 39
7.1.2.2.2
Hypoglycemia....................................................................................... 39
Vital Signs.................................................................................................... 39
7.1.2.3
12-lead ECG................................................................................................. 40
7.1.2.4
Laboratory Procedures/Assessments................................................................... 40
7.1.3
Laboratory Efficacy Evaluations ................................................................. 40
7.1.3.1
Laboratory Safety Evaluations..................................................................... 40
7.1.3.2
Other Procedures................................................................................................. 41
7.1.4
Withdrawal/Discontinuation........................................................................ 41
7.1.4.1
Blinding/Unblinding .................................................................................... 42
7.1.4.2
Calibration of Critical Equipment................................................................ 42
7.1.4.3
Visit Requirements.............................................................................................. 42
7.1.5
Screening Period .......................................................................................... 43
7.1.5.1
7.1.5.1.1
Visit 1/Screening................................................................................... 43
Pre-treatment Period .................................................................................... 43
7.1.5.2


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7.1.5.2.1
Visit 2/Week -10 (Only for Group A)................................................... 43
7.1.5.2.2
Telephone contact/Week -6 (Only for Group A).................................. 44
7.1.5.2.3
Visit 3/Week -2 (Only for Group A)..................................................... 44
Treatment Period.......................................................................................... 44
7.1.5.3
7.1.5.3.1
Visit 4/Week 0 ...................................................................................... 44
7.1.5.3.2
From Visit 5/Week 4 to Visit 14/Week 44 ........................................... 45
7.1.5.3.3
Visit 15/Week 52 or discontinuation visit ............................................ 45
7.1.5.3.4
Rescue Visit .......................................................................................... 45
After Last Dose of Study Medication .......................................................... 45
7.1.5.4
Assessing and Recording Adverse Events .......................................................... 45
7.2
Definition of an Overdose for This Protocol and Reporting of Overdose to 
7.2.1
the Sponsor.......................................................................................................... 46
Reporting of Pregnancy and Lactation to the Sponsor ....................................... 47
7.2.2
Immediate Reporting of Adverse Events to the Sponsor.................................... 47
7.2.3
Serious Adverse Events ............................................................................... 47
7.2.3.1
Events of Clinical Interest............................................................................ 48
7.2.3.2
Evaluating Adverse Events ................................................................................. 49
7.2.4
Sponsor Responsibility for Reporting Adverse Events....................................... 52
7.2.5
8.0
STATISTICAL ANALYSIS PLAN......................................................................... 52
Statistical Analysis Plan Summary ..................................................................... 52
8.1
Responsibility for Analyses/In-House Blinding ................................................. 53
8.2
Hypotheses/Estimation ......................................................................................... 53
8.3
Analysis Endpoints ............................................................................................... 53
8.4
Safety Endpoints ................................................................................................. 53
8.4.1
Efficacy Endpoints.............................................................................................. 53
8.4.2
Analysis Populations............................................................................................. 53
8.5
Safety Analysis Populations................................................................................ 53
8.5.1
Efficacy Analysis Populations ............................................................................ 53
8.5.2
Statistical Methods................................................................................................ 54
8.6
Statistical Methods for Safety Analyses ............................................................. 54
8.6.1
Statistical Methods for Efficacy Analyses .......................................................... 54
8.6.2
Summaries of Baseline Characteristics, Demographics, and Other Analyses .... 54
8.6.3


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Interim Analyses ................................................................................................... 54
8.7
Multiplicity ............................................................................................................ 55
8.8
Sample Size and Power Calculations .................................................................. 55
8.9
Subgroup Analyses and Effect of Baseline Factors ........................................... 55
8.10
Compliance (Medication Adherence).................................................................. 55
8.11
Extent of Exposure................................................................................................ 55
8.12
9.0
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES ................................................................................................................. 56
Investigational Product ........................................................................................ 56
9.1
Packaging and Labeling Information ................................................................. 56
9.2
Clinical Supplies Disclosure................................................................................. 56
9.3
Storage and Handling Requirements.................................................................. 56
9.4
Discard/Destruction/Returns and Reconciliation .............................................. 57
9.5
10.0
ADMINISTRATIVE AND REGULATORY DETAILS....................................... 57
Confidentiality....................................................................................................... 57
10.1
Confidentiality of Data........................................................................................ 57
10.1.1
Confidentiality of Subject Records ..................................................................... 57
10.1.2
Confidentiality of Investigator Information........................................................ 57
10.1.3
Confidentiality of IRB/IEC Information............................................................. 58
10.1.4
Compliance with Financial Disclosure Requirements....................................... 58
10.2
Compliance with Law, Audit and Debarment ................................................... 59
10.3
Compliance with Trial Registration and Results Posting Requirements ........ 60
10.4
Quality Management System............................................................................... 61
10.5
Data Management................................................................................................. 61
10.6
Publications ........................................................................................................... 61
10.7
11.0
LIST OF REFERENCES......................................................................................... 63
12.0
APPENDICES........................................................................................................... 65
Merck Code of Conduct for Clinical Trials........................................................ 65
12.1
List of Abbreviations ............................................................................................ 67
12.2
Standard Operating Procedures for Liver Enzyme Elevations........................ 69
12.3
Anthropometric Measurement ............................................................................ 71
12.4
Blood Pressure .................................................................................................... 71
12.4.1


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Body Weight ....................................................................................................... 71
12.4.2
Height.................................................................................................................. 71
12.4.3
Entry of Hypoglycemic Episode into eCRF........................................................ 73
12.5
Clinical Study Conduct System ........................................................................... 74
12.6
13.0
SIGNATURES........................................................................................................... 75
Sponsor's Representative ..................................................................................... 75
13.1
Investigator............................................................................................................ 75
13.2


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LIST OF TABLES
Table 1
Laboratory Inclusion Criteria (Visit 1) (Group B Only)................................................... 18
Table 2
Laboratory Inclusion Criteria (Visit 3) (Group A Only)................................................... 19
Table 3
Laboratory Exclusion Criteria (Visit 1) ............................................................................ 21
Table 4
Laboratory Exclusion Criteria (Visit 3) ............................................................................ 23
Table 5
Trial Treatment ................................................................................................................. 24
Table 6
Rescue Criteria.................................................................................................................. 27
Table 7
Discontinuation Criteria of eGFR..................................................................................... 30
Table 8
Laboratory Tests (Efficacy).............................................................................................. 40
Table 9
Laboratory Tests (Safety) ................................................................................................. 41
Table 10
Evaluating Adverse Events............................................................................................... 50
Table 11
Product Descriptions......................................................................................................... 56


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LIST OF FIGURES
          
Figure 1
Trial design.......................................................................................................................12


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1.0 TRIAL SUMMARY
Abbreviated Title
MK-0431J Phase III Ipragliflozin Add-on LTSS in T2DM Patients on 
Sitagliptin
Sponsor Product Identifiers
MK-0431J
sitagliptin phosphate hydrate and ipragliflozin L-proline
Trial Phase
III
Clinical Indication
Type 2 Diabetes Mellitus
Trial Type
Interventional
Type of control
No treatment control
Route of administration
Oral
Trial Blinding
Unblinded Open-label
Treatment Groups
Ipragliflozin 50 mg once-daily (q.d.)
Number of trial subjects
Approximately 75 subjects will be enrolled.
Estimated duration of trial
The Sponsor estimates that the trial will require approximately 18
months from the time the first subject signs the informed consent until 
the last subject’s last study-related phone call or visit.  Study Duration: 
From September 2015 to April 2017 (Subject enrollment will be 
discontinued once the target number of subjects has been achieved).
Duration of Participation
Each subject will participate in the trial for up to 64 weeks from the time 
the subject signs the Informed Consent Form (ICF) through the final 
visit.  After a screening period of up to 2 weeks followed by a pre-
treatment period of 0 or 10 weeks, each subject will receive the assigned 
treatment for approximately 52 weeks.  After the end of treatment each 
subject will be followed for 14 days.
A list of abbreviations used in this document can be found in Section 12.2.


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2.0 TRIAL DESIGN
Trial Design
2.1
This is a non-controlled, multicenter, open-label trial of addition of ipragliflozin in Japanese 
patients with type 2 diabetes mellitus (T2DM) who have inadequate glycemic control on 
sitagliptin monotherapy in addition to diet and exercise therapy, to be conducted in 
conformance with Good Clinical Practices.
This study consists of a screening period of up to 2 weeks, a pre-treatment period of 0 weeks
or 10 weeks, and a treatment period of 52 weeks.
For the duration of the pre-treatment 
period, subjects will be assigned to Group A (10 weeks) or Group B (0 weeks) based on their 
pre-treatment for T2DM (use or no use of other AHAs within 10 weeks of Visit 1).
Subjects will take one ipragliflozin 50 mg tablet daily (q.d.) orally for 52 weeks in an open-
label manner. Treatment with a stable dose of sitagliptin will be maintained throughout the 
clinical study.  Rescue therapy (administration of glimepiride) will be initiated if the subject 
meets the hyperglycemia rescue criteria after Visit 4/Week 0.
Approximately 75 subjects will be enrolled.  The target population includes Japanese patients 
≥20 years of age with T2DM who have inadequate glycemic control on sitagliptin 50 mg q.d. 
monotherapy in addition to diet and exercise therapy, with HbA1c ≥7.0% and ≤10.0% for all 
subjects regardless of Groups A or B.
Specific procedures to be performed during the trial, as well as their prescribed times and 
associated visit windows, are outlined in the Trial Flow Chart - Section 6.0. Details of each 
procedure are provided in Section 7.0 – Trial Procedures.


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Trial Diagram
2.2
The trial design is depicted in Figure 1.
SCR = Screening, TC = Telephone contact
*1
A subject in Group B proceeds to Visit 4 after Visit 1, skipping Visit 2 and Visit 3.
*2
Visit 4/Week 0 is baseline.
Figure 1
Trial design
Ipragliflozin 50 mg q.d.
Sitagliptin 50 mg q.d. with a stable dose and diet and exercise therapy
SCR period
(within 2 weeks)
Pre-treatment period
(0 or 10 weeks)
Treatment period
(52 weeks)
Japanese patients with T2DM of ≥20 years
Group A (pre-treatment period is 10 weeks): HbA1c ≥6.5% and ≤9.0%
•
Is currently treated with diet and exercise therapy, AND
•
Has been on a stable dose of sitagliptin 50 mg q.d. for 4 weeks or longer, AND
•
Has been on any additional AHAs in the past 10 weeks
Group B (pre-treatment period is 0 weeks: HbA1c ≥7.0% and ≤10.0% AND FPG ≤230 mg/dL
•
Is currently treated with diet and exercise therapy≥53 days (8 weeks – 3 days), AND
•
Has been on a stable dose of sitagliptin 50 mg q.d. ≥81 days (12 weeks – 3 days), AND
•
Has not been on any additional AHAs in the past 67 days (10 weeks – 3 days)
All subjects (Groups A and B) must meet the following criteria:
•
Diet and exercise therapy≥53 days (8 weeks – 3 days)
•
AHAs except for sitagliptin washout ≥67 days (10 weeks – 
3 days)
•
Administration of a stable dose of sitagliptin 50 mg q.d. 
≥81 days (12 weeks – 3 days)
Group A (10 weeks)
Need wash-off of prior AHA other than sitagliptin
Group B (0 weeks)
Not need wash-off of AHA
Week 36
Visit 13
every 4 weeks
every 8 weeks
Group A subjects must meet the following criteria: 
•
Diet and exercise therapy≥39 days (6 weeks – 3 days)
•
AHAs except for sitagliptin washout ≥53 days (8 weeks – 3 days)
•
Administration of a stable dose of sitagliptin 50 mg q.d. ≥67 days (10 weeks – 3 days)
•
HbA1c ≥7.0% and<10.0%
•
Fasting plasma glucose (FPG) ≤230 mg/dL
Week 52
Visit 15
SCR
Visit 1
Week -10 *1
Visit 2 *1
Week -6 *1
TC *1
Week -2 *1
Visit 3 *1 Week 0 *2
Visit 4 *2


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3.0 OBJECTIVE(S) & HYPOTHESIS(ES)
Primary Objective(s) & Hypothesis(es)
3.1
In Japanese patients with T2DM who have inadequate glycemic control on sitagliptin 50 mg 
monotherapy in addition to diet and exercise therapy:
Objective: To assess safety and tolerability of the addition of treatment with ipragliflozin 
50 mg q.d. over 52 weeks.
Secondary Objective(s) & Hypothesis(es)
3.2
In Japanese patients with T2DM who have inadequate glycemic control on sitagliptin 50 mg 
monotherapy in addition to diet and exercise therapy:
Objective: To describe the effect of the addition of ipragliflozin 50 mg q.d. on the change 
from baseline (Week 0) in HbA1c over 52 weeks.
Tertiary Objectives
3.3
In Japanese patients with T2DM who have inadequate glycemic control on sitagliptin 50 mg 
monotherapy in addition to diet and exercise therapy:
Objectives: To describe the effect of the addition of treatment with ipragliflozin 50 mg q.d. 
on the following parameters over 52 weeks.

Change from baseline (Week 0) in fasting plasma glucose (FPG)

Change from baseline (Week 0) in body weight

Percentage of subjects with HbA1c <7.0%
4.0 BACKGROUND & RATIONALE
Background
4.1
Refer to the Investigator’s Brochure (IB)/approved labeling of sitagliptin and ipragliflozin for
detailed background information on MK-0431J.
Pharmaceutical and Therapeutic Background
4.1.1
Diabetes mellitus (DM) is a metabolic disorder characterized by chronic hyperglycemia due
to insufficient insulin action [1] [2]. DM is classified into two types on the basis of its
etiology: Type 1 DM (due to an autoimmune mechanism, idiopathic) and Type 2 DM
(T2DM) (due to insulin resistance increased and an insulin secretory defect). T2DM, which 
accounts for more than 95% of DM [2], is associated with environmental factors, aging and 
several genetic factors [1]. 
Chronic hyperglycemia contributes to the development of 


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diabetic complications such as retinopathy, nephropathy, neuropathy and atherosclerosis, and 
significantly poor quality of life (QOL) of patients with DM [1].
In Japan, the improvement of lifestyle by diet, exercise, and patient education is the 
foundation of treatment for T2DM. If the target value of glycemic control is not achieved 
with diet and exercise for 2 or 3 months, medication treatment is initiated according to 
clinical condition of individual patient [1].  For the selection of medication treatment, age, 
degree of obesity, intensity of chronic complication, renal and hepatic function, and capacity 
of insulin secretion and the intensity of insulin resistance, in addition to severity of metabolic 
disorder, should be considered, and an oral antihyperglycemic agent (AHA) such as 
sulfonylureas, glinides, biguanides, thiazolidinediones, α-glucosidase inhibitors, dipeptidyl 
peptidase 4 (DPP-4) inhibitors, and sodium glucose cotransporter 2 (SGLT2) inhibitors or 
injectable AHAs, such as insulin or glucagon-like peptide 1 (GLP-1) receptor agonists can be 
selected [1].  When glycemic control is inadequately maintained with monotherapy and 
modification of lifestyle, up-titration of the oral AHA, co-administration of oral AHAs with 
different mechanisms of action, switching to GLP-1 receptor agonists or insulin, or co-
administration of oral AHAs with a GLP-1 receptor agonist or insulin can be considered [1].
It is estimated that 382 million people worldwide (8.3% of adults) have DM in 2013, and the 
number of people with the disease is predicted to rise to 592 million by 2035 (55% increase 
compared to 2013) [3]. The number of adult people with DM is also rising in Japan. 
According to the National Health and Nutrition Examination Survey by the Ministry of 
Health, Labour and Welfare (MHLW), the number of people ≥20 years old in Japan who are 
strongly suspected of DM is increasing annually, counting approximately 7.4 million in 
2002, 8.9 million in 2007, and 9.5 million in 2012 [4].  Of those, approximately more than 
65% of the people are expected to take some kind of AHAs [4]; however, there are many 
patients with T2DM who have inadequate glycemic control.  The survey in the fiscal of 2013 
of Japan Diabetes Clinical Data Management Study Group indicates that 40% or more of 
patients with T2DM do not achieve the HbA1c goal <7.0% for prevention of complication.  
Non-adherence to AHAs is a significant barrier to achieving glycemic treatment goals of 
patients with T2DM [5]. In the treatment of T2DM, common patient-reported reasons for 
poor medication adherence are side effects associated with oral AHA therapies that include 
hypoglycemia, weight gain, and gastrointestinal intolerance [6] [7] [8]. Poor medication 
adherence to oral AHAs is also directly related to dosing burden (polytherapy) and dosing 
frequency [9] [10] [11] [12] [13]. Studies of ex-Japan patients have demonstrated that 
medication adherence is markedly decreased (ranging from 15% to 54%) when patients were 
prescribed multiple drugs to treat DM [14].  Among the patient with T2DM using 
combination therapy, it is reported that adherence tends to be greater with fixed-dose 
combinations (FDCs) thank with separate pills and greater after switching from monotherapy 
to an FDC rather than to separate-pill combinations [14] [15] [16] [17].
Based on the above, it is considered that a FDC product with low number of tablets and 
containing the products which have low risk of hypoglycemia, weight gain, and
gastrointestinal intolerance, for which some other oral AHAs are known, is an important 
option for the patients who have inadequate glycemic control on AHA monotherapy and 
have benefit of improvement of the status of medication adherence.


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MK-0431J is a FDC drug containing two active ingredients; a DPP-4 selective inhibitor, 
sitagliptin phosphate, and a SGLT2 selective inhibitor, ipragliflozin L-proline.
Sitagliptin slows the degradation of the incretin peptides, such as glucagon-like peptide 1 
(GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), by inhibiting DPP-4.  The 
resulting increase in the active forms of these incretin hormones leads to glucose-dependent 
increases in insulin levels and reductions in glucagon levels, which together improve 
glycemic control in patients with T2DM.  Previous clinical studies show that sitagliptin has 
significant lowering effect on HbA1c and FPG, as well as on postmeal hyperglycemia.  In the 
safety side, sitagliptin has a low risk of gastrointestinal side effects for which some other oral 
AHAs are known, as well as weight gain.  Hypoglycemia did not increase with sitagliptin
monotherapy, or co-administration therapy with an additional AHA which has a low risk for 
hypoglycemia.
Ipragliflozin provides glucose-lowering effect without depending on insulin action by 
inhibiting SGLT2 in the renal proximal tubule and suppressing the reabsorption of glucose,
resulting in elimination of excessive blood glucose from the body.  In the conducted clinical 
studies, ipragliflozin improved overall glycemic control (lowering HbA1c) and also lowered 
fasting and postmeal hyperglycemia.  Ipragliflozin reduced body weight significantly 
compared to placebo in the placebo-controlled studies, an effect which is in contrast to some 
other AHAs that can lead to weight gain.  In the safety side, there was a low risk for 
hypoglycemia in ipragliflozin monotherapy or in the combination with ipragliflozin and 
another AHA.
As indicated above, ipragliflozin and sitagliptin are AHAs with different mechanisms of 
actions.  From this point, since it is considered that the combination of ipragliflozin and 
sitagliptin can provide additive glucose-lowering effect with low risk of hypoglycemia, 
weight gain, and so on, for which some other oral AHAs are known, the Sponsor believes 
that combination therapy with ipragliflozin and sitagliptin will come to be one of the useful 
treatments for patients with T2DM.  In addition, reducing the number of tablets will be 
helpful for the patients to improve and maintain their drug compliance.  Because of these 
rationales, the Sponsor plans to develop of FDC containing ipragliflozin and sitagliptin, MK-
0431J.
Rationale
4.2
Rationale for the Trial and Selected Subject Population
4.2.1
The one strength of MK-0431J sitagliptin 50 mg/ipragliflozin 50 mg will be developed and 
the target population of MK-0431J will be patients with T2DM who have inadequate 
glycemic control on ipragliflozin monotherapy, patients with T2DM who have inadequate 
glycemic control on sitagliptin monotherapy, or patients with T2DM co-administered of 
sitagliptin and ipragliflozin.  Therefore, the target population of this trial, i.e., target 
treatment population, is patients with T2DM who have inadequate glycemic control on 
sitagliptin 50 mg monotherapy to study the efficacy and the safety of addition of ipragliflozin 


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50 mg in patients with T2DM who have inadequate glycemic control on sitagliptin 50 mg 
monotherapy.
Rationale for Dose Selection/Regimen
4.2.2
The regimen of MK-0431J will be once-daily to conform to the regimens of ipragliflozin and 
sitagliptin.  In addition, considering the standard daily dose of both products and the drug 
utilization situations in the clinical practice (50 mg/day is most common for each product), 
the combination ratio of MK-0431J was sitagliptin 50 mg/ipragliflozin 50 mg.
Note that in this study, sitagliptin 50 mg and ipragliflozin 50 mg will be co-administered as 
separate tablets, not as a fixed-dose combination tablet.
Rationale for Endpoints
4.2.3
Safety Endpoints
4.2.3.1
The following endpoints will be collected to assess the safety when co-administered with 
sitagliptin and ipragliflozin.
•
Adverse events (including hypoglycaemia)
•
Vital signs (body weight, blood pressure, and pulse rate)
•
Laboratory tests
•
ECG
Efficacy Endpoints
4.2.3.2
HbA1c is recommended as a parameter of glycemic control in “Guideline on Clinical 
Evaluation Methods for Oral Hypoglycaemic Agents”, PFSB/ELD Notification No. 0709-1, 
9th July 2010.
Based on the above, the key efficacy endpoint is change from baseline in HbA1c.
Rationale for duration of the treatment period
4.2.4
By reference to ‘Considering the number of subjects required for evaluating safety according 
to ICH E1 Guideline, it is set to be one year or longer.’ for a long-term study with safety 
assessment as a primary endpoint in “Guideline on Clinical Evaluation Methods for Oral 
Hypoglycaemic Agents”, PFSB/ELD Notification No. 0709-1, 9th July 2010, the duration of 
the treatment period of this trial is 52 weeks.


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Benefit/Risk
4.3
Subjects in clinical trials generally cannot expect to receive direct benefit from treatment 
during participation, as clinical trials are designed to provide information about the safety 
and effectiveness of an investigational medicine.
Additional details regarding specific benefits and risks for subjects participating in this 
clinical trial may be found in the accompanying Investigators Brochure (IB) and Informed 
Consent documents.
5.0 METHODOLOGY
Entry Criteria
5.1
Diagnosis/Condition for Entry into the Trial
5.1.1
Male/Female subjects with T2DM at least 20 years of age who have inadequate glycemic 
control on sitagliptin 50 mg monotherapy in addition to diet and exercise therapy, will be 
enrolled in this trial.
Subject Inclusion Criteria
5.1.2
In order to be eligible for participation in this trial, the subject must:
At Visit 1/Screening
1)
have T2DM
2)
be ≥20 years of age on the day of signing the informed consent form
3)
meet any one of following criteria at Visit 1:
Group A (pre-treatment period is 10 weeks): HbA1c ≥6.5% and ≤9.0%
•
is currently treated with diet and exercise therapy, AND
•
has been on a stable dose of sitagliptin 50 mg q.d. for 4 weeks or longer, AND
•
has been on any additional antihyperglycemic agent (AHA) monotherapy 
(single active ingredient) or low-dose dual combination therapy (i.e., ≤50% 
maximum labeled dose of each active ingredient) in the past 10 weeks
Group B (pre-treatment period is 0 weeks): the following laboratory criteria
•
is currently treated with diet and exercise therapy ≥53 days (8 weeks – 3 days), 
AND


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•
has been on a stable dose of sitagliptin 50 mg q.d. ≥81 days (12 weeks – 3 
days), AND
•
has not been on any additional AHAs in the past 67 days (10 weeks – 3 days)
Table 1
Laboratory Inclusion Criteria (Visit 1) (Group B Only)
Parameter
Study Limit for Inclusion
HbA1c
≥7.0% and ≤10.0%
FPG 1
≤230 mg/dL
1
FPG may be re-tested once (within approximately 3 days after receiving the report) 
upon the investigators discretion if he/she believes that the value does not reflect the 
subject’s recent glycemic control.
4)
meet one of the following criteria:
(1) is a male
(2) is a female not of reproductive potential defined as one who has either
a)
reached natural menopause (defined as ≥12 months of spontaneous 
amenorrhea in women 45 years of age), or
b)
had bilateral oophorectomy and/or hysterectomy or had bilateral tubal 
ligation at least 8 weeks prior to Visit 1.
(3) is a female of reproductive potential and: 
a)
agrees to remain abstinent from heterosexual activity, or
b)
agrees to use (or have their partner use) acceptable contraception to prevent 
pregnancy within the projected duration of the study and for 14 days after the 
last dose of study medication.  Acceptable methods of contraception include: 
•
Hormonal contraception
•
IUD
•
Diaphragm with spermicide
•
Condom for male partner
•
Vasectomy for male partner
5)
understand the study procedures, alternative treatments available, and risks involved 
with the study, and voluntarily agrees to participate by giving written informed 
consent.


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At Visit 3/Week -2 (Group A Only)
6) be treated with diet and exercise therapy ≥39 days (6 weeks - 3 days)
Note: Compliance with diet and exercise therapy will be assessed comprehensively 
throughout the above period.  In the case of exercise therapy, this condition does 
not necessarily need to be met if it is judged to be inappropriate for a subject 
because of complication[s].
7) not be on 
AHAs except for sitagliptin ≥53 days (8 weeks - 3 days)
8) be on a stable dose of sitagliptin 50mg q.d. ≥67 days (10 weeks - 3 days)
9) meet all following glycemic criteria at Visit 3
Table 2
Laboratory Inclusion Criteria (Visit 3) (Group A
 Only)
Parameter
Study Limit for Inclusion
HbA1c
≥7.0% and ≤10.0%
FPG 1
≤230mg/dL
1
FPG may be re-tested once (within approximately 3 days after receiving the report) 
upon the investigators discretion if he/she believes that the value does not reflect the 
subject’s recent glycemic control.
At Visit 4/Week 0
10)be treated with diet and exercise therapy ≥53 days (8 weeks - 3 days)
Note: Compliance with diet and exercise therapy will be assessed comprehensively 
throughout the above period.  In the case of exercise therapy, this condition does 
not necessarily need to be met if it is judged to be inappropriate for a subject 
because of complication[s].
11)not be on AHAs except for sitagliptin ≥67 days (10 weeks - 3 days)
12)be on a stable dose of sitagliptin 50mg q.d. ≥81 days (12 weeks - 3 days)
Subject Exclusion Criteria
5.1.3
The subject must be excluded from participating in the trial if the subject:
Note: Subjects with laboratory screening values meeting protocol exclusion criteria may, 
at the discretion of the investigator
, have one repeat determination performed by the 
central laboratory. If the repeat value does not meet the criterion, the subject may 
continue in the screening process. Only laboratory tests meeting exclusion criteria are to 
be repeated (not the entire panel).  Note that repeat determination can be performed only 
once for each laboratory test during the Screening and Pre-treatment Period.


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At Visit 1/Screening
Criteria related to Diabetes
1) has type 1 diabetes mellitus or has a history of diabetic ketoacidosis.
2) has ahistory of being administered any of the following AHAsincluding FDC 
containing the following ingredients:
• Insulin: within 12 weeks prior to Visit 1
• Thiazolidinediones(TZD):within 12 weeks prior to Visit 1
• SGLT2 inhibitors: any time
Diabetic complications
3) has unstable diabetic retinopathy
Note:Unstable diabetic retinopathy means that a subjecthas received therapy
*for 
diabetic retinopathy within3 monthsprior toVisit 1, or requires therapy
*for diabetic 
retinopathy during the studyperiod.
*
Laser therapy, vitreous surgery, steroidinjection, or vascular endothelial 
growth factor (VEGF) therapy, etc.
Concomitant Disease of Organs and Systems
4) Group Aonly:has poorly controlled hypertension defined as systolic blood pressure 
of ≥160mm Hg or diastolic blood pressure of ≥100mmHg and blood pressure is 
unlikely to be within these limits by V
isit 3/Week -2 with an adjustment in 
antihypertensive medication.
Note:Investigators are encouraged to maximize blood pressure control.  Subject 
may have blood pressure medications adjusted at least 4 weeks and be enrolled if 
repeat blood pressure measurement no longer meetsexclusion criterion.
Group BOnly:has poorly controlled hypertension defined as systolic blood pressure 
of ≥160mm Hg or diastolic blood pressure of ≥100mmHg.
Note:If subject meets this exclusion criterion, he/sheis excluded. After blood 
pressure medications adjusted at least 4 weeks, re-screening is acceptable.
5) has any of the following disorders within the past 3 monthsprior to Visit 1:
• Acute coronary syndrome (e.g., MI or unstable angina)
• Coronary artery intervention (e.g., CABG,PTCA, or similar procedure)
• Stroke or transient ischemic neurological disorder


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Hepatobiliary disorders
6)
has hepatic cirrhosis, chronic active hepatitis, or symptomatic gallbladder disorder.
Renal or urological disorders
7)
has a history of medically important renal disorders (such as renovascular occlusion
disease, nephrectomy, or renal transplant).
8)
currently has a symptom of dysuria, anuria, oliguria, or urinary retention.
9)
currently has a urinary tract infection or genital infection with subjective symptom.
10) has a history of recurrent urinary tract infection such as occurred 3 times or more 
within 6 months of Visit 1.
Laboratory Abnormalities
11) has any exclusionary laboratory values as listed in Table 3 below at Visit 1.
Table 3
Laboratory Exclusion Criteria (Visit 1)
Parameter
Population
Study Limit for Exclusion
Alanine aminotransferase (ALT)
>2 times ULN
Aspartate aminotransferase (AST)
>2 times ULN
C-peptide
<0.6 ng/mL
Estimated glomerular filtration rate (eGFR) 1
<60 mL/min/1.73 m2
Hemoglobin
Male
Female
<11 g/dL
<10 g/dL
Thyroid-stimulating hormone (TSH)
Outside central laboratory normal 
range
1
eGFR (mL/min/1.73 m2) = 194 x serum Cr -1.094 x age (years) -0.287 (x 0.739 for female).
Medications
12) requires treatment with a prohibited medication (See Section 5.5.1).
13) has received another investigational compound or device in the past 3 months at Visit 
1 or is currently receiving treatment with another investigational compound or device.
Other Conditions
14) meets one or more following criteria related to malignancy.
•
has a history of malignancy ≤5 years prior to Visit 1. (Subject who has a 
history adequately treated basal cell or squamous cell skin cancer, or in situ 
cervical cancer may be enrolled.)


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• has evidence of residual or recurrent disease.
• has any history of melanoma, leukemia, lymphoma, or renal cell carcinoma.
15)has a clinically important hematological disorder (such as aplastic anemia, 
myeloproliferative syndrome, myelodysplastic syndrome, or thrombocytopenia).
16)has a history of severe drug allergy (e.g., anaphylactoid reaction).
Other Criteria
17)is currentlyhospitalized or has planned hospitalization during the study period.
18) meets any contraindication or warning listed on package inserts of sitagliptin and 
ipragliflozinand which are not contained in the exclusion criteria of this study 
protocol.
19)hasa body mass index (BMI) <20.0kg/m2and >45.0kg/m2.
20)has a history of alcohol abuse in the past 2 yearsat Visit 1, or consumes >50g/day of 
alcohol on average (e.g., at least three 350mL cans of beer per day).
21)has undergone surgery in the past 8 weeksat Visit 1, or has major surgery planned 
during the study
.
Note:Subjects with a history of minor surgery (e.g., using local anesthesia) who 
are recovered may be eligible to participate in the study.
22)is pregnant or breast-feeding, or is expecting to conceive during the study, including 
14days following the last dose of study medication.
23)For women of childbearing potential:hasa positive urine pregnancy test.
24)Is or has an immediate family member (e.g., spouse, parent/legal guardian, sibling or child) who is 
investigational site or sponsor staff directly involved with this trial.
25)isdisqualified from the study by the primary investigator or sub-investigator for any 
reasons other than those given above.
At Visit 2/Week -10 (Group Aonly)
Other Criteria
26)isdisqualified from the study by the primary investigator or sub-investigator for any 
reasons other than those given above.


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At Visit 3/Week -2 (Group A only)
Concomitant Disease of Organs and Systems
27) has poorly controlled hypertension defined as systolic blood pressure of ≥160 mm Hg 
or diastolic blood pressure of ≥100 mm Hg.
Renal or urological disorders
28) has or had urinary tract infection or genital infection with subjective symptom from 
Visit 1/Screening.
Laboratory Abnormalities
29) has any exclusionary laboratory values as listed in Table 4 below at Visit 3.
Table 4
Laboratory Exclusion Criteria (Visit 3)
Parameter
Population
Study Limit for Exclusion
Alanine aminotransferase (ALT)
>2 times ULN
Aspartate aminotransferase (AST)
>2 times ULN
Estimated glomerular filtration rate (eGFR) 1
<60 mL/min/1.73 m2
Hemoglobin
Male
Female
<11 g/dL
<10 g/dL
1
eGFR (mL/min/1.73 m2) = 194 x serum Cr -1.094 x age (years) -0.287 (x 0.739 for female).
Other Criteria
30) For women of childbearing potential: has a positive urine pregnancy test.
31) is disqualified from the study by the primary investigator or sub-investigator for any 
reasons other than those given above.
At Visit 4/Week 0
Renal or urological disorders
32) has or had urinary tract infection or genital infection with subjective symptom from 
Visit 1/Screening.
Other Criteria
33) For women of childbearing potential: has a positive urine pregnancy test.
34) is disqualified from the study by the primary investigator or sub-investigator for any 
reasons other than those given above.


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Trial Treatment(s)
5.2
The treatments to be used in this trial are outlined below in Table 5.
Table 5
Trial Treatment
Drug
Dose/Potency
Dose 
Frequency
Route of 
Administration
Regimen/Treatment 
Period
Use
Screening and pre-treatment periods
sitagliptin
50 mg tablet
QD
Oral
Up to 12 weeks
Base therapy
Treatment period
sitagliptin
50 mg tablet
QD
Oral
52 weeks
Base therapy
ipragliflozin
50 mg tablet
QD
Oral
52 weeks
Experimental
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of trial 
treatments in accordance with the protocol and any applicable laws and regulations.
Dose Selection
5.2.1
Dose Selection (Preparation)
5.2.1.1
The rationale for selection of doses to be used in this trial is provided in Section 4.0 –
Background & Rationale.  There are no specific calculations or evaluations required to be 
performed in order to administer the proper dose to each subject.
Timing of Dose Administration
5.2.2
From screening period to pre-treatment period (From the day after Visit 
5.2.2.1
1/Screening to the day of Visit 4/Week 0)
From the day after Visit 1, each subject will take one tablet of sitagliptin 50 mg for this study
once daily orally in the morning (it may be taken with or without regard to meals) for up to 
12 weeks in an open-label manner.
Treatment period (From the day after Visit 4/Week 0 to the day before Visit 
5.2.2.2
15/Week 52 or discontinuation visit)
From the day after Visit 4, each subject will take one tablet of ipragliflozin 50 mg for the 
treatment period once daily orally in the morning (it may be taken with or without regard to 
meals) for 52 weeks in an open-label manner at the same time as taking one tablet of 
sitagliptin 50 mg for this study.


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Handling of Missed Doses
5.2.2.3
If the subject missed a dose(s) in the morning, the missed dose(s) of study medication may be 
taken on that day as soon as he/she remembers.  Two or more tablets of the same medication 
must not be taken on the same day, even if the subject failed to take drug(s) the day (or more 
days) before.
Timing of Dosing of Study Drug on Days of Study Visits
5.2.2.4
After Visit 1/Screening, on the day of study visit, the subject should visit the study site before 
taking study medication(s) and the study medications (sitagliptin for the study and 
ipragliflozin for the study) prescribed at the previous visit should be taken as a witnessed 
dose after completion of all study visit procedures.
The study medications will not be administered at Visit 15/Week52 or discontinuation visit.
Trial Blinding/Masking
5.2.3
This is an open-label trial; therefore, the Sponsor, investigator and subject will know the 
treatments administered.
Randomization or Treatment Allocation
5.3
Subjects participating in this trial will be allocated by non-random assignment.
Stratification
5.4
No stratification based on age, sex or other characteristics will be used in this trial.
Concomitant Medications/Vaccinations (Allowed & Prohibited)
5.5
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial.  If there is a clinical indication for any medication or vaccination 
specifically prohibited during the trial, discontinuation from trial therapy or vaccination may 
be required.  The investigator should discuss any questions regarding this with the Sponsor 
Clinical Director.  The final decision on any supportive therapy or vaccination rests with the 
investigator and/or the subject's primary physician.  However, the decision to continue the 
subject on trial therapy or vaccination schedule requires the mutual agreement of the 
investigator, the Sponsor and the subject.
Prohibited medications
5.5.1
From the day after Visit 1
•
For Group A: The following antihyperglycemic agents except sitagliptin for the study
•
Insulin


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• Thiazolidinediones (TZD) (pioglitazone)
• SGLT2 inhibitors
• DPP-4 inhibitors
• Fix dose combination products containing the above active ingredient(s)
For Group B: All antihyperglycemic agents except sitagliptin for the study
• Systemic corticosteroids ≥14 consecutive days or repeated courses
• Other investigational medications
After Visit 2
• All antihyperglycemic agents except sitagliptin for the study, ipragliflozin for the 
study and rescue medication.
Example:
• Sulfonylureas (SUs) (sulfonylureas, sulfonamides)
• Glinides (nateglinide , mitiglinide, repaglinide, etc)
• α-glucosidase inhibitors (α-GIs)
• Biguanides (BGs)
• GLP-1 receptor agonists
• Fix dose combination products containing the above active ingredient(s)
Within 10 hours of the visit
• Intravenous fluids (other than those having a volume <50mL without any glucose 
content)
• Glucagon
Limited Concomitant Medications
5.5.2
Medications for complication, which are used prior to Visit 1 and do not meet “Prohibited 
concomitant medications” in the above section, should be used throughout the study and any 
changes to the current regimen (e.g., the dosage or administration schedule) are prohibited 
throughout the study.  However the regimen change of the concomitant medications is 
allowed, only in the case that the primary investigator or sub-investigator judges that it is 
necessary to change the regimen considering the individual subject
's condition and safety.


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Note:(For Group A) Initiation or adjustment of dose or regimen of antihypertensive agent 
(s) is allowed by investigator’s judgment to make the BP of subject stable by Visit 3/Week -
2, if the subject has inadequately controlled hypertensionat Visit 1.  The procedures from
Visit 3/Week -2 should be followed to the above.
Rescue Medications & Supportive Care
5.6
Timing of Dose Administration
5.6.1
The subject who meets the following rescue criteria in Table 6should initiate rescuetherapy 
with open-label glimepiride.  The investigator is responsible for determining the starting dose 
of rescue medication based on the condition of each individualsubject.
Table 6
Rescue Criteria
Timing
Criteria
Administration
Timing
After Visit 4/Week 0
FPG (as reported by the central lab) is
repeatedly* confirmed >240mg/dL twotimes
At the nextscheduled 
orunscheduledVisit 
(= Rescue Visit)
After Visit 10/Week 24
FPG (as reported by the central lab) is
repeatedly* confirmed >200mg/dL twotimes
* Repeatedly at the scheduled visit (or at unscheduled visit as needed).  After initiation of rescue 
therapy, rescue medication can be adjustedbyjudgment of the investigator even if the FPG does 
not show "repeatedly" the abovecriteria.
Once the rescue therapy is initiated, the investigator is responsible for the management of
adjustment (up-titration, down-titrationor discontinuation)of rescue medication(s) based on 
the condition of each individualsubject. Reassessment of FPG and adjustment of rescue 
medication should continue at the scheduled visit (or at unscheduled visit as needed)until the 
subject no longer meets rescue criteria. The maximum dosage of rescue medication should 
be the maximal tolerated dose for individual subject judged bythe investigator or the
maximal approved dose based on its package insert.
Subjects will continue on study medicationafter initiation of rescue therapyuntilcompletion 
unless they meet discontinuation criteria(Section 5.8).
Handling of Missed Doses
5.6.2
Themissed dose should be taken in accordance with the package insert and/or available
subject
's leaflet for glimepiride.
Timing of Dosing of Rescue Medicationon Days of Study Visits
5.6.3
On the day of study visit, subjects should not take their rescue medication before visits. 
Subjects should taketheir rescue medication aftercompletion of all study proceduresandin 
accordance with the package insert.


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Diet/Activity/Other Considerations
5.7
Diet therapy
5.7.1
The subject will be instructed to continue the diet therapy which was undergone at Visit 1.  
Diet therapy is mandatory and should remain stable throughout the study.
Exercise therapy
5.7.2
The subject will be asked to continue the exercise therapy which was undergone at Visit 1.  
Exercise therapy is mandatory and should remain stable throughout the study, unless it is
judged by the investigator to be inappropriate for a subject to observe this rule because of
concomitant diseases and adverse experience (e.g., arthritis in a lower limb).
Subject Withdrawal/Discontinuation Criteria
5.8
Subjects may withdraw consent at any time for any reason or be dropped from the trial at the 
discretion of the investigator should any untoward effect occur.  In addition, a subject may be 
withdrawn by the investigator or the Sponsor if enrollment into the trial is inappropriate, the 
trial plan is violated, or for administrative and/or other safety reasons.  Specific details 
regarding discontinuation or withdrawal procedures are provided in Section 7.1.4 – Other 
Procedures.
Discontinuation from treatment is “permanent”.  Once a subject is discontinued, he/she shall 
not be allowed to restart treatment.
A subject must be discontinued from the trial for any of the following reasons:
●
The subject withdraws consent.

Lack of efficacy
The effect of the study medication is not sufficient and study continuation is judged
inappropriate by the primary investigator or sub-investigator. If the following case
occurs, the primary investigator or sub-investigator should consider the discontinuation:
•
After Visit 4/Week 0 to Visit 10/Week 24, FPG >240 mg/dL (as reported by the 
central lab) and is confirmed again (by the central lab) ≥4 weeks after 
administration of rescue therapy at the maximal tolerated dose for the individual
subject or the maximal approved dose based on its package insert.
•
After Visit 10/Week 24, FPG >200 mg/dL (as reported by the central lab) and is 
confirmed again (by the central lab) ≥4 weeks after administration of rescue 
therapy at the maximal tolerated dose for the individual subject or the maximal 
approved dose based on its package insert.


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Note:The primary investigator or sub-investigator should instruct the subject to visit 
the study site as soon as possible to perform the repeat test once he/she meets the 
threshold ofFPG criteria.
Adverse event
In the case that the primary investigatoror sub-investigator assesses that administration 
of the study medication should bediscontinued due to the occurrence of adverse 
experiences. When subjects meet the following criteria, they shoulddiscontinuethe 
study, regardless of the investigator’s assessment.
• Hypoglycemia
Subject meets any one of the following criteria without a reasonable explanation
(such as increased physical activity or skipped meal)
• Repeated (2 or more episodes since the prior study visit) FPG (as reported by 
thecentral lab) or fingerstick glucose <50mg/dL with or without symptoms 
ofhypoglycemia
OR
• Repeated (2 or more episodes since the prior study visit) FPG (as reported by 
thecentral lab) or fingerstick glucose ≤70mg/dL with symptoms of 
hypoglycemia
• Increased ALT or AST
a) ALT or AST ≥3-fold above the ULN continuously.
Note:See Section 12.3, if the subject meets the above criterion.
b) Elevations in ALT or AST ≥3-times the upper limit of normal with concurrent 
total bilirubin ≥2-times the upper limit of normal and alkaline phosphatase 
<2-times the upper limit of normal.
Note:See "Event of Clinical Interest (ECI) Guidance for Potential DILI 
(Drug-Induced Liver Injury) in Clinical Trials guidance document"), if the 
subject meets the above criterion.
• Decreased renal function
If the repeat measurement performed as early as possible meets the criteria in Table 
7, the subject must discontinue the study.


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Table 7
Discontinuation Criteria of eGFR
Parameter
Study Limit for Discontinuation
eGFR 1
<50 mL/min/1.73 m2
1
eGFR (mL/min/1.73 m2) = 194 x serum Cr -1.094 x age (years) -0.287 (x 0.739 for female).
•
Pancreatitis
If a subject is suspected of having pancreatitis, study medication should be 
interrupted and if pancreatitis is confirmed, study medication should be 
discontinued.

Protocol Violation
It becomes inappropriate to continue study treatment as a result of a significant protocol 
deviation.

Non-compliance with study drug
There is an indication that a subject has not agreed with or followed the instructions 
related to the study medication.

Lost to follow-up
When a subject stops visiting a site after initiating study drug, he or she will be contacted 
via letter or telephone call to confirm the reason for missed visits, dosing of study drug, 
and the subsequent course as much as possible.

Subject moved
When the subject has either moved or relocated and is no longer able to participate in the 
study.

Pregnancy
A positive urine pregnancy test after initiating study medication for the treatment period
requires immediate interruption of study medication until serum β-hCG can be performed 
and found to be negative.  Subject will be able to restart the study medication intake if 
serum β-hCG test has found to be negative.  Subject must be permanently discontinued 
from study treatment if pregnancy is confirmed by a positive serum pregnancy test.  In 
addition, the investigator or study coordinator must notify the Sponsor.

Physician Decision
In addition, the primary investigator or sub-investigator judges that subject should 
discontinue for any other reason.


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Example: The subject required the prohibited medication specified in Section 5.5.1., 
the subject who is considered to be inappropriate for treatment with glimepiride 
although he/she meets the rescue criteria.
Subject Replacement Strategy
5.9
A subject whodiscontinues from the trial will not be replaced.
Beginning and End of the Trial
5.10
The overall trial begins when the first subject signs the informed consent form.  The overall 
trial ends when the last subject completes the last study-related phone-call or visit,
discontinues from the trial or is lost to follow-up (i.e. the subject is unable to be contacted by 
the investigator).
Clinical Criteria for Early Trial Termination
5.11
The clinical trial may be terminated early if the extent (incidence and/or severity) of 
emerging effects/clinical endpoints is such that the risk/benefit ratio to the trial population as 
a whole is unacceptable.  In addition, further recruitment in the trial or at (a) particular trial 
site(s) may be stopped due to insufficient compliance with the protocol, GCP and/or other 
applicable regulatory requirements, procedure-related problems or the number of 
discontinuations for administrative reasons is too high.


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6.0 TRIAL FLOW CHART
Screening 
Period
(≤2 weeks)
Pre-treatment Period 
(0 weeks or 10 weeks) 
1
Treatment Period (52 weeks)
Discontinuation Visit
Telephone contact
Week
-10 2
-6 2
-2 2
0
4
8
12
16
20
24
28
32
36
44
52
Rescue 
Visit
Visit
1
2 2
TC 2
3 2
4
5
6
7
8
9
10
11
12
13
14
15
Scheduling Window (days)
Pre-treatment Period
0
±7
±3
±3
Treatment Period
0
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
≤3 after last 
dose of 
study drug
≥14 after 
last dose of 
study drug
Administrative Procedures
Informed Consent
X 3
Inclusion/Exclusion Criteria
X
A
A
X
Medical History
X
Concomitant Medication Review
X
A
A
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Patient Registration
X
A
A
X
Subject Identification Card
X
Diet and Exercise Therapy Counseling
X
A
A
X
X
X
X
X
X
X
X
X
X
X
Patient's Log Dispensing
X 4
A
A
X
X
X
X
X
X
X
X
X
X
X
Collection and Review of Patient’s Log
A
A
A
X
X
X
X
X
X
X
X
X
X
X
X
X
Self-monitoring blood glucose (SMBG) 
instruction
A
B
Instructions on Hypoglycemic Symptoms, 
Management, and Recording of 
Hypoglycemic Assessment Log (HAL)
X
Assignment of Treatment Number
X
Sitagliptin for the study Dispensing
X
A
A
X
X
X
X
X
X
X
X
X
X
X
Ipragliflozin for the study Dispensing
X
X
X
X
X
X
X
X
X
X
X
Study Medications (sitagliptin and/or 
ipragliflozin) Compliance Monitoring
A
A
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Clinical Procedures/Assessments
Collection and Review of HAL
X
X
X
X
X
X
X
X
X
X
X
X
X
Diet and exercise therapy monitoring
X
A
A
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital Sign (body weight, blood pressure, 
and pulse rate)
X
A
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital Sign (height)
X
12-lead electrocardiogram (ECG) Locally
X
X
X
X
X
Assessment of need for rescue therapy
X
X
X
X
X
X
X
X
X
X
Adverse experience monitoring
A
A
A
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X


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Screening 
Period
(≤2 weeks)
Pre-treatment Period 
(0 weeks or 10 weeks) 
1
Treatment Period (52 weeks)
Discontinuation Visit
Telephone contact
Week
-10 2
-6 2
-2 2
0
4
8
12
16
20
24
28
32
36
44
52
Rescue 
Visit
Visit
1
2 2
TC 2
3 2
4
5
6
7
8
9
10
11
12
13
14
15
Scheduling Window (days)
Pre-treatment Period
0
±7
±3
±3
Treatment Period
0
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
≤3 after last 
dose of 
study drug
≥14 after 
last dose of 
study drug
Laboratory Procedures/Assessments
HbA1c
X
A
X
X
X
X
X
X
X
X
X
X
X
X
X
X 5
Glucose
X
A
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Insulin
X
X
X
X
X
Hematology
X
A
X
X
X
X
X
X
X
X
Chemistry
X
A
X
X
X
X
X
X
X
X
Endocrinological 6
X
Urinalysis
X
A
X
X
X
X
X
X
X
X
Urine Pregnancy Test 7
X
A
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X: Essential items, A: Only Group A, B: Only Group B, TC: Telephone Contact
1
For a subject who needs wash-off of AHA, the duration of the pre-treatment period is 10 weeks (Group A).  For a subject who does not need wash-off of AHA, the duration of the pre-treatment
period is 0 weeks (Group B).
2
For subjects in Group A.  A subject in Group B proceeds to Visit 4 after Visit 1, skipping Visit 2 and Visit 3.
3
Informed consent must be obtained before any study procedures of Visit 1.
4
Instructions on recording of patient’s log is provided.
5
HbA1c should not be drawn if Discontinuation Visit occurs within 4 weeks after Visit 4/Week 0.
6
C-peptide and thyroid-stimulating hormone (TSH)
7
Urinary hCG.  Only for females of childbearing potential.  Subjects with a positive urine pregnancy test at the site after taking study medication for the treatment priod will have a confirmatory 
serum β-hCG test at central laboratory as a pregnancy test.


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7.0 TRIAL PROCEDURES
Trial Procedures
7.1
The Trial Flow Chart - Section 6.0 summarizes the trial procedures to be performed at each 
visit.  Individual trial procedures are described in detail below.  It may be necessary to 
perform these procedures at unscheduled time points if deemed clinically necessary by the 
investigator.
Furthermore, additional evaluations/testing may be deemed necessary by the investigator and 
or the Sponsor for reasons related to subject safety. In some cases, such evaluation/testing 
may be potentially sensitive in nature (e.g., HIV, Hepatitis C, etc.), and thus local regulations 
may require that additional informed consent be obtained from the subject.  In these cases, 
such evaluations/testing will be performed in accordance with those regulations.
Administrative Procedures
7.1.1
Informed Consent
7.1.1.1
The investigator or qualified designee must obtain documented consent from each potential 
subject prior to participating in a clinical trial. If there are changes to the subject’s status 
during the trial (e.g., health or age of majority requirements), the investigator or qualified 
designee must ensure the appropriate consent is in place. 
7.1.1.1.1 General Informed Consent
Consent must be documented by the subject’s dated signature on a consent form along with 
the dated signature of the person conducting the consent discussion. 
A copy of the signed and dated consent form should be given to the subject before 
participation in the trial.
The initial informed consent form, any subsequent revised written informed consent form 
and any written information provided to the subject must receive the IRB/ERC’s 
approval/favorable opinion in advance of use.  The subject should be informed in a timely 
manner if new information becomes available that may be relevant to the subject’s 
willingness to continue participation in the trial.  The communication of this information will 
be provided and documented via a revised consent form or addendum to the original consent 
form that captures the subject’s dated signature.
Specifics about a trial and the trial population will be added to the consent form template at 
the protocol level.  
The informed consent will adhere to IRB/ERC requirements, applicable laws and regulations 
and Sponsor requirements.


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Inclusion/Exclusion Criteria
7.1.1.2
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee 
to ensure that the subject qualifies for the trial.
Subject Identification Card
7.1.1.3
All subjects will be given a Subject Identification Card identifying them as participants in a 
research trial.  The card will contain trial site contact information (including direct telephone 
numbers) to be utilized in the event of an emergency.  The investigator or qualified designee 
will provide the subject with a Subject Identification Card immediately after the subject 
provides written informed consent.
The subject identification card also contains contact information for the emergency 
unblinding call center so that a health care provider can obtain information about trial 
medication/vaccination in emergency situations where the investigator is not available.
Medical History
7.1.1.4
A medical history will be obtained by the investigator or qualified designee.
Prior and Concomitant Medications Review
7.1.1.5
7.1.1.5.1 Prior Medications
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record any prior medication taken by the subject 
below;
•
SGLT2 inhibitors: any time
•
Antihyperglycemic agents other than SGLT2 inhibitors: within 12 weeks prior to Visit 1.
•
Prior medications other than antihyperglycemic agents: within 4 weeks prior to Visit 1.
7.1.1.5.2 Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the subject 
during the trial.
Assignment of Screening Number
7.1.1.6
All consented subjects will be given a unique screening number that will be used to identify 
the subject for all procedures that occur prior to randomization or treatment allocation.  Each 
subject will be assigned only one screening number.  Screening numbers must not be re-used 
for different subjects.


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Any subject who is screened multiple times will retain the original screening number 
assigned at the initial screening visit.
Specific details on the screening visit requirements (screening/rescreening) are provided in 
Section 7.1.5.1.
Assignment of Treatment/Randomization Number
7.1.1.7
All eligible subjects will be allocated, by non-random assignment, and will receive a 
treatment/randomization number.  The treatment/randomization number identifies the subject 
for all procedures occurring after treatment allocation/randomization.   Once a 
treatment/randomization number is assigned to a subject, it can never be re-assigned to 
another subject.
A single subject cannot be assigned more than 1 treatment/randomization number.
Trial Compliance (Medication/Diet/Activity/Other)
7.1.1.8
The investigator or qualified designee will ask the subject about compliance with study 
medications based upon the number of tablets returned, information recorded in the patient's 
log, and patient's interview.  In the event that the number of tablets returned is inconsistent 
with the number of tablets reported by the subject, the subject's reporting will be adopted.
Interruptions from the protocol specified treatment plan for compliance <75% require 
consultation between the investigator and the Sponsor and written documentation of the 
collaborative decision on subject management.
Diet And Exercise Therapy Counseling
7.1.1.9
From Visit 1, the subject will be asked to continue the diet and exercise therapy which was 
undergone at Visit 1 with reference to “Treatment Guidance for Diabetes” (edited by Japan 
Diabetes Society).  Diet and exercise therapy is mandatory and should remain stable 
throughout the study. In the case of exercise therapy, this condition does not necessarily 
need to be met if it is judged to be inappropriate for a subject because of complication[s] and 
adverse event[s] (e.g., joint disease in a lower limb).
The concrete instruction may be changed as long as it can be thought that the change does 
not have impact on glycemic control based on the intake/consume calories instructed at Visit 
1, if the subject’s physical activity changed or he/she became unable to adhere to the exercise 
therapy instructed at Visit 1 due to an adverse event and so on.


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Example:
• The daily intake calorie was reduced since the subject’s physical activity was changed 
from heavy manual work to desk work due to job switch.
• The instruction was changed to the exercise of the upper body which consumes similar 
daily calorie to walking since a walking is difficult for the subject due to ankle sprain.
Patient Registration
7.1.1.10
The investigator or clinical research coordinatorwill register the subjects via the system of 
the patient registration center.
Instruction and Dispensing Recording of Patient’s Log
7.1.1.11
The subject will be instructed to record diet and exercise therapy compliance and study 
medication compliance in the patient’s logfrom the day after Visit 1.  From Visit 2 (Group 
A) or from Visit 4(Group B), the subject will be instructed to record SMBG data in the 
patient’s login addition to dietandexercise therapy compliance and study medication 
compliance.
The patient’s log will be dispensedat Visit 1.  The subject will be told to bring the subject-
completedpatient’slog to the study site at each visit.
Collection and Review of Patient’s Log
7.1.1.12
The patient’s log dispensedat the previousvisit will be collected, and the investigator should 
check the diet and exercise therapy compliance, study medication compliance, and SMBG 
value.  The investigator should make effort to prevent the reoccurrenceof non-compliance by 
an instruction to the subject, if the non-compliance withdiet and exercise therapyand/or 
taking study medication were found.  If SMBG value ≤70mg/dL is in patient’s log, the 
investigator should check that its information is also in the HAL.
Self-Monitoring Blood Glucose Procedures
7.1.1.13
Glucose meters will be supplied to all subjects at Visit 2 (Group A) or Visit 4(Group B)in
order to perform SMBG. The subjects will be instructed on the procedure to perform 
fingerstickglucose measurements. The subjectswill monitor their fingerstick glucose 
concentrations with afrequency determined appropriate by the investigator with a minimum 
of 2 fasting(without takingstudy medication) determinations per week(2 or more frequency 
may be set based upon his/her assessment of thesubject’s risk of increasing glucose 
concentrations).  The subject will also be instructed to perform SMBG without fail if any 
hypoglycemic symptom[s] occurs.
The subjects should be counseled to contact the study sitesince it is necessary that the 
investigator assesses an adverse eventand a need for rescue therapyand judges the 
continuation of the study for the subjects.


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• Fingerstick glucose ≤70mg/dLthroughout theduration of the entire study
• Fasting fingerstick glucose >230mg/dL before Visit 4/Week 0
• Fasting fingerstick glucose >240mg/dL after Visit 4/ Week 0through Visit 10/Week 
24
• Fasting fingerstick glucose >200mg/dLafter Visit 10/Week 24
Instructions on Hypoglycemic Symptoms, Management, and Recording of 
7.1.1.14
Hypoglycemic Assessment Log
The subject will be informed that there is a possibility of developing hypoglycemic 
symptoms (e.g., sweating, anxiety, palpitations, headache, blurred vision, and clouding of 
consciousness) after administration of the study medications.  If a symptom that may be 
considered hypoglycemiaoccursand/or fingerstick glucose≤70mg/dL with or without 
symptoms, the subject will be instructed to;
• Promptly take countermeasures, such as the ingestion of glucose (5-10 g) or glucose 
supplement
• If a symptom that may be considered hypoglycemiaoccurs:Immediately (before 
taking glucose or within 2-3 minutes after taking glucose)performa fingerstick 
glucose measurement
• Complete all symptoms which occurredin HAL
•
Contact the investigational siteand report (the subject’s condition and/or symptom at 
occurrence, with/without SMBG measurement and SMBG value, with/without taking 
glucose, a need for assistance, entry of HAL, etc.)
• Bring HAL completedby the subjects at the next visit.
Study Medication Dispensing
7.1.1.15
From Visit 1, the study medications with an arbitrarycomponent ID will be dispensedto the 
subjectat eachscheduled visit excepting the final visit, after all study procedures are 
completed.
Note:Diuretic action due to ipragliflozin may induce polyuriaand/or pollakiuria. In 
addition, the subjects should be instructedappropriate amount of waterintakeand be 
monitored since ipragliflozin may cause hypovolemia.  Ifanabnormal symptomsuch as 
dehydration or hypotension occurs, an appropriate action should be taken, e.g., 
interruptionof ipragliflozinor rehydration.  Especially, for patients who have a risk of 
hypovolemia, e.g., elderlypatients or patients who are taking diuretic agents, the 
following diseasesshould be paid to attention; dehydration, diabetic ketoacidosis, 


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hyperosmolar hyperglycemicsyndrome, and thrombosisor embolismincluding cerebral 
infarction.
Clinical Procedures/Assessments
7.1.2
In order to minimize variability, it is preferred that the same individual(s) perform the same
procedure(s)/evaluation(s) for all subjects at each trial site.
Collection and Review of HAL
7.1.2.1
Based on review of the subject-completed HAL at each clinic visit, the investigator must 
assess the fingerstick glucose measurementsand/orsymptoms that they believe are related to 
hypoglycemia.  Regardless of whether an episode is considered an adverse event, the HA 
eCRF must becompleted for the following:  For the entry of hypoglycemia episode into 
eCRF, see Section 12.5.
• all episodes determined by the investigator to be hypoglycemia (symptomatic or
asymptomatic)
• all glucose values ≤70mg/dL(with or without symptom)
Adverse Experience Monitoring
7.1.2.2
7.1.2.2.1 Hyperglycemia
A subject should be considered to have an adverse event of hyperglycemia if the subject has 
one or more symptoms (e.g., increased thirst, polyuria) typically associated with an increased 
glucose level.  At the discretion of the investigator, this may be captured as an adverse event
of “hyperglycemia.”  This diagnosis may be supported by, but does not require, results from 
a glucose meter or the trial central laboratory.  Further, at the discretion of the investigator, 
an elevated blood glucose value without associated symptoms that is considered to be an 
adverse event may be reported as an adverse event of “blood glucose increased.”
7.1.2.2.2 Hypoglycemia
If the fingerstick glucose measurements reportedby the subject and/orsymptoms that they 
believe are related to hypoglycemia areconsidered by theinvestigator to be an adverse
experience of hypoglycemia or asymptomatic hypoglycemia, the event should bereported on 
the adverse eventseCRF as an adverse experience of “hypoglycaemia” or“asymptomatic 
hypoglycaemia”, respectively.  For the entry of hypoglycemia episode into eCRF, see 
Section 12.5.
Vital Signs
7.1.2.3
Vital signs will be measured according to the procedures in Section 12.4.


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12-lead ECG
7.1.2.4
12-lead ECG will be measured in each site and the investigator will read it.
Laboratory Procedures/Assessments
7.1.3
Details regarding specific laboratory procedures/assessments to be performed in this trial are 
provided below.
Laboratory Efficacy Evaluations
7.1.3.1
Laboratory efficacy tests are specified in Table 8.  All items will be measured by the central 
laboratory.
Table 8
Laboratory Tests (Efficacy)
Chemistry
Other
Glucose
Insulin
HbA1c 
At fasting
Laboratory fating tests will be performed after at least a 10-hour fast.
Laboratory Safety Evaluations
7.1.3.2
Laboratory safety tests are specified in Table 9.


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Table 9
Laboratory Tests (Safety)
Hematology
Chemistry
Urinalysis
Other
Hematocrit
Albumin
Ketones (qualitative)
Serum β-hCG
Hemoglobin
ALP
pH
TSH
Platelet
ALT
Protein (qualitative)
C-Peptide
RBC
AST
Blood (qualitative)
Insulin
WBC (total)
Urea Nitrogen
Sediment
WBC (differential)
Calcium
Chloride
Creatinine/eGFR
CK
γ-GTP
Glucose
HbA1c
HDL cholesterol
LDH
LDL cholesterol
Magnesium
Phosphorus
Potassium
Sodium
Bilirubin, Total
Cholesterol, Total
Protein, Total
Triglycerides
Uric acid
Laboratory safety tests other than hematology tests, HbA1c and serum β-hCG will be 
performed after at least a 10-hour fast.
Urine pregnancy test
Urine pregnancy test will be performed at each study site.  Subjects with a positive urine 
pregnancy test after taking study medications for the treatment period will have a 
confirmatory serum β-hCG test at central laboratory as a pregnancy test.
Other Procedures
7.1.4
Withdrawal/Discontinuation
7.1.4.1
When a subject discontinues/withdraws from participation in the trial, all applicable activities 
scheduled for the discontinuation visit should be performed at the time of discontinuation.  
Any adverse events which are present at the time of discontinuation/withdrawal should be 
followed in accordance with the safety requirements outlined in Section 7.2 - Assessing and 
Recording Adverse Events.


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Blinding/Unblinding
7.1.4.2
This is an open label trial; there is no blinding for this trial.
Calibration of Critical Equipment
7.1.4.3
The investigator or qualified designee has the responsibility to ensure that any critical device
or instrument used for a clinical evaluation/test during a clinical trial that provides important 
information about inclusion/exclusion criteria and/or safety or efficacy parameters shall be 
suitably calibrated and maintained to ensure that the data obtained is reliable and/or 
reproducible.  Documentation of equipment calibration must be retained as source 
documentation at the trial site.
Critical Equipment for this trial includes:
None.
Visit Requirements
7.1.5
Visit requirements are outlined in Section 6.0 - Trial Flow Chart.   Specific procedure-related 
details are provided above in Section 7.1 - Trial Procedures.
Considerations before Visit
The investigator or clinical research coordinator will instruct the subjects to observe the 
following standards throughout the entire duration of the study period.  The subject who does 
not meet the following criteria at Screening should re-visit.
•
Fasting
The subjects should visit the study site at which the fasting samples are collected after 
having fasted (except for water) for 10 hours.
•
Concomitant medications
The subjects should not have been on intravenous fluids (excluding those having a 
volume <50 mL without any sugar content) and/or glucagon within 10 hours of the visit 
to the study site.
•
Study visit
Subjects should visit the study site in the morning.
•
Study medication and rescue medication
At the study visit, the subjects should visit the study site before taking study 
medications and rescue medication. 
The subject should bring any unused study 
medications prescribed at the last visit, without disposal and intake.


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Screening Period
7.1.5.1
7.1.5.1.1 Visit 1/Screening
Inclusion/exclusion criteria will be evaluated after obtaining the consent from the subject.  
For the duration of apre-treatmentperiod, the subjects will be assigned to Group A (10 
weeks) or Group B (0 weeks)based on their pre-treatment for T2DM (i.e., use or no use of 
otherAHAswithin 10weeks of Visit 1).
For the subject who meets all the eligibility criteria of Visit 1, all study procedures of Visit 1 
including the following instructions AND excepting patient registration and study medication 
(sitagliptin for the study) dispensingwill be conducted.
• Diet and exercise therapy
• Recoding of patient’s log
After the above procedures are completed, the patient registration and study medication 
dispensingwill be conducted.  The subject will be instructed to take the dispensed study 
medication from the day after tomorrow.
Visit 2(for thesubject in GroupA)or Visit 4(for thesubject in GroupB; Visit 2 and Visit 3 
will be skipped) is arranged within 2weeks after Visit 1. The subject who meets laboratory
criteria of Visit 1 canproceed to Visit 2.
Note:Subject of Group B who meets the exclusioncriteria #4 related to hypertension must be 
excluded.  In this case, subjects may have received re-screening after blood pressure 
medications adjusted at least 4 weeks and blood pressure measurements become stable.
Pre-treatment Period
7.1.5.2
7.1.5.2.1 Visit 2/Week -10 (Only for Group A)
For the subject who meets the enrollment criteria of Visit 2and can continue the studybased 
on the review of concomitant medications,the monitoring of adverse experiences, 
implementation status of dietand exercise therapy, and study medication (sitagliptinfor the 
study) compliance, all study procedures of Visit 2 including the following instructions AND 
excepting study medication administration, patient registration and study medication 
dispensingwill be conducted.
• SMBG
After the above procedures are completed, the study medication dispensedat the last visit 
should be taken as a witnessed dose.  After that, the patient registration and new study 
medication dispensing will be conducted.
Visit 3 is arranged approximately 8weeksafter Visit 2.


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7.1.5.2.2 Telephone contact/Week -6 (Only for Group A)
The investigator or the clinical research coordinator will confirm the following subject’s 
status with a telephone;
•
Adverse events (including confirmation of SMBG value)
•
Implementation status of diet and exercise therapy
•
Maintenance of diet and exercise therapy instructed at Visit 1
•
Study medication (sitagliptin for the study) compliance
7.1.5.2.3 Visit 3/Week -2 (Only for Group A)
For the subject who meets the enrollment criteria of Visit 3 and can continue the study based 
on the review of concomitant medications, the monitoring of adverse experiences, 
implementation status of diet and exercise therapy, and study medication (sitagliptin for the 
study) compliance, all study procedures of Visit 3 excepting study medication administration, 
patient registration and study medication dispensing will be conducted.
After the above procedures are completed, the study medication dispensed at the last visit 
should be taken as a witnessed dose.  After that, the patient registration and new study 
medications (sitagliptin for the study) dispensing will be conducted.
Visit 4 is arranged approximately 2 weeks after Visit 3.
Treatment Period
7.1.5.3
As of Visit 4, the subject will visit at every 4 weeks visit until Week 36, at every 8 weeks 
visit after Week 36 to assess the efficacy and safety.
7.1.5.3.1 Visit 4/Week 0
For the subject who meets the enrollment criteria of Visit 4 and can continue the study based 
on the review of concomitant medications, the monitoring of adverse experiences, 
implementation status of diet and exercise therapy, and study medications (sitagliptin for the 
study) compliance, all study procedures of Visit 4 including the following instructions AND 
excepting study medication administration, patient registration and study medication 
dispensing will be conducted.
•
SMBG (only for Group B)
•
Hypoglycemic symptoms, management and recording of HAL
For subjects who meet the enrollment criteria of Visit 4 and are judged as eligibility,
assignment of treatment number occurs only at Visit 4. After registering the subject, new


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study medications(sitagliptin for thestudy and ipragliflozin for the study) will be dispensed 
to thesubject.    The subject will be instructed to take 2 tablets of the newly-dispensed study 
medications (one tablet of each study medication) once daily in the morning at the same 
timingfrom the day after tomorrow.
Visit 5is arranged approximately 4 weeks after Visit 4.
7.1.5.3.2 From Visit 5/Week 4 to Visit 14/Week 44
For the subject who can continue the studybased on the review of concomitant medications,
the monitoring of adverse experiences, implementation status of dietand exercise therapy, 
and study medications compliance, all study procedures will be conducted.
Form this visit, the next visit is arranged approximately every 4 weeksor every 8 weeks.
7.1.5.3.3 Visit 15/Week 52 or discontinuation visit
All study procedures of Visit 15 or discontinuation visit will be conducted.
7.1.5.3.4 Rescue Visit
Rescue therapy must be initiated at either a scheduled or unscheduled visit at the 
investigational site, and not by a telephonevisit. Immediately prior to initiation of rescue 
therapy (at a scheduled or unscheduled visit),subjects meeting rescue criteria must undergo 
the rescue visit procedures.
After Last Dose of Study Medication
7.1.5.4
Fourteen days after the last dose of study medication, a follow up contact will beconducted 
by having subject visit or contacting the subject via telephone to collect theserious adverse 
experience information that might have occurred within the 14 days.
Note: In the event any serious drug-related adverse experience occurred later than 14 days 
after the last dose of study medication, it will be subjected to the follow-up evaluation.
Assessing and RecordingAdverse Events
7.2
An adverse event is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily 
have to have a causal relationship with this treatment. An adverse event can therefore be any 
unfavourable and unintended sign (including an abnormal laboratory finding, for example), 
symptom, or disease temporally associated with the use of a medicinal product or protocol-
specified procedure, whether or not considered related to the medicinal product or protocol-
specified procedure.  Any worsening (i.e., any clinically significant adversechange in 
frequency and/or intensity) of a preexisting condition that is temporally associated with the 
use of the Sponsor’s product, is also an adverse event.


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Changes resulting from normal growth and development that do not vary significantly in 
frequency or severity from expected levels are not to be considered adverse events.  
Examples of this may include, but are not limited to, teething, typical crying in infants and 
children and onset of menses or menopause occurring at a physiologically appropriate time.
Sponsor's product includes any pharmaceutical product, biological product, device, 
diagnostic agent or protocol-specified procedure, whether investigational (including placebo 
or active comparator medication) or marketed, manufactured by, licensed by, provided by or 
distributed by the Sponsor for human use.
Adverse events may occur during clinical trials, or as prescribed in clinical practice, from 
overdose (whether accidental or intentional), from abuse and from withdrawal.
All adverse events that occur after the consent form is signed but before taking study 
medication must be reported by the investigator if they cause the subject to be excluded from 
the trial, or are the result of a protocol-specified intervention, including but not limited to 
washout or discontinuation of usual therapy, diet, placebo treatment or a procedure. From the 
time of taking study medication through 14 days following cessation of treatment, all adverse 
events must be reported by the investigator. Such events will be recorded at each 
examination on the Adverse Event case report forms/worksheets.  The reporting timeframe 
for adverse events meeting any serious criteria is described in section 7.2.3.1. The 
investigator will make every attempt to follow all subjects with non-serious adverse events 
for outcome.
Electronic reporting procedures can be found in the Electronic Data Capture (EDC) data 
entry guidelines. Paper reporting procedures can be found in the Investigator Trial File 
Binder (or equivalent).
Definition of an Overdose for This Protocol and Reporting of Overdose to the 
7.2.1
Sponsor
In this trial, an overdose is defined as below; 
•
Dosing with higher than a total of 100 mg/day of sitagliptin. 
Or,
•
Dosing with higher than a total of 100 mg/day of ipragliflozin.
If an adverse event(s) is associated with (“results from”) the overdose of Sponsor's product or 
vaccine, the adverse event(s) is reported as a serious adverse event, even if no other 
seriousness criteria are met.
If a dose of Sponsor's product or vaccine meeting the protocol definition of overdose is taken 
without any associated clinical symptoms or abnormal laboratory results, the overdose is 
reported as a non-serious Event of Clinical Interest (ECI), using the terminology “accidental 
or intentional overdose without adverse effect.”


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All reports of overdose with and without an adverse event must be reported by the 
investigator within 24 hours to the Sponsor either by electronic media or paper. Electronic 
reporting procedures can be found in the EDC data entry guidelines. Paper reporting 
procedures can be found in the Investigator Trial File Binder (or equivalent).
Reporting of Pregnancy and Lactation to the Sponsor
7.2.2
Although pregnancy and lactation are not considered adverse events, it is the responsibility of 
investigators or their designees to report any pregnancy or lactation in a subject 
(spontaneously reported to them) that occurs during the trial.
Pregnancies and lactations that occur after the consent form is signed but before taking study 
medication must be reported by the investigator if they cause the subject to be excluded from 
the trial, or are the result of a protocol-specified intervention, including but not limited to 
washout or discontinuation of usual therapy, diet, placebo treatment or a procedure.  
Pregnancies and lactations that occur from the time of taking study medication through 14 
days following cessation of Sponsor’s product must be reported by the investigator.  All 
reported pregnancies  must be followed to the completion/termination of the pregnancy. 
Pregnancy outcomes of spontaneous abortion, missed abortion, benign hydatidiform mole, 
blighted ovum, fetal death, intrauterine death, miscarriage and stillbirth must be reported as 
serious events (Important Medical Events). If the pregnancy continues to term, the outcome 
(health of infant) must also be reported.
Such events must be reported within 24 hours to the Sponsor either by electronic media or 
paper. Electronic reporting procedures can be found in the EDC data entry guidelines. Paper 
reporting procedures can be found in the Investigator Trial File Binder (or equivalent).
Immediate Reporting of Adverse Events to the Sponsor
7.2.3
Serious Adverse Events
7.2.3.1
A serious adverse event is any adverse event occurring at any dose or during any use of 
Sponsor's product that:
●
Results in death;
●
Is life threatening;
●
Results in persistent or significant disability/incapacity;
●
Results in or prolongs an existing inpatient hospitalization;
●
Is a congenital anomaly/birth defect;
●
Is an other important medical event.
Note: In addition to the above criteria, adverse events meeting either of the below criteria, 
although not serious per ICH definition, are reportable to the Sponsor in the same timeframe 
as SAEs to meet certain local requirements. Therefore, these events are considered serious by 
the Sponsor for collection purposes.


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●
Is a cancer;
●
Is associated with an overdose.
Refer to Table 10 for additional details regarding each of the above criteria.
For the time period beginning when the consent form is signed until taking study medication, 
any serious adverse event, or follow up to a serious adverse event, including death due to any 
cause, that occurs to any subject must be reported within 24 hours to the Sponsor if it causes 
the subject to be excluded from the trial, or is the result of a protocol-specified intervention, 
including but not limited to washout or discontinuation of usual therapy, diet, placebo 
treatment or a procedure.
For the time period beginning at taking study medication through 14 days following 
cessation of treatment, any serious adverse event, or follow up to a serious adverse event, 
including death due to any cause, whether or not related to the Sponsor's product, must be 
reported within 24 hours to the Sponsor either by electronic media or paper. Electronic 
reporting procedures can be found in the EDC data entry guidelines. Paper reporting 
procedures can be found in the Investigator Trial File Binder (or equivalent).
Additionally, any serious adverse event, considered by an investigator who is a qualified 
physician to be related to the Sponsor's product that is brought to the attention of the 
investigator at any time outside of the time period specified in the previous paragraph also 
must be reported immediately to the Sponsor.
All subjects with serious adverse events must be followed up for outcome.
Events of Clinical Interest
7.2.3.2
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI)  and must be reported to the Sponsor.
For the time period beginning when the consent form is signed until taking study medication, 
any ECI, or follow up to an ECI, that occurs to any subject must be reported within 24 hours 
to the Sponsor if it causes the subject to be excluded from the trial, or is the result of a 
protocol-specified intervention, including but not limited to washout or discontinuation of 
usual therapy, diet, placebo treatment or a procedure.
For the time period beginning at taking study medication through 14 days following 
cessation of treatment, any ECI, or follow up to an ECI, whether or not related to the 
Sponsor’s product, must be reported within 24 hours to the Sponsor, either by electronic 
media or paper.  Electronic reporting procedures can be found in the EDC data entry 
guidelines.  Paper reporting procedures can be found in the Investigator Trial File Binder (or 
equivalent).


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Events of clinical interest for this trial include:
1. an overdose of Sponsor's product, as defined in Section 7.2.1 - Definition of an Overdose 
for This Protocol and Reporting of Overdose to the Sponsor, that is not associated with 
clinical symptoms or abnormal laboratory results. 
2. an elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of 
normal and an elevated total bilirubin lab value that is greater than or equal to 2X the 
upper limit of normal and, at the same time, an alkaline phosphatase lab value that is less 
than 2X the upper limit of normal, as determined by way of protocol-specified laboratory 
testing or unscheduled laboratory testing.*
*Note:  These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may require 
an additional evaluation for an underlying etiology. The trial site guidance for assessment 
and follow up of these criteria can be found in the Investigator Trial File Binder (or 
equivalent).
Evaluating Adverse Events
7.2.4
An investigator who is a qualified physician will evaluate all adverse events with respect to 
the elements outlined in Table 10. The investigator’s assessment of causality is required for 
each adverse event.  Refer to Table 10 for instructions in evaluating adverse events.


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Table 10
Evaluating Adverse Events
Maximum
Mild
awareness of sign or symptom, but easily tolerated  (for pediatric trials, awareness of symptom, but easily tolerated)
Intensity
Moderate
discomfort enough to cause interference with usual activity (for pediatric trials, definitely acting like something is wrong)
Severe
incapacitating with inability to work or do usual activity (for pediatric trials, extremely distressed or unable to do usual activities)
Seriousness
A serious adverse event (AE) is any adverse event occurring at any dose or during any use of Sponsor's product that:
†Results in death; or
†Is life threatening; or places the subject, in the view of the investigator, at immediate risk of death from the event as it occurred [Note: This does not include an 
adverse event  that, had it occurred in a more severe form, might have caused death.]; or
†Results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to conduct normal life functions); or
†Results in or prolongs an existing inpatient hospitalization (hospitalization is defined as an inpatient admission, regardless of length of stay, even if the 
hospitalization is a precautionary measure for continued observation.   (Note: Hospitalization for an elective procedure to treat a pre-existing condition that has not 
worsened is not a serious adverse event.  A pre-existing condition is a clinical condition that is diagnosed prior to the use of a Merck product and is documented in the 
patient’s medical history.); or
†Is a congenital anomaly/birth defect  (in offspring of subject taking the product regardless of time to diagnosis); or
Is a cancer (although not serious per ICH definition, is reportable to the Sponsor within 24 hours to meet certain local requirements); or
Is associated with an overdose (whether accidental or intentional).  Any adverse event associated with an overdose is considered a serious adverse event for 
collection purposes. An overdose that is not associated with an adverse event is considered a non-serious event of clinical interest and must be reported within 24 
hours.
Other important medical events that may not result in death, not be life threatening, or not require hospitalization may be considered a serious adverse event when, 
based upon appropriate medical judgment, the event may jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes listed 
previously (designated above by a †).
Duration
Record the start and stop dates of the adverse event.  If less than 1 day, indicate the appropriate length of time and units
Action taken 
Did the adverse event cause the Sponsor's product to be discontinued?
Relationship to 
Sponsor's 
Product
Did the Sponsor's product cause the adverse event?   The determination of the likelihood that the Sponsor's product caused the adverse event will be provided by an 
investigator who is a qualified physician.  The investigator’s signed/dated initials on the source document or worksheet that supports the causality noted on the AE 
form, ensures that a medically qualified assessment of causality was done.  This initialed document must be retained for the required regulatory time frame.  The 
criteria below are intended as reference guidelines to assist the investigator in assessing the likelihood of a relationship between the test drug and the adverse event 
based upon the available information
The following components are to be used to assess the relationship between the Sponsor's product and the AE; the greater the correlation with the components 
and their respective elements (in number and/or intensity), the more likely the Sponsor's product caused the adverse event:
Exposure
Is there evidence that the subject was actually exposed to the Sponsor's product such as:  reliable history, acceptable compliance assessment (pill 
count, diary, etc.), expected pharmacologic effect, or measurement of drug/metabolite in bodily specimen?
Time Course
Did the AE follow in a reasonable temporal sequence from administration of the Sponsor's product? 
Is the time of onset of the AE compatible with a drug-induced effect (applies to trials with investigational medicinal product)?
Likely Cause
Is the AE not reasonably explained by another etiology such as underlying disease, other drug(s)/vaccine(s), or other host or environmental 
factors


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Relationship
The following components are to be used to assess the relationship between the Sponsor's product and the AE:  (continued)
to Sponsor's 
Product
(continued) 
Dechallenge
Was the Sponsor's product discontinued or dose/exposure/frequency reduced?
      If yes, did the AE resolve or improve?
           If yes, this is a positive dechallenge.    If no, this is a negative dechallenge.
(Note:  This criterion is not applicable if:  (1) the AE resulted in death or permanent disability; (2) the AE resolved/improved despite 
continuation of the Sponsor's product; (3) the trial is a single-dose drug trial); or (4) Sponsor's product(s) is/are only used one time.)
Rechallenge
Was the subject re-exposed to the Sponsor's product in this trial?
      If yes, did the AE recur or worsen?
          If yes, this is a positive rechallenge.    If no, this is a negative rechallenge.
(Note:  This criterion is not applicable if:  (1) the initial AE resulted in death or permanent disability, or (2) the trial is a single-dose drug trial); 
or (3) Sponsor's product(s) is/are used only one time.)
NOTE:  IF A RECHALLENGE IS PLANNED FOR AN ADVERSE EVENT WHICH WAS SERIOUS AND WHICH MAY HAVE BEEN 
CAUSED BY THE SPONSOR'S PRODUCT, OR IF RE-EXPOSURE TO THE SPONSOR'S PRODUCT POSES ADDITIONAL POTENTIAL 
SIGNIFICANT RISK TO THE SUBJECT THEN THE RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE SPONSOR
CLINICAL DIRECTOR AND THE INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE.
Consistency 
with Trial 
Treatment 
Profile
Is the clinical/pathological presentation of the AE consistent with previous knowledge regarding the Sponsor's product or drug class 
pharmacology or toxicology?
The assessment of relationship will be reported on the case report forms /worksheets by an investigator who is a qualified physician according to his/her best clinical judgment, including 
consideration of the above elements.
Record one of the following:
Use the following scale of criteria as guidance (not all criteria must be present to be indicative of a Sponsor's product relationship).
Yes, there is a reasonable 
possibility of Sponsor's product 
relationship.
There is evidence of exposure to the Sponsor's product.  The temporal sequence of the AE onset relative to the administration of the Sponsor's 
product is reasonable.  The AE is more likely explained by the Sponsor's product than by another cause. 
No, there is not a reasonable 
possibility of Sponsor's product 
relationship
Subject did not receive the Sponsor's product OR temporal sequence of the AE onset relative to administration of the Sponsor's product is not 
reasonable OR the AE is more likely explained by another cause than the Sponsor’s product.  (Also entered for a subject with overdose without 
an associated AE.)


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Sponsor Responsibility for Reporting Adverse Events
7.2.5
All Adverse Events will be reported to regulatory authorities, IRB/IECs and investigators in 
accordance with all applicable global laws and regulations, i.e., per ICH Topic E6 (R1) 
Guidelines for Good Clinical Practice.
8.0 STATISTICAL ANALYSIS PLAN
This section outlines the statistical analysis strategy and procedures for the study. Changes to 
the analyses made after the protocol has been finalized will be documented in a supplemental 
statistical analysis plan (sSAP) and referenced in the Clinical Study Report (CSR) for the 
study. Post hoc exploratory analyses will be clearly identified in the CSR.
Statistical Analysis Plan Summary
8.1
Key elements of the statistical analysis plan are summarized below; the comprehensive plan 
is provided in Sections 8.2-8.12.
Study Design Overview
PhIII ipragliflozin add-on study in T2DM patients on sitagliptin
Treatment Assignment
All subjects enrolled in the study will receive open-label 
ipragliflozin 50 mg.
Analysis Populations
Safety
All Subject as Treated (ASaT) population, defined as all subjects 
who received at least one dose of treatment period study 
medication.
Efficacy
Full Analysis Set (FAS) population, defined as all subjects who:

received at least one dose of treatment period study 
medication

have at least one measurement of the outcome variable 
(baseline or post-baseline)

have baseline data for those analyses that require baseline data
Primary Endpoint
AEs, pre-defined limits of change (PDLCs) in laboratory tests and 
vital signs, as well as change from baseline in laboratory tests, vital 
signs and ECG.
Secondary Endpoint
Change from baseline in HbA1c at respective timepoints
Statistical Methods for Key 
Safety Analyses
AEs and PDLCs will be summarized by the number and 
percentage of the subjects who experienced respective events. 
Change from baseline in laboratory tests, vital signs and ECG at 
respective timepoints will be summarized by descriptive statistics.
Statistical Methods for Key 
Efficacy Analyses
Change from baseline in HbA1c at respective timepoints will be 
summarized by descriptive statistics and 95% confidence intervals 
(CIs).
Interim Analyses
The results up to Week 24 will be summarized after all subjects 
remaining in the trial have completed Week 24.
Multiplicity
Not applicable.
Sample Size and Power
A total of 75 subjects will be enrolled. Assuming a discontinuation 
rate of approximately 14%, 64 subjects will complete 52 weeks of 
treatment.


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Responsibility for Analyses/In-House Blinding
8.2
The statistical analysis of the data obtained from this study will be the responsibility of the 
Clinical Biostatistics department of the SPONSOR. This study will be conducted as a single-
arm, open-label study.
Hypotheses/Estimation
8.3
Objectives of the study are stated in Section 3.
Analysis Endpoints
8.4
Safety and efficacy endpoints that will be evaluated for within-treatment differences are 
listed below. For both safety and efficacy parameters, the baseline value is defined as the last 
available measurement prior to enrollment, which typically corresponds to the measurement 
obtained at Visit 4.
Safety Endpoints
8.4.1
Refer to Section 4.2.3.1 for a list of safety endpoints.
Efficacy Endpoints
8.4.2
Refer to Section 4.2.3.2 for a list of efficacy endpoints.
Analysis Populations
8.5
Safety Analysis Populations
8.5.1
The ASaT population will be used for the analysis of safety data in this study. The ASaT 
population consists of all subjects who received at least one dose of treatment period study 
medication.
At least one laboratory, vital sign or ECG measurement obtained subsequent to at least one 
dose of treatment period study medication is required for inclusion in the analysis of each 
specific parameter. To assess change from baseline, a baseline measurement is also required.
Efficacy Analysis Populations
8.5.2
The FAS population will serve as the population for the analysis of efficacy data in this 
study. The FAS population consists of all subjects who:
•
received at least one dose of treatment period study medication
•
have at least one measurement of the outcome variable (baseline or post-baseline)
•
have baseline data for those analyses that require baseline data


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Statistical Methods
8.6
Statistical Methods for Safety Analyses
8.6.1
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
AEs, laboratory tests, vital signs and ECG.
For analyses of AEs and PDLCs, the following two approaches will be used. The primary 
approach will include all safety-related data points that occurred prior to the initiation of 
rescue therapy or all safety-related data points if no rescue therapy was initiated. The 
secondary approach will include all safety-related data points for a subject, regardless of 
presence or absence of rescue therapy. Only the primary approach will be used to summarize 
hypoglycemia.
AEs and other safety events will be summarized by the number and percentage of the 
subjects who experienced respective events. Change from baseline in laboratory tests, vital 
signs and ECG at respective timepoints will be summarized by descriptive statistics. Missing 
values will not be imputed.
Statistical Methods for Efficacy Analyses
8.6.2
To avoid the confounding influence of rescue therapy on efficacy, the efficacy analyses will 
treat data as missing after the initiation of rescue therapy.
Change from baseline in HbA1c at respective timepoints will be summarized by descriptive 
statistics and 95% CIs. Missing values will not be imputed. Continuous tertiary endpoints 
will be summarized in a similar fashion.
The number and percentage of subjects achieving HbA1c <7.0%,
along with the 
corresponding 95% CI based on the method of Clopper and Pearson [18], will be provided by 
timepoint. The denominator will be the number of subjects who are included in the FAS 
population and have HbA1c measurement at respective timepoints. Missing values will not 
be imputed.
Summaries of Baseline Characteristics, Demographics, and Other Analyses
8.6.3
The number and percentage of subjects screened, enrolled, the primary reasons for screening 
failure, and the primary reason for discontinuation will be displayed. Demographic variables, 
baseline characteristics, primary and secondary diagnoses, and prior and concomitant 
therapies will be summarized either by descriptive statistics or categorical tables.
Interim Analyses
8.7
For the purpose of filing, all the safety and efficacy results up to Week 24 will be 
summarized after all subjects remaining in the trial have completed Week 24.


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Multiplicity
8.8
No adjustment for multiplicity is planned for the study.
Sample Size and Power Calculations
8.9
A total of 75 subjects will be enrolled in the study. Assuming a discontinuation rate of 
approximately 14% based on those subjects treated with the active drug for 52 weeks in 
MK3102-020, 64 subjects will complete 52 weeks of treatment. In the study previously 
conducted for the filing of the single entity of ipragliflozin (CL-0110), there were 77 subjects 
treated with coadministration of sitagliptin and ipragliflozin for 52 weeks (45 of them were 
treated with coadministration of sitagliptin 50 mg and ipragliflozin 50 mg). Hence, with the 
planned sample size of this study, it is possible to obtain adequate amount of data from 
coadministration of sitagliptin and ipragliflozin for 52 weeks.
For an AE or a specific safety event of interest, if the underlying incidence is 2%, then there 
is 78% chance that it is observed in at least one subject among the 75 subjects enrolled. If 
none of the 75 subjects experiences the event, then the 95% upper confidence limit of the 
underlying incidence rate will be 4.8%.
With N=75, the half-width of the 95% CI for change from baseline in HbA1c will be 0.23% 
if the standard deviation estimate is 1%.
Subgroup Analyses and Effect of Baseline Factors
8.10
No subgroup analysis is planned in this study.
Compliance (Medication Adherence)
8.11
For each subject, percent compliance will be calculated using the following formula:
Compliance  =
Number of Compliant Days
× 100%.
Number of Days in the Treatment Period
A subject will be considered compliant with study medication on a given day if the subject 
takes both one tablet of sitagliptin 50 mg and one tablet of ipragliflozin 50 mg. The "Number 
of Days in the Treatment Period" is defined for each subject as the total number of days from 
the date of the first administration of the study medication to the day before Visit 15 for those 
subjects who completed the study, and from the date of the first administration of the study 
medication to the date of the last administration of study medication for those subjects who 
discontinued from the study.
Descriptive statistics will be provided on percent compliance for the FAS population.
Extent of Exposure
8.12
The dose level and treatment duration will be summarized for the ASaT population.


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9.0 LABELING, PACKAGING,
STORAGE AND RETURN OF CLINICAL 
SUPPLIES
Investigational Product
9.1
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of 
investigational product in accordance with the protocol and any applicable laws and 
regulations.
Clinical Supplies will be provided by the Sponsor as summarized in Table 11.
Table 11
Product Descriptions
Product Name & Potency
Dosage Form
Sitagliptin phosphate 50 mg
Tablet
Ipragliflozin L-proline 50 mg
Packaging and Labeling Information
9.2
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements.
In the screening period, subjects will receive one (1) open label bottle of Sitagliptin 50 mg.
In the pre-treatment period, subjects in Group A will receive two (2) and one (1) open label 
bottles of Sitagliptin 50 mg at Visit 2 and 3, respectively.
In the treatment period, subjects in Group A and B will receive one (1) open label kit of 
Ipragliflozin 50 mg and one (1) open label bottle of Sitagliptin 50 mg every 4 weeks until 
Visit 12, and receive two (2) open label kits of Ipragliflozin 50 mg and two (2) open label 
bottles of Sitagliptin 50 mg every 8 weeks at Visit 13 or later. Each kit of Ipragliflozin 50 mg 
will contain three (3) blister sheets.
Clinical Supplies Disclosure
9.3
This trial is open-label; therefore, the subject, the trial site personnel, the Sponsor and/or 
designee are not blinded. Treatment (name, strength or potency) is included in the label text; 
random code/disclosure envelopes or lists are not provided.
Storage and Handling Requirements
9.4
Clinical supplies must be stored in a secure, limited-access location under the storage 
conditions specified on the label.  


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Receipt and dispensing of trial medication must be recorded by an authorized person at the 
trial site.
Clinical supplies may not be used for any purpose other than that stated in the protocol.
Discard/Destruction/Returns and Reconciliation
9.5
The investigator is responsible for keeping accurate records of the clinical supplies received 
from the Sponsor or designee, the amount dispensed to and returned by the subjects and the 
amount remaining at the conclusion of the trial. For all trial sites, the local country Sponsor 
personnel or designee will provide appropriate documentation that must be completed for 
drug accountability and return, or local discard and destruction if appropriate.   Where local 
discard and destruction is appropriate, the investigator is responsible for ensuring that a local 
discard/destruction procedure is documented.
10.0 ADMINISTRATIVE AND REGULATORY DETAILS
Confidentiality
10.1
Confidentiality of Data
10.1.1
By signing this protocol, the investigator affirms to the Sponsor that information furnished to 
the investigator by the Sponsor will be maintained in confidence, and such information will 
be divulged to the institutional review board, ethics review committee (IRB/ERC) or similar 
or expert committee; affiliated institution and employees, only under an appropriate 
understanding of confidentiality with such board or committee, affiliated institution and 
employees.  Data generated by this trial will be considered confidential by the investigator, 
except to the extent that it is included in a publication as provided in the Publications section 
of this protocol.
Confidentiality of Subject Records
10.1.2
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/ERC, or regulatory authority representatives may consult and/or copy trial documents in 
order to verify worksheet/case report form data.  By signing the consent form, the subject 
agrees to this process.  If trial documents will be photocopied during the process of verifying 
worksheet/case report form information, the subject will be identified by unique code only; 
full names/initials will be masked prior to transmission to the Sponsor.
By signing this protocol, the investigator agrees to treat all subject data used and disclosed in 
connection with this trial in accordance with all applicable privacy laws, rules and 
regulations.
Confidentiality of Investigator Information
10.1.3
By signing this protocol, the investigator recognizes that certain personal identifying 
information with respect to the investigator, and all subinvestigators and trial site personnel, 


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may be used and disclosed for trial management purposes, as part of a regulatory 
submissions, and as required by law.  This information may include:
1. name, address, telephone number and e-mail address;
2. hospital or clinic address and telephone number;
3. curriculum vitae or other summary of qualifications and credentials; and
4. other professional documentation.
Consistent with the purposes described above, this information may be transmitted to the 
Sponsor, and subsidiaries, affiliates and agents of the Sponsor, in your country and other 
countries, including countries that do not have laws protecting such information.  
Additionally, the investigator’s name and business contact information may be included 
when reporting certain serious adverse events to regulatory authorities or to other 
investigators.  By signing this protocol, the investigator expressly consents to these uses and 
disclosures.
If this is a multicenter trial, in order to facilitate contact between investigators, the Sponsor 
may share an investigator’s name and contact information with other participating 
investigators upon request.
Confidentiality of IRB/IEC Information
10.1.4
The Sponsor is required to record the name and address of each IRB/IEC that reviews and 
approves this trial.  The Sponsor is also required to document that each IRB/IEC meets 
regulatory and ICH GCP requirements by requesting and maintaining records of the names 
and qualifications of the IRB/IEC members and to make these records available for 
regulatory agency review upon request by those agencies.
Compliance with Financial Disclosure Requirements
10.2
Financial Disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54).  It is the 
Sponsor's responsibility to determine, based on these regulations, whether a request for 
Financial Disclosure information is required.  It is the investigator's/subinvestigator's 
responsibility to comply with any such request.  
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21 
CFR Part 54, to provide his/her financial interests in and/or arrangements with the Sponsor to 
allow for the submission of complete and accurate certification and disclosure statements.  
The investigator/subinvestigator(s) further agree to provide this information on a 
Certification/Disclosure Form, commonly known as a financial disclosure form, provided by 
the Sponsor. The investigator/subinvestigator(s) also consent to the transmission of this 
information to the Sponsor in the United States for these purposes.  This may involve the 
transmission of information to countries that do not have laws protecting personal data.


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Compliance with Law, Audit and Debarment
10.3
By signing this protocol, the investigator agrees to conduct the trial in an efficient and 
diligent manner and in conformance with this protocol; generally accepted standards of Good 
Clinical Practice (e.g., International Conference on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human Use Good Clinical Practice: 
Consolidated Guideline and other generally accepted standards of good clinical practice); and 
all applicable federal, state and local laws, rules and regulations relating to the conduct of the 
clinical trial.
The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by Merck, is provided in Section 12.1 -
Merck Code of Conduct for Clinical Trials.
The investigator also agrees to allow monitoring, audits, IRB/ERC review and regulatory 
authority inspection of trial-related documents and procedures and provide for direct access 
to all trial-related source data and documents.
The investigator agrees not to seek reimbursement from subjects, their insurance providers or 
from government programs for procedures included as part of the trial reimbursed to the 
investigator by the Sponsor.
The investigator shall prepare and maintain complete and accurate trial documentation in 
compliance with Good Clinical Practice standards and applicable federal, state and local 
laws, rules and regulations; and, for each subject participating in the trial, provide all data, 
and, upon completion or termination of the clinical trial, submit any other reports to the 
Sponsor as required by this protocol or as otherwise required pursuant to any agreement with 
the Sponsor.
Trial documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the trial site upon request for inspection, 
copying, review and audit at reasonable times by representatives of the Sponsor or any 
regulatory authorities.  The investigator agrees to promptly take any reasonable steps that are 
requested by the Sponsor as a result of an audit to cure deficiencies in the trial documentation 
and worksheets/case report forms.
The investigator must maintain copies of all documentation and records relating to the 
conduct of the trial in compliance with all applicable legal and regulatory requirements.  This 
documentation includes, but is not limited to, the protocol, worksheets/case report forms, 
advertising for subject participation, adverse event reports, subject source data, 
correspondence with regulatory authorities and IRBs/ERCs, consent forms, investigator’s 
curricula vitae, monitor visit logs, laboratory reference ranges, laboratory certification or 
quality control procedures and laboratory director curriculum vitae.  By signing this protocol, 
the investigator agrees that documentation shall be retained until at least 2 years after the last 
approval of a marketing application in an ICH region or until there are no pending or 
contemplated marketing applications in an ICH region or until at least 2 years have elapsed 


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since the formal discontinuation of clinical development of the investigational product.  
Because the clinical development and marketing application process is variable, it is 
anticipated that the retention period can be up to 15 years or longer after protocol database 
lock. The Sponsor will determine the minimum retention period and notify the investigator 
when documents may be destroyed.  The Sponsor will determine the minimum retention 
period and upon request, will provide guidance to the investigator when documents no longer 
need to be retained.  The sponsor also recognizes that documents may need to be retained for 
a longer period if required by local regulatory requirements. All trial documents shall be 
made available if required by relevant regulatory authorities. The investigator must consult 
with and obtain written approval by the Sponsor prior to destroying trial and/or subject files.  
ICH Good Clinical Practice guidelines recommend that the investigator inform the subject’s 
primary physician about the subject’s participation in the trial if the subject has a primary 
physician and if the subject agrees to the primary physician being informed.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this trial.
Persons debarred from conducting or working on clinical trials by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s trials.  The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the trial is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
In the event the Sponsor prematurely terminates a particular trial site, the Sponsor will 
promptly notify that trial site’s IRB/IEC.
According to European legislation, a Sponsor must designate an overall coordinating 
investigator for a multi-center trial (including multinational).  When more than one trial site 
is open in an EU country, Merck, as the Sponsor, will designate, per country, a national 
principal coordinator (Protocol CI), responsible for coordinating the work of the principal 
investigators at the different trial sites in that Member State, according to national 
regulations.  For a single-center trial, the Protocol CI is the principal investigator.  In 
addition, the Sponsor must designate a principal or coordinating investigator to review the 
trial report that summarizes the trial results and confirm that, to the best of his/her 
knowledge, the report accurately describes the conduct and results of the trial [Clinical Study 
Report (CSR) CI].  The Sponsor may consider one or more factors in the selection of the 
individual to serve as the Protocol CI and or CSR CI (e.g., availability of the CI during the 
anticipated review process, thorough understanding of clinical trial methods, appropriate 
enrollment of subject cohort, timely achievement of trial milestones).  The Protocol CI must 
be a participating trial investigator.
Compliance with Trial Registration and Results Posting Requirements
10.4
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and the 
Food and Drug Administration Amendments Act (FDAAA), the Sponsor of the trial is solely 


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responsible for determining whether the trial and its results are subject to the requirements 
for submission to the Clinical Trials Data Bank, http://www.clinicaltrials.gov.  Merck, as 
Sponsor of this trial, will review this protocol and submit the information necessary to fulfill 
these requirements.  Merck entries are not limited to FDAMA/FDAAA mandated trials. 
Information posted will allow subjects to identify potentially appropriate trials for their 
disease conditions and pursue participation by calling a central contact number for further 
information on appropriate trial locations and trial site contact information.    
By signing this protocol, the investigator acknowledges that the statutory obligations under 
FDAMA/FDAAA are that of the Sponsor and agrees not to submit any information about this 
trial or its results to the Clinical Trials Data Bank.
Quality Management System
10.5
By signing this protocol, the Sponsor agrees to be responsible for implementing and 
maintaining a quality management system with written development procedures and 
functional area standard operating procedures (SOPs) to ensure that trials are conducted and 
data are generated, documented, and reported in compliance with the protocol, accepted 
standards of Good Clinical Practice, and all applicable federal, state, and local laws, rules and 
regulations relating to the conduct of the clinical trial.
Data Management
10.6
The investigator or qualified designee is responsible for recording and verifying the accuracy 
of subject data.  By signing this protocol, the investigator acknowledges that his/her 
electronic signature is the legally binding equivalent of a written signature.  By entering 
his/her electronic signature, the investigator confirms that all recorded data have been 
verified as accurate.
Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
Publications
10.7
This trial is intended for publication, even if terminated prematurely. Publication may include 
any or all of the following: posting of a synopsis online, abstract and/or presentation at a 
scientific conference, or publication of a full manuscript.  The Sponsor will work with the 
authors to submit a manuscript describing trial results within 12 months after the last data 
become available, which may take up to several months after the last subject visit in some 
cases such as vaccine trials.  However, manuscript submission timelines may be extended on 
OTC trials.  For trials intended for pediatric-related regulatory filings, the investigator agrees 
to delay publication of the trial results until the Sponsor notifies the investigator that all 
relevant regulatory authority decisions on the trial drug have been made with regard to 
pediatric-related regulatory filings. Merck will post a synopsis of trial results for approved 
products on www.clinicaltrials.gov by 12 months after the last subject's last visit for the 


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primary outcome, 12 months after the decision to discontinue development, or product 
marketing (dispensed, administered, delivered or promoted), whichever is later.
These timelines may be extended for products that are not yet marketed, if additional time is 
needed for analysis, to protect intellectual property, or to comply with confidentiality 
agreements with other parties.  Authors of the primary results manuscript will be provided 
the complete results from the Clinical Study Report, subject to the confidentiality agreement. 
When a manuscript is submitted to a biomedical journal, the Sponsor's policy is to also 
include the protocol and statistical analysis plan to facilitate the peer and editorial review of 
the manuscript.  If the manuscript is subsequently accepted for publication, the Sponsor will 
allow the journal, if it so desires, to post on its website the key sections of the protocol that 
are relevant to evaluating the trial, specifically those sections describing the trial objectives 
and hypotheses, the subject inclusion and exclusion criteria, the trial design and procedures, 
the efficacy and safety measures, the statistical analysis plan, and any amendments relating to 
those sections.  The Sponsor reserves the right to redact proprietary information.
For multicenter trials, subsequent to the multicenter publication (or after public disclosure of 
the results online at www.clinicaltrials.gov if a multicenter manuscript is not planned), an 
investigator and his/her colleagues may publish their data independently.  In most cases, 
publication of individual trial site data does not add value to complete multicenter results, 
due to statistical concerns.  In rare cases, publication of single trial site data prior to the main 
paper may be of value.  Limitations of single trial site observations in a multicenter trial 
should always be described in such a manuscript.
Authorship credit should be based on 1) substantial contributions to conception and design, 
or acquisition of data, or analysis and interpretation of data; 2) drafting the article or revising 
it critically for important intellectual content; and 3) final approval of the version to be 
published. Authors must meet conditions 1, 2 and 3.  Significant contributions to trial 
execution may also be taken into account to determine authorship, provided that 
contributions have also been made to all three of the preceding authorship criteria.  Although 
publication planning may begin before conducting the trial, final decisions on authorship and 
the order of authors’ names will be made based on participation and actual contributions to 
the trial and writing, as discussed above. The first author is responsible for defending the 
integrity of the data, method(s) of data analysis and the scientific content of the manuscript.
The Sponsor must have the opportunity to review all proposed abstracts, manuscripts or 
presentations regarding this trial 45 days prior to submission for publication/presentation. 
Any information identified by the Sponsor as confidential must be deleted prior to 
submission; this confidentiality does not include efficacy and safety results. Sponsor review 
can be expedited to meet publication timelines.


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11.0LIST OF REFERENCES
1. Japan Diabetes Society. Diabetes Treatment Guideline 2014-2015. 2014. Japanese
2. Japan Diabetes Society. Scientific evidence-based diabetes practice guideline 2013. 
Nankodo. 2013. Japanese
3. International Diabetes Federation. DIABETES ATLAS. Sixth edition. 2013 Executive 
Summary. International Diabetes Federation. 2013.
4. Heath Service Bureau, Ministry of Health, Labor and Welfare. National Health and 
Nutrition Examination Survey in 2012. December-2012. Japanese
5. de Pablos-Velasco P, Parhofer KG, Bradley C, Eschwège E, Gönder-Frederick L, 
Maheux P, et al. Current level of glycaemic control and its associated factors in patients 
with type 2 diabetes across Europe: data from the PANORAMA study. Clin Endocrinol 
(Oxf). 2014; 80: 47-56.
6. Hauber AB, Tunceli K, Yang JC, Gantz I, Brodovicz KG, Alexander CM, et al. 
Treatment preferences and medication adherence of people with Type 2 diabetes using 
oral glucose-lowering agents. Diabet Med. 2009; 26: 416-24.
7. Larkin AT1, Hoffman C, Stevens A, Douglas A, Bloomgarden Z. Determinants of 
adherence todiabetes treatment. J Diabetes. 2015 Jan 7.
8. Matsumura N, Nakano H.Drug adherence in type 2 diabetics.Nihon Rinsho. 2015;73:
470-3.Japanese
9. Pullar T, Birtwell AJ, Wiles PG, Hay A, Feely MP. Use of a pharmacologic indicator to 
comparecompliance with tablets prescribed to be taken once, twice, or three times 
daily. Clin PharmacolTher. 1988; 44: 540-5.
10. Dezii CM, Kawabata H, Tran M. Effects of once-daily and twice-daily dosing on 
adherence withprescribed glipizide oral therapy for type 2 diabetes. South Med J. 2002; 
95: 68-71.
11. Winkler A, Teuscher AU, Mueller B, Diem P. Monotoring adherence to prescribed 
medication intype 2 diabetic patients treated with sulfonylureas. Swiss Med Wkly. 
2002; 132: 379-85.
12. Kardas P. The DIACOM study (effectof DosIng frequency of oral Antidiabetic agents 
on theCOMpliance and biochemical control of type 2 diabetes). Diabetes Obes Metab. 
2005; 7: 722-8.
13. Srivastava K, Arora A, Kataria A, Cappelleri JC, Sadosky A, Peterson AM. Impact of 
reducing dosing frequency on adherence to oral therapies: a literature review and meta-
analysis. Patient Prefer Adherence. 2013;7:419-34.


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14. Cheong C, Barner JC, Lawson KA, Johnsrud MT. Patient adherence and reimbursement 
amount for antidiabetic fixed-dose combination products compared with dual therapy 
among Texas Medicaid recipients. Clin Ther. 2008; 30: 1893-907.
15. Melikian C, White TJ, Vanderplas A, et al. Dezii CM, Chang E. Adherence to oral 
antidiabetic therapy in a managed care organization: a comparison of monotherapy, 
combination therapy, and fixed-dose combination therapy. Clin Ther. 2002; 24: 460-7.
16. Blonde L, Wogen J, Kreilick C, et al. Greater reductions in A1C in type 2 diabetic 
patients new to therapy with glyburide/metformin tablets as compared to glyburide co-
administered with metformin. Diabetes Obes Metab. 2003; 5: 424-31.
17. Pan F, Chernew ME, Fendrick AM. Impact of fixed-dose combination drugs on 
adherence to prescription medications. J Gen Intern Med. 2008; 23(5):611-4.
18. Clopper CJ, Pearaon ES. The use of confidence or fiducial limits illustrated in the case 
of the Binomial. Biometrika; 26: 404-13.


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12.0 APPENDICES
Merck Code of Conduct for Clinical Trials
12.1
Merck*
Code of Conduct for Clinical Trials
I.
Introduction
A. Purpose
Merck, through its subsidiaries, conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, implementing, conducting, analyzing and reporting these trials in 
compliance with the highest ethical and scientific standards. Protection of subject safety is the overriding concern in 
the design of clinical trials. In all cases, Merck clinical trials will be conducted in compliance with local and/or 
national regulations and in accordance with the ethical principles that have their origin in the Declaration of Helsinki. 
B. Scope
Such standards shall be endorsed for all clinical interventional investigations sponsored by Merck irrespective of the 
party (parties) employed for their execution (e.g., contract research organizations, collaborative research efforts). This 
Code is not intended to apply to trials which are observational in nature, or which are retrospective. Further, this Code 
does not apply to investigator-initiated trials which are not under the control of Merck.
II. Scientific Issues
A. Trial Conduct
1. Trial Design
Except for pilot or estimation trials, clinical trial protocols will be hypothesis-driven to assess safety, efficacy 
and/or pharmacokinetic or pharmacodynamic indices of Merck or comparator products.  Alternatively, Merck may 
conduct outcomes research trials, trials to assess or validate various endpoint measures, or trials to determine 
subject preferences, etc.  
The design (i.e., subject population, duration, statistical power) must be adequate to address the specific purpose 
of the trial.  Research subjects must meet protocol entry criteria to be enrolled in the trial. 
2. Site Selection
Merck selects investigative sites based on medical expertise, access to appropriate subjects, adequacy of facilities 
and staff, previous performance in Merck trials, as well as budgetary considerations.  Prior to trial initiation, sites 
are evaluated by Merck personnel to assess the ability to successfully conduct the trial.
3. Site Monitoring/Scientific Integrity
Trial sites are monitored to assess compliance with the trial protocol and general principles of Good Clinical 
Practice.  Merck reviews clinical data for accuracy, completeness and consistency. Data are verified versus source 
documentation according to standard operating procedures.  Per Merck policies and procedures, if fraud, 
misconduct or serious GCP-non-Compliance are suspected, the issues are promptly investigated. When necessary, 
the clinical site will be closed, the responsible regulatory authorities and ethics review committees notified and 
data disclosed accordingly. 
B. Publication and Authorship
To the extent scientifically appropriate, Merck seeks to publish the results of trials it conducts.  Some early phase or 
pilot trials are intended to be hypothesis-generating rather than hypothesis testing.  In such cases, publication of 
results may not be appropriate since the trial may be underpowered and the analyses complicated by statistical issues 
of multiplicity.
Merck’s policy on authorship is consistent with the requirements outlined in the ICH-Good Clinical Practice 
guidelines. In summary, authorship should reflect significant contribution to the design and conduct of the trial, 
performance or interpretation of the analysis, and/or writing of the manuscript.  All named authors must be able to 
defend the trial results and conclusions.  Merck funding of a trial will be acknowledged in publications. 


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III. Subject Protection
A. IRB/ERC review
All clinical trials will be reviewed and approved by an independent IRB/ERC before being initiated at each site.  
Significant changes or revisions to the protocol will be approved by the IRB/ERC prior to implementation, except that 
changes required urgently to protect subject safety and well-being may be enacted in anticipation of IRB/ERC 
approval. For each site, the IRB/ERC and Merck will approve the subject informed consent form. 
B. Safety
The guiding principle in decision-making in clinical trials is that subject welfare is of primary importance.  Potential 
subjects will be informed of the risks and benefits of, as well as alternatives to, trial participation. At a minimum, trial 
designs will take into account the local standard of care.  Subjects are never denied access to appropriate medical care 
based on participation in a Merck clinical trial. 
All participation in Merck clinical trials is voluntary.  Subjects are enrolled only after providing informed consent for 
participation.  Subjects may withdraw from a Merck trial at any time, without any influence on their access to, or 
receipt of, medical care that may otherwise be available to them.
C. Confidentiality
Merck is committed to safeguarding subject confidentiality, to the greatest extent possible. Unless required by law, 
only the investigator, sponsor (or representative) and/or regulatory authorities will have access to confidential medical 
records that might identify the research subject by name.  
D. Genomic Research
Genomic Research will only be conducted in accordance with informed consent and/or as specifically authorized by 
an Ethics Committee.
IV. Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive.  It is Merck’s policy to compensate investigators (or the sponsoring 
institution) in a fair manner for the work performed in support of Merck trials.   Merck does not pay incentives to 
enroll subjects in its trials.  However, when enrollment is particularly challenging, additional payments may be made
to compensate for the time spent in extra recruiting efforts.
Merck does not pay for subject referrals.  However, Merck may compensate referring physicians for time spent on 
chart review to identify potentially eligible subjects.
B. Clinical Research Funding 
Informed consent forms will disclose that the trial is sponsored by Merck, and that the investigator or sponsoring 
institution is being paid or provided a grant for performing the trial.  However, the local IRB/ERC may wish to alter 
the wording of the disclosure statement to be consistent with financial practices at that institution.  As noted above, 
publications resulting from Merck trials will indicate Merck as a source of funding.
C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (e.g., to scientific meetings, investigator meetings, etc.) will be 
consistent with local guidelines and practices including, in the U.S., those established by the American Medical 
Association (AMA). 
V. Investigator Commitment
Investigators will be expected to review Merck’s Code of Conduct as an appendix to the trial protocol, and in signing 
the protocol, agree to support these ethical and scientific standards.
* In this document, "Merck" refers to Merck Sharp & Dohme Corp. and Schering Corporation, each of which is a 
subsidiary of Merck & Co., Inc.  Merck is known as MSD outside of the United States and Canada.  As warranted by 
context, Merck also includes affiliates and subsidiaries of Merck & Co., Inc."


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List of Abbreviations
12.2
Abbreviations
Definition
2-hr PMG
2-hour postmeal glucose
AE
adverse experience
AHA
antihyperglycemic agent
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
ASaT
All subject as treated
AST
aspartate aminotransferase
AUC
area under the plasma concentration-time curve
BG
biguanide
BMI
body mass index
BP
blood pressure
CABG
coronary artery bypass grafting
CI
confidence interval
CK
creatine phosphokinase
cLDA
constrained longitudinal data analysis
Cr
creatinine
CSR
clinical Study Report
DILI
drug-induced liver injury
DM
diabetes mellitus
DPP-4
dipeptidyl peptidase-4
ECG
electrocardiogram
ECI
event of clinical interest
eCRF
electronic case report form
EDC
electronic data capture
eGFR
estimated glomerular filtration rate
ERC
ethics review committee
FAS
full analysis set
FDAAA
Food and Drug Administration Amendments Act
FDAMA
Food and Drug Administration Modernization Act
FDC
fix dose combination
FPG
fasting plasma glucose
GCP
Good Clinical Practice
GIP
gastric inhibitory peptide
GLP-1
glucagon-like peptide-1
HAL
hypoglycemia assessment log
HbA1c
hemoglobin A1c (glycosylated hemoglobin A1c)
hCG
human chorionic gonadotropin
HDL-C
high-density lipoprotein cholesterol
HIV
human immunodeficiency virus
IB
Investigator's brochure
ICF
informed consent form
ICH
international conference on harmonisation of technical requirements for registration of 
pharmaceuticals for human use 
IRB
institutional review board
IUD
intrauterine device
IVRS
interactive voice response system


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Abbreviations
Definition
LDH
lactic acid dehydrogenase
LDL-C
Low-density lipoprotein cholesterol
MHLW
Ministry of Health, Labour and Welfare
MI
myocardial infarction
MTT
meal tolerance test
OTC
over-the-counter
PDLC
pre-defined limit of change
PP
per-protocol
PTCA
percutaneous transluminal coronary angioplasty
q.d.
quaque die
QOL
quality of life
RBC
red blood cell
SAE
serious adverse experience
SAP
statistical analysis plan
SD
standard deviation
SGLT2
sodium glucose cotransporter 2
SMBG
self monitoring blood glucose
SOC
system organ classes
SOP
standard operating procedure
SU
sulfonylurea
T2DM
type 2 diabetes mellitus
TSH
thyroid-stimulating hormone
TZD
thiazolidinedione
ULN
upper limit of normal
VEGF
vascular endothelial growth factor
WBC
white blood cell
α-GI
α-glucosidase inhibitor
γ-GTP
γ-glutamyltranspeptidase


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Standard Operating Procedures for Liver Enzyme Elevations
12.3
Every increase in ALT, and/or AST, above the limits described in the protocol is defined as 
clinically significant (i.e., ALT or AST ≥3-times the upper limit of normal [ULN]). In 
addition, when ALT and/or AST levels are elevated beyond the clinical significant margin 
above, the investigators/coordinators must recall the subject, attempt to identify the cause of 
the elevation, and repeat the blood test(s).  Detailed instructions are provided below.
Note:For subjects who have ALT or AST increases (either ALT or AST ≥3-times the ULN) 
with a total bilirubin lab value ≥2-times ULN and, at the same time, the alkaline 
phosphatase lab value is <2-times ULN, please follow the guidance document entitled 
"Event of Clinical Interest (ECI) Guidance for Potential DILI (Drug-Induced Liver Injury) 
in Clinical Trials" located in the Investigator Trial File Binder and refer to the ECI 
guidance in the protocol (Section 7.2.3.2).
For subjects with ALT or AST increases (either ALT or AST ≥3-times the ULN) but who do 
notalso meet the above criteria for both total bilirubin and alkaline phosphatase, the 
process below should be followed.  These events do not qualify as ECIs per protocol (see 
Section 7.2.3.2).
1) Subjects should return to the center within 3 days for the following: (history can be 
obtained over the phone in the interim)
1. Obtain further information.
2. Careful questioning of recent alcohol consumption, including a recent change in 
pattern of alcohol use.
3. Search for drug-related causes of hepatitis and liver injuries (acetaminophen; 
amiodarone; aspirin; chlorpromazine; dantrolene; erythromycin; halothane; isoniazid; 
methyldopa; phenytoin; propylthiouracil; rifampin; sulfonamides; tetracyclines) or 
other new medications.
4. Search for alternative medical causes such as cholelithiasis, recent alcohol 
consumption, history of intercurrent illness (e.g., viral syndrome), hepatitis, or 
potential exposure to viral hepatitis (transfusion).
5. Repeat determination of ALT, AST, total bilirubin, and alkaline phosphatase.
6. Perform serologic tests including: (a) Hepatitis A (IgM); (b) Hepatitis B (surface 
antigen and core IgM); (c) Hepatitis C (antibody).
7. Based upon initial abnormal ALT/AST level:
• If ALT or AST levels are ≥3-times ULN, but ≤5-times ULN, consideration can 
be given to keeping subject on study medication until repeat determination.


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• If ALT or AST levelsare >5-times ULN, subjects should have their study 
medication interrupted immediately.
Note: Once interrupted, reinstatement of therapy must occur only after 
consultation with a Clinical Monitor (SPONSOR or its delegate).
2) Based upon repeat determination (performed within 3 days of initially reported 
abnormal ALT or AST level):
1. If ALT and/or AST levels are <3-times ULN, consultation with a Clinical Monitor 
(SPONSOR or its delegate) is required prior to continuing the subject in the trial.
2. If ALT and/or AST levels are ≥3-times ULN, subjects will be discontinued from 
study medication.
Note:If the repeat determination is still ≥3-times elevated, but has substantially 
decreased (>30% decline) from the initial abnormal value, a second repeat 
should be performed within 3 days of the initial repeat.  If ALT and/or AST levels 
return below the 3-times margin consideration can be given to continue the 
subject in the trial after a discussion with, and approval by, the Clinical Monitor 
(SPONSOR or its delegate).
All persistent elevations in ALT or AST ≥3-times ULN at the completion/discontinuation of 
study medication will warrant follow-up including a repeat blood test within 1 week and until 
complete resolution of the abnormality.


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Anthropometric Measurement
12.4
The following items should be measured in accordance with the following procedures.
If possible, a single staff person will perform the measurements across the study for a given 
subject.
Blood Pressure
12.4.1
A consistent arm should be used across the study for each measurement on a given subject.
[Instrument]
Sphygmomanometer used in routine practice in each site [Mercury 
sphygmomanometer 
(least 
graduation 
of 
2 mm Hg), 
automated 
sphygmomanometer, etc.]
[Procedure]
1)
Measure in duplicate after the subject has been sitting quietly for at least 5 minutes.
2)
Use Korotkoff Phase V for diastolic blood pressure determinations, and read the 
measurement to the nearest even mm Hg in case of using a mercury 
sphygmomanometer. (Reading of last 1 digit should be 0, 2, 4, 6, or 8 mm Hg.  Do not 
round off the last 1 digit)
3)
Continue to measure sitting blood pressure until becoming consecutive measurements 
within 5 mm Hg.  Separate the 2 measurements by 1 ~ 2 minutes.
4)
Record the 2nd measurement when consecutive measurements become within 5 mm Hg 
on the worksheet.
Body Weight
12.4.2
[Instrument]
Scale at each study site
[Clothing]
The subject should go the same condition (i.e., take off the jacket and/or 
socks, etc.) at each measurement, if possible.
[Procedure]
1)
Read the measurements down to one place of decimal. (e.g., 79.4 kg)
2)
Record the measurement (to one place of decimal) on the worksheet.
Height
12.4.3
Some people may have physical conditions that may limit the ability to measure height 
accurately (e.g., complication).  In such cases, height should be measured in accordance with 
the following procedures as much as possible.


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Measure the height at Visit 1 only.
[Instrument]
Scale at each study site
[Clothing]
The subject should remove his/her shoes and be measured bare foot.
[Procedure]
1)
Make the subject stand against the vertical backboard.
2)
Make the subject stand with the heels of their feet on the floor, look straight ahead, and 
put their chin down.
3)
Read the measurements down to one place of decimal. (e.g., 167.5 cm)
4)
Record the measurement (to one place of decimal) on the worksheet.


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Entry of Hypoglycemic Episode into eCRF
12.5
Report from Subject
Investigator’s Judgment
Enter into eCRF
Subjective 
symptom
SMBG
Hypoglycemic 
episode
Adverse 
event
HA
FSG
AE
With
(e.g., 
headache, 
feeling 
hungry)
>70 mg/dL
or
No data
Yes
Yes
X
X 1
“ hypoglycaemia”
No
Yes
Relevant AE term (e.g., 
“headache”)
No
≤70 mg/dL 
-
Yes
X
X
“hypoglycaemia”
No
X
X
Without
≤70 mg/dL
-
Yes
X
X
“asymptomatic 
hypoglycaemia”
No
X
X
HA
: Hypoglycemia Assessment eCRF
FSG : Fingerstick Glucose eCRF
AE
: Adverse Events eCRF
-
: Investigator’s judgment is not needed (SMBG ≤70 mg/dL must be handled as a hypoglycemic 
episode)
1
SMBG value should be entered into FSG form if SMBG value is available.


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Clinical Study Conduct System
12.6
For clinical study conduct system, refer to protocol of Japanese version.


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13.0 SIGNATURES
Sponsor's Representative
13.1
TYPED NAME
TITLE
SIGNATURE
DATE SIGNED
Investigator
13.2
I agree to conduct this clinical trial in accordance with the design outlined in this protocol 
and to abide by all provisions of this protocol (including other manuals and documents 
referenced from this protocol).  I agree to conduct the trial in accordance with generally 
accepted standards of Good Clinical Practice.  I also agree to report all information or data in 
accordance with the protocol and, in particular, I agree to report any serious adverse events 
as defined in Section 7.0 – TRIAL PROCEDURES (Assessing and Recording Adverse 
Events).  I also agree to handle all clinical supplies provided by the Sponsor and collect and 
handle all clinical specimens in accordance with the protocol.  I understand that information 
that identifies me will be used and disclosed as described in the protocol, and that such 
information may be transferred to countries that do not have laws protecting such 
information.  Since the information in this protocol and the referenced Investigator’s 
Brochure is confidential, I understand that its disclosure to any third parties, other than those 
involved in approval, supervision, or conduct of the trial is prohibited.  I will ensure that the 
necessary precautions are taken to protect such information from loss, inadvertent disclosure 
or access by third parties.
TYPED NAME
TITLE
SIGNATURE
DATE SIGNED