A Phase IV, Multicenter, Randomized, Placebo-Controlled, Parallel-Group, Double-Blind Trial and Subsequent Open-Label, Extension Trial to Assess the Safety and Efficacy of Addition of Omarigliptin in Japanese Patients With Type 2 Diabetes Mellitus Who Have Inadequate Glycemic Control on Insulin Monotherapy in Addition to Diet and Exercise Therapy
Phase: PHASE4
Conditions: Type 2 Diabetes Mellitus
Sponsor: Merck Sharp & Dohme LLC

Official Protocol Title: 
NCT number: 
NCT02906709 
Document Date: 
10-Mar-2017
A Phase IV, Multicenter, Randomized, Placebo-Controlled, Parallel-Group, 
Double-Blind Trial and Subsequent Open-Label, Extension Trial to Assess 
the Safety and Efficacy of Addition of Omarigliptin in Japanese Patients 
with Type 2 Diabetes Mellitus Who Have Inadequate Glycemic Control on 
Insulin Monotherapy in Addition to Diet and Exercise Therapy

Product:  MK-3102
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Protocol/Amendment No.: 039-01
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Confidential
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 IV, Multicenter, Randomized, Placebo-Controlled, Parallel-Group, Double-Blind 
Trial and Subsequent Open-Label, Extension Trial to Assess the Safety and Efficacy of 
Addition of Omarigliptin in Japanese Patients with Type 2 Diabetes Mellitus Who Have 
Inadequate Glycemic Control on Insulin Monotherapy in Addition to Diet and Exercise 
Therapy
EudraCT NUMBER:  Not Applicable
 
 
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TABLE OF CONTENTS
SUMMARY OF CHANGES................................................................................................ 10
1.0
TRIAL SUMMARY.................................................................................................. 11
2.0
TRIAL DESIGN........................................................................................................ 11
Trial Design ........................................................................................................... 11
2.1
Trial Diagram........................................................................................................ 13
2.2
3.0
OBJECTIVE(S) & HYPOTHESIS(ES).................................................................. 14
Primary Objective(s) & Hypothesis(es) .............................................................. 14
3.1
Secondary Objective(s) & Hypothesis(es)........................................................... 14
3.2
4.0
BACKGROUND & RATIONALE.......................................................................... 14
Background ........................................................................................................... 14
4.1
Pharmaceutical and Therapeutic Background .................................................... 15
4.1.1
Rationale................................................................................................................ 16
4.2
Rationale for the Trial and Selected Subject Population .................................... 16
4.2.1
Rationale for Dose Selection/Regimen............................................................... 17
4.2.2
Rationale for the Use of Placebo ................................................................. 17
4.2.2.1
4.2.2.1.1
Rationale for the use of placebo for the pre-treatment period .............. 17
4.2.2.1.2
Rationale for the use of placebo for the treatment period..................... 17
Rationale for Duration of Treatment Period ................................................ 17
4.2.2.2
Rationale for Endpoints ...................................................................................... 18
4.2.3
Efficacy Endpoints....................................................................................... 18
4.2.3.1
Safety Endpoints.......................................................................................... 18
4.2.3.2
Future Biomedical Research........................................................................ 18
4.2.3.3
Benefit/Risk ........................................................................................................... 18
4.3
5.0
METHODOLOGY ................................................................................................... 19
Entry Criteria........................................................................................................ 19
5.1
Diagnosis/Condition for Entry into the Trial ...................................................... 19
5.1.1
Subject Inclusion Criteria.................................................................................... 19
5.1.2
Subject Exclusion Criteria .................................................................................. 22
5.1.3
 
 
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Trial Treatment(s) ................................................................................................ 26
5.2
Dose Selection .................................................................................................... 27
5.2.1
Dose Selection (Preparation) ....................................................................... 27
5.2.1.1
Timing of Dose Administration .......................................................................... 27
5.2.2
Administration of study medication............................................................. 27
5.2.2.1
Timing of Dosing of Pre-Treatment Period, and Treatment Period
5.2.2.2
Medication on Days of Study Visits............................................................ 28
Handling of Missed Doses........................................................................... 28
5.2.2.3
Trial Blinding...................................................................................................... 28
5.2.3
Randomization or Treatment Allocation............................................................ 28
5.3
Stratification.......................................................................................................... 29
5.4
Concomitant Medications/Vaccinations (Allowed & Prohibited).................... 29
5.5
Prohibited medications........................................................................................ 29
5.5.1
Limited Concomitant Medications ..................................................................... 30
5.5.2
Rescue Medications & Supportive Care............................................................. 30
5.6
Rescue treatment (up-titration of insulin)........................................................... 30
5.6.1
Down-titration of insulin..................................................................................... 31
5.6.2
Diet/Activity/Other Considerations..................................................................... 31
5.7
Diet therapy......................................................................................................... 31
5.7.1
Exercise therapy.................................................................................................. 31
5.7.2
Insulin therapy .................................................................................................... 31
5.7.3
Subject Withdrawal/Discontinuation Criteria................................................... 32
5.8
Subject Replacement Strategy............................................................................. 34
5.9
Beginning and End of the Trial ........................................................................... 35
5.10
Clinical Criteria for Early Trial Termination ................................................... 35
5.11
6.0
TRIAL FLOW CHART ........................................................................................... 36
7.0
TRIAL PROCEDURES ........................................................................................... 39
Trial Procedures ................................................................................................... 39
7.1
Administrative Procedures.................................................................................. 39
7.1.1
Informed Consent......................................................................................... 39
7.1.1.1
7.1.1.1.1
General Informed Consent.................................................................... 39
 
 
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7.1.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research................................................................................................ 39
Inclusion/Exclusion Criteria ........................................................................ 40
7.1.1.2
7.1.1.2.1
Contraception........................................................................................ 40
Subject Identification Card .......................................................................... 40
7.1.1.3
Medical History ........................................................................................... 40
7.1.1.4
Prior and Concomitant Medications Review ............................................... 40
7.1.1.5
7.1.1.5.1
Prior Medications.................................................................................. 40
7.1.1.5.2
Concomitant Medications..................................................................... 41
Assignment of Screening Number............................................................... 41
7.1.1.6
Assignment of Treatment/Randomization Number ..................................... 41
7.1.1.7
Trial Compliance (Medication/Diet/Activity/Other) ................................... 41
7.1.1.8
Diet and exercise therapy counseling .......................................................... 41
7.1.1.9
Patient Registration...................................................................................... 42
7.1.1.10
Instruction for recording of patient’s log and dispensing ............................ 42
7.1.1.11
Collection and review of patient’s log ......................................................... 42
7.1.1.12
Providing SMBG devise and instruction ..................................................... 42
7.1.1.13
Instructions on hypoglycemic symptoms, management, and recording 
7.1.1.14
of HAL......................................................................................................... 43
Dispensing HAL .......................................................................................... 43
7.1.1.15
Instruction to discontinue oral AHA (except for insulin agents)................. 43
7.1.1.16
Clinical Procedures/Assessments........................................................................ 43
7.1.2
Confirmation of Diet and exercise therapy.................................................. 43
7.1.2.1
Measuring of Vital signs.............................................................................. 43
7.1.2.2
SMBG at each visits..................................................................................... 44
7.1.2.3
Review of HAL and assessment of hypoglycemia ...................................... 44
7.1.2.4
12 lead ECG................................................................................................. 44
7.1.2.5
Assessment for necessity of rescue treatment (up-titration of insulin 
7.1.2.6
agents).......................................................................................................... 44
Laboratory Procedures/Assessments .................................................................. 44
7.1.3
Laboratory efficacy Evaluations (Hematology and blood chemistry)......... 44
7.1.3.1
Laboratory safety tests (Hematology, blood chemistry, urinalysis and 
7.1.3.2
other)............................................................................................................ 44
Future Biomedical Research Samples ......................................................... 46
7.1.3.3
 
 
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Other Procedures................................................................................................. 46
7.1.4
Withdrawal/Discontinuation........................................................................ 46
7.1.4.1
7.1.4.1.1
Withdrawal From Future Biomedical Research ................................... 46
Subject Blinding/Unblinding ....................................................................... 46
7.1.4.2
Calibration of Critical Equipment................................................................ 47
7.1.4.3
Visit Requirements.............................................................................................. 47
7.1.5
Screening...................................................................................................... 48
7.1.5.1
Pre-Treatment Period................................................................................... 49
7.1.5.2
Treatment Period.......................................................................................... 50
7.1.5.3
Post trial ....................................................................................................... 51
7.1.5.4
Assessing and Recording Adverse Events .......................................................... 51
7.2
Definition of an Overdose for This Protocol and Reporting of Overdose to 
7.2.1
the Sponsor.......................................................................................................... 52
Reporting of Pregnancy and Lactation to the Sponsor ....................................... 53
7.2.2
Immediate Reporting of Adverse Events to the Sponsor.................................... 53
7.2.3
Serious Adverse Events ............................................................................... 53
7.2.3.1
Events of Clinical Interest............................................................................ 54
7.2.3.2
Guidance on Adverse Events Related to Glycemia ............................................ 55
7.2.4
Hyperglycemia............................................................................................. 55
7.2.4.1
Hypoglycemia.............................................................................................. 55
7.2.4.2
Evaluating Adverse Events ................................................................................. 55
7.2.5
Sponsor Responsibility for Reporting Adverse Events ...................................... 58
7.2.6
TRIAL GOVERNANCE AND OVERSIGHT ................................................... 58
7.3
Clinical Adjudication Committee ....................................................................... 58
7.3.1
8.0
STATISTICAL ANALYSIS PLAN ........................................................................ 58
Statistical Analysis Plan Summary ..................................................................... 59
8.1
Responsibility for Analyses/In-House Blinding ................................................. 60
8.2
Hypotheses/ Estimation ........................................................................................ 60
8.3
Analysis Endpoints ............................................................................................... 60
8.4
Efficacy Endpoints.............................................................................................. 60
8.4.1
Safety Endpoints ................................................................................................. 61
8.4.2
Analysis Populations............................................................................................. 62
8.5
 
 
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Efficacy Analysis Populations ............................................................................ 62
8.5.1
Safety Analysis Populations ............................................................................... 63
8.5.2
Statistical Methods................................................................................................ 63
8.6
Efficacy Analysis ................................................................................................ 63
8.6.1
Safety Analysis ................................................................................................... 66
8.6.2
Interim Analyses ................................................................................................... 68
8.7
Multiplicity ............................................................................................................ 68
8.8
Sample Size and Power Calculations .................................................................. 69
8.9
Subgroup Analyses and Effect of Baseline Factors ........................................... 70
8.10
Compliance (Medication Adherence).................................................................. 70
8.11
Extent of Exposure................................................................................................ 71
8.12
9.0
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES ................................................................................................................. 71
Investigational Product ........................................................................................ 71
9.1
Packaging and Labeling Information ................................................................. 72
9.2
Clinical Supplies Disclosure................................................................................. 72
9.3
Storage and Handling Requirements.................................................................. 72
9.4
Discard/Destruction/Returns and Reconciliation .............................................. 72
9.5
10.0
ADMINISTRATIVE AND REGULATORY DETAILS....................................... 73
Confidentiality....................................................................................................... 73
10.1
Confidentiality of Data ....................................................................................... 73
10.1.1
Confidentiality of Subject Records ..................................................................... 73
10.1.2
Confidentiality of Investigator Information........................................................ 73
10.1.3
Confidentiality of IRB/IEC Information............................................................. 74
10.1.4
Compliance with Financial Disclosure Requirements....................................... 74
10.2
Compliance with Law, Audit and Debarment ................................................... 74
10.3
Compliance with Trial Registration and Results Posting Requirements ........ 76
10.4
Quality Management System............................................................................... 76
10.5
Data Management................................................................................................. 76
10.6
Publications ........................................................................................................... 77
10.7
11.0
LIST OF REFERENCES......................................................................................... 78
 
 
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12.0
APPENDICES........................................................................................................... 80
Merck Code of Conduct for Clinical Trials........................................................ 80
12.1
Collection and Management of Specimens for Future Biomedical 
12.2
Research................................................................................................................. 82
List of Abbreviations ............................................................................................ 86
12.3
Measurement of blood pressure, body weight and height ................................ 88
12.4
Blood Pressure .................................................................................................... 88
12.4.1
Body Weight ....................................................................................................... 88
12.4.2
Height.................................................................................................................. 88
12.4.3
Standard Operating Procedures for Liver Enzyme Elevations........................ 90
12.5
Entry of Hypoglycemic Episode into eCRF........................................................ 92
12.6
Clinical Study Conduct System ........................................................................... 93
12.7
13.0
SIGNATURES........................................................................................................... 94
Sponsor's Representative ..................................................................................... 94
13.1
Investigator............................................................................................................ 94
13.2
 
 
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LIST OF TABLES
    
Table 1 Laboratory Exclusion Criteria (Visit 1/Screening)................................................... 24
Table 2  Laboratory Exclusion Criteria (Visit 3/Week -2) ..................................................... 25
Table 3  Trial Treatments........................................................................................................ 26
Table 4  Rescue criteria........................................................................................................... 30
Table 5  Discontinuation criterion of eGFR ........................................................................... 34
Table 6  Laboratory Efficacy Tests (Hematology, Blood chemistry)..................................... 44
Table 7  Laboratory Safety Tests (Hematology, Blood Chemistry, Urinalysis and Other).... 45
Table 8  Evaluating Adverse Events....................................................................................... 56
Table 9  Efficacy Endpoints.................................................................................................... 61
Table 10  Analysis Strategy for Key Efficacy Variables........................................................ 65
Table 11 Analysis Strategy for Safety Parameters ................................................................ 67
Table 12  Definitions of Study Periods................................................................................... 71
Table 13  Product Descriptions............................................................................................... 71
 
 
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LIST OF FIGURES
          
Figure 1 Trial design.............................................................................................................. 13
Figure 2  Selection of subject group (Visit 1/Screening)........................................................ 49
 
 
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SUMMARY OF CHANGES
PRIMARY REASON(S) FOR THIS AMENDMENT:
Section 
Number (s)
Section Title(s)
Description of Change (s)
Rationale
N/A
N/A
N/A
To correct translation errors
in Exclusion 
Criteria #3 and #32 related to the word 
hypoglycemia that are present in the Japanese 
version of P039-00. An incorrect Japanese 
word that means ‘symptom of hypoglycemia’ 
was used instead of the intended word 
‘hypoglycemia’. These errors are not present in 
the English version of P039-00.
ADDITIONAL CHANGE(S) FOR THIS AMENDMENT:
Section 
Number (s)
Section Title (s)
Description of Change (s)
Rationale
5.5.1
Prohibited medications
(1) ‘TZD’ was added as Item e) 
and the subsequent items were 
modified to f) to j).
Clear obvious discrepancy
5.8
Subject 
Withdrawal/Discontinuation 
Criteria
Added ‘progressive’ in the last 
sentence of a) Hypoglycemia 
(1).
Typographic error
7.1.1.11
Instruction for recording of 
patient’s log and dispensing
Deleted ‘the day after’ to clarify 
the timing from when 
the 
patient’s log is recorded.
Typographic error
 
 
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1.0 TRIAL SUMMARY
Abbreviated Title
Omarigliptin Phase IV Study
-Omarigliptin Add-on to Insulin in Japanese T2DM
Sponsor Product Identifiers
MK-3102
Omarigliptin
Trial Phase
Phase IV
Clinical Indication
Not Applicable
Trial Type
Interventional
Type of control
Placebo
Route of administration
Oral
Trial Blinding
Double-blind
Treatment Groups
Phase A; Omarigliptin 25 mg once weekly (q.w.) or placebo
Phase B; Omarigliptin 25 mg once weekly (q.w.)
Number of trial subjects
Approximately 180 subjects will be enrolled.
Estimated duration of trial
The Sponsor estimates that the trial will require approximately 
23 months from the time the first subject signs the informed consent 
until the last subject’s last study-related phone call or visit.
Duration of Participation
Each subject will participate in the trial for up to 71 weeks from the 
time the subject signs the Informed Consent Form through the final 
contact.  After a screening period of up to 2 weeks followed by a pre-
treatment period of 2 or 10 weeks, each subject will be receiving 
assigned treatment for approximately 16 weeks (Phase A) and 
36 weeks (Phase B).  After the end of treatment each subject will be 
followed for 21 days.
A list of abbreviations used in this document can be found in Section 12.3.
2.0 TRIAL DESIGN
Trial Design
2.1
This is a randomized, placebo-controlled, parallel-group, multi-site, double-blind trial and 
subsequent open-label, extension trial of MARIZEV®/omarigliptin (MK-3102) in Japanese 
subjects with type 2 diabetes mellitus (T2DM) who have inadequate glycemic control on 
insulin monotherapy in addition to diet and exercise therapy, to be conducted in conformance 
with Good Clinical Practices (GCP) and Good Post-marketing Study Practice.
Note: In the pre-treatment period, ‘Group A’ and ‘Group B’ are used to distinguish two 
groups of subjects: Subjects on oral anti-hyperglycemic agent (AHA) at Visit 1/Screening 
who require wash-out of the oral AHA from Visit 2/Week-10 (Group A) and subjects that are 
not on oral AHA at screening and therefore do not require washout (Group B).  See the text 
provided below and Trial Diagram in 2.2 for the detail.
This trial consists of a screening period of up to 2 weeks, a pre-treatment period of 2 weeks 
or 10 weeks (which includes 2-week single-blind placebo run-in period), and a treatment 
period of 52 weeks.  Subjects on insulin in combination with an oral AHA, (referred to as 
Group A) will have a pre-treatment wash-out period of 10 weeks (to wash-out the oral AHA), 
Randomization Ratio
Subjects will be randomized in a 2:1 ratio to omarigliptin 25 mg once 
weekly (q.w.) or placebo and stratified by use of oral AHA at 
Visit 1/Screening
 
 
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and subjects on insulin in monotherapy with no other AHAs (referred to as Group B) will 
have a pre-treatment period (single-blind placebo run-in period) of 2 weeks. The treatment 
period is composed of a 16-week double-blind period (Phase A) and a 36-week open-label 
period (Phase B).  Randomization will be stratified based on their use of an oral AHA at 
Visit 1/Screening (insulin + oral AHA or insulin monotherapy).  
After the 2-week, single-blind, placebo run-in period, subjects will be randomized in a 2:1 
ratio to receive either omarigliptin 25 mg once weekly (q.w.) or placebo, and they will take 
one tablet of trial medication (Omarigliptin 25 mg tablet or matching placebo tablet) once 
weekly (q.w.) orally for 16 weeks in a double-blind manner (Phase A). Subsequently in 
Phase B, all subjects will take one open-label tablet of omarigliptin 25 mg once weekly 
(q.w.) orally for 36 weeks.
Approximately 180 subjects will be randomized.  The target randomized population includes 
Japanese patients ≥20 years of age with T2DM who have inadequate glycemic control on 
insulin monotherapy in addition to diet and exercise therapy, with hemoglobin A1c (HbA1c)
≥7.5% and ≤10.0% at Visit 3/Week -2. 
Subjects on pre-mixed/fixed ratio combination (content percentage of rapid-acting or ultra 
rapid-acting insulin is lower than or equal to 30%), intermediate or long-acting insulin
monotherapy are eligible to participate.
Consistent dosage and administration schedule of insulin will be used during the trial. In 
Phase A (double-blind period), the dosage must be kept at the dosage used at 
Visit 1/Screening, unless the subject meets hypoglycemia criteria for down-titration, or 
glycemic rescue criteria for up-titration of insulin.  During Phase B (open-label period), the 
investigator can modify dose of insulin as clinically required for appropriate glycemic 
control, 
in 
addition 
to 
insulin 
adjustment 
based 
on 
the 
protocol-specified 
rescue/hypoglycemia criteria.
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.
R = Randomization
*1
  During Phase B (open-label period), dosage adjustments of insulin will be allowed as clinically appropriate to manage the subject’s 
glycemic control.  
*2
  Subjects in Group B proceeds to Visit 3/Week -2 after Visit 1/Screening, skipping Visit 2/Week -10.
*3
  If subjects in Group B performed the procedures of Visit 3/Week -2 within 2 weeks after Visit 1/Screening, HbA1c measurement is 
not needed at Visit 3/Week -2.  The subjects may be deemed to meet the HbA1c criterion of Visit 3/Week -2 by HbA1c value of 
Visit 1/Screening.
*4
  Visit 4/Day 1/Randomization is baseline.
Figure 1 Trial design
 
 
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3.0 OBJECTIVE(S) & HYPOTHESIS(ES)
In Japanese patients with T2DM who have inadequate glycemic control on insulin 
monotherapy in addition to diet and exercise therapy:
Primary Objective(s) & Hypothesis(es)
3.1
1. Objective:  To assess the efficacy of omarigliptin 25 mg q.w. compared to placebo 
based upon change from baseline in HbA1c at Week 16 [Phase A (double-blind 
period)].
Hypothesis:  Omarigliptin 25 mg q.w. provides greater reduction in HbA1c 
compared with placebo as assessed by change from baseline to Week 16 [Phase A 
(double-blind period)].
2. Objective:  To assess the safety and tolerability of omarigliptin 25 mg q.w. through 
16 weeks [Phase A (double-blind period)].
3. Objective:  To assess the safety and tolerability of omarigliptin 25 mg q.w. for up to 
52 weeks [Phase A (double-blind period) and Phase B (open-label period)].
Secondary Objective(s) & Hypothesis(es)
3.2
[Phase A (double-blind period)]
1. Objective:  To assess the efficacy of omarigliptin 25 mg q.w. compared to placebo 
based upon change from baseline in fasting plasma glucose (FPG) at Week 16.
Hypothesis:  Omarigliptin 25 mg q.w. provides greater reduction in FPG compared 
with placebo as assessed by change from baseline to Week 16.
2. Objective: To assess the efficacy of omarigliptin 25 mg q.w. compared to placebo 
based upon proportion to goal of HbA1c <7.0% or <6.5% at Week 16.
3. Objective: To assess the efficacy of omarigliptin 25 mg q.w. compared to placebo 
based upon change from baseline in 1, 5-anhydroglucitol (1, 5-AG) at Week 16.
[Phase A (double-blind period) and Phase B (open-label period)]
4. Objective: To assess the efficacy of omarigliptin 25 mg q.w. for up to 52 weeks on 
glycemic control parameters (change from baseline in HbA1c and FPG, and 
proportion to goal of HbA1c <7.0% or <6.5%). 
4.0 BACKGROUND & RATIONALE
Background
4.1
Refer to the approved labeling for information on omarigliptin (MK-3102).
 
 
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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) [1] [2].  T2DM, 
which accounts for more than 95% of DM [2], is associated developing with environmental 
factors, aging and several genetic factors [1].  Chronic hyperglycemia contributes to the 
development of diabetic complications such as retinopathy, nephropathy, neuropathy and 
atherosclerosis, and significantly poor quality of life (QOL) of patients with DM [1].
It is estimated that 415 million people worldwide (8.8% of adults) have DM in 2015, and the 
number of people with the disease is predicted to rise to 642 million by 2040 (Approximately 
55% increase compared to 2015) [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, Labor 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].
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 AHA such as sulfonylureas (SU), glinides, 
biguanides (BGs), thiazolidinediones (TZD), α-glucosidase inhibitors (α-GI), 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].
In 2013, proportion of the T2DM patients who received insulin (insulin monotherapy or co-
therapy of insulin and oral AHAs) is approximately 21.6% in Japan. This percentage is the 
second highest following the percentage of the patients (59.4%) who were treated with any 
oral AHAs only, indicating that insulin treatment is commonly used in Japan [5].  When 
glycemic control is inadequately treatment with insulin monotherapy, up-titration of insulin 
or insulin intensification therapy will be administered to improve hyperglycemia after eating.  
However, it is considered as barrier to adequate glycemic control since it may cause risks of 
increasing of hypoglycemia, or it may cause increasing burden of frequently injection of 
insulin.  On the other hand, combination with insulin and oral AHAs (SUs, BGs, TZD, α-GI, 
DPP-4 inhibitors) will show improving of glycemic control or decreasing insulin totally 
dosage [2].  
DPP-4 inhibitors such as omarigliptin improve glycemic control in subjects with T2DM by
increasing insulin secretion, mediated by an enhancement of the "incretin" axis. Incretins,
 
 
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which are gut-derived hormones that include GLP-1 and glucose-dependent insulinotropic 
peptide (GIP), are endogenous insulin secretagogues that act in a glucose-dependent manner 
to stimulate insulin secretion [6, 7, 8 and 9]. Following a meal, incretins are released from 
intestinal cells into the circulation. Both GLP-1 and GIP stimulate insulin release; in addition, 
GLP-1 suppresses glucagon release [9].
Therapies that target the incretin axis, including DPP-4 inhibitors such as omarigliptin, have
several potential advantages over conventional insulin secretagogues such as SUs. First, as 
noted above, incretin stimulation of insulin release is glucose-dependent. For this reason, the 
risk of hypoglycemia when DPP-4 inhibitors are administered as monotherapy or in 
combination with agents not known to cause hypoglycemia is low. Second, DPP-4 inhibitors 
have generally neutral effects on body weight, whereas SUs are associated with an increase 
in body weight [10].
Omarigliptin is unlike the presently marketed DPP-4 inhibitors that are administered once or 
twice daily, omarigliptin has a half-life (t1/2) that supports once-weekly dosing.  The 
efficacy, safety, and tolerability of omarigliptin 25 mg once weekly was evaluated in two 
Japanese studies (in monotherapy and as add-on therapy to 5 classes of AHA) in patients 
with T2DM.  In the double-blind period of Japan phase III placebo- and sitagliptin-controlled 
monotherapy study (P020) omarigliptin 25 mg once-weekly demonstrated superiority to 
placebo and non-inferiority to sitagliptin 50 mg once-daily in change from baseline in HbA1c 
at Week 24. When administered omarigliptin 25 mg once-weekly for up to 52 weeks, 
omarigliptin achieved a sustained effect with generally safe and well tolerated profile. In the 
double-blind period of Japan phase III add-on to oral AHA study (P015), omarigliptin 25 mg 
once weekly was added-on to other classes of oral AHA monotherapy with different 
mechanisms of action likely to be used clinically in Japan including SUs, glinides, BGs, TZD, 
or α-GI. As combination with all of the aforementioned AHA classes, the change from 
baseline in HbA1c at Week 24 with the addition of omarigliptin 25 mg was superior to the 
addition of placebo. When administered omarigliptin 25 mg once-weekly for up to 52 weeks, 
omarigliptin achieved a sustained effect with generally safe and well tolerated profile.
Based on above results, omarigliptin was launched in the market in Japan in November 26 
2015, for the treatment of T2DM.
As indicated above, the addition of omarigliptin to the subjects with T2DM who received 
insulin therapy will be anticipated to show good efficacy and safety profile.
Rationale
4.2
Rationale for the Trial and Selected Subject Population
4.2.1
The trial is a randomized, placebo-controlled, parallel-group, multicenter and 16 weeks of 
double-blinded trial, and subsequent of 36 weeks open-label extension trial of omarigliptin in 
Japanese subjects with T2DM who have inadequate glycemic control on insulin monotherapy 
in addition to diet and exercise therapy.  
Recently, insulin self-injection is widely used for T2DM in addition to type 1 DM since 
environment of insulin therapy is dramatically improved by insulin formulation, devise was 
improved and/or self-monitoring blood glucose (SMBG) was familiarized. Additionally, 
insulin therapy is widely used combination with variant DPP-4 inhibitors [1] [2].
 
 
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Omarigliptin was launched in November 2015, and it is anticipated to be used with insulin 
therapy similar to other marketed DPP-4 inhibitors. However, a clinical trial in which 
omarigliptin and insulin are used in combination to assess safety and efficacy has not yet 
been conducted.  
Based on the above, the trial will be conducted as one of pharmacovigilance activities and 
investigation/study for assessment of efficacy in order to examine the safety and efficacy of 
omarigliptin, weekly DPP-4 inhibitor, in Japanese subjects with T2DM who have inadequate 
glycemic control on insulin monotherapy.
Rationale for Dose Selection/Regimen
4.2.2
Dosage and administration of omarigliptin was approved in Japan as “usually, for adults, 
25 mg of omarigliptin is orally administrated once weekly”.  In this study, the dosage and 
administration is set as omarigliptin 25 mg per week according to the Japan Label.
Rationale for the Use of Placebo
4.2.2.1
4.2.2.1.1 Rationale for the use of placebo for the pre-treatment period
To exclude subjects who are unlikely to comply with the administration of study drug before 
entry into the treatment period, a 2-week placebo run-in period is designed into the pre-
treatment period.
4.2.2.1.2 Rationale for the use of placebo for the treatment period
In addition to comparison between pre-dose and post-dose, comparison between omarigliptin 
25 mg q.w. group and placebo group enables an exclusion of influences of the subject 
population, changes over time, and other factors, and an accurate characterization of the 
glycemic control potential of omarigliptin.  In addition, the variability in any measurements 
in patients with T2DM requires a placebo group to adequately characterize any potential 
positive/negative effects of omarigliptin in patients with T2DM.  Considering the importance 
of this study in adequately characterizing the efficacy and safety of omarigliptin for 16 weeks, 
the placebo group is designed into the treatment period.
Rationale for Duration of Treatment Period
4.2.2.2
To assess the long-term safety of omarigliptin when administered with insulin, the treatment 
period is defined as 52 weeks based on the “Guideline on Clinical Evaluation Methods for 
Oral Hypoglycemic Agents”, MHLW Pharmaceutical and Food Safety Bureau (PFSB), Draft,
19th May 2014 [11](hear after “Guideline draft”).  For efficacy assessment, the Guideline
draft [11] recommends having 12-24 weeks double-blinded period in which dosage and 
administration of insulin is maintained in principle.  The rationales of 16 weeks for the 
double-blinded placebo-controlled period for the study are followings; (1) based on the 
results of previous studies with omarigliptin conducted in Japan, 16 weeks will provide 
sufficient time to observe the maximal reduction in HbA1c with omarigliptin and (2) it 
minimizes the duration of the use of placebo. 
 
 
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Rationale for Endpoints
4.2.3
Efficacy Endpoints
4.2.3.1
HbA1c, the primary endpoints, is recommended as a parameter during the double-blind 
period (during the period dosage and administration of insulin shall be stable) in long-term 
trial of co-administration of insulin and oral AHAs in Guideline draft [11].  
The Treatment Guide for Diabetes [1] states that HbA1c is an important parameter of 
glycemic control in patients, and the evaluation should be complemented with FPG etc.  
Based on the above, the primary efficacy endpoint is change from baseline in HbA1c, the 
secondary efficacy endpoint is change from baseline in FPG. 
In addition, 1, 5-AG reflects postprandial hyperglycemia, therefore, change from baseline in 
1, 5-AG is added as a secondary efficacy endpoint.
Safety Endpoints
4.2.3.2
The following endpoints will be collected to assess the safety of omarigliptin when co-
administered with insulin.

Adverse events (including hypoglycemia)

Vital signs (body weight, blood pressure, and pulse rate)

Laboratory tests

Electrocardiogram (ECG)
Future Biomedical Research
4.2.3.3
The Sponsor will conduct Future Biomedical Research on specimens consented for future 
biomedical research during this clinical trial.  This research may include genetic analyses 
(DNA), gene expression profiling (RNA), proteomics, metabolomics (serum, plasma) and/or 
the measurement of other analytes, depending on which specimens are consented for future 
biomedical research.
Such research is for biomarker testing to address emergent questions not described elsewhere 
in the protocol (as part of the main trial) and will only be conducted on specimens from 
appropriately consented subjects. The objective of collecting/retaining specimens for Future 
Biomedical Research is to explore and identify biomarkers that inform the scientific 
understanding of diseases and/or their therapeutic treatments. The overarching goal is to use 
such information to develop safer, more effective drugs/vaccines, and/or to ensure that 
subjects receive the correct dose of the correct drug/vaccine at the correct time.  The details 
of this Future Biomedical Research sub-trial are presented in Section 12.2 – Collection and 
Management of Specimens for Future Biomedical Research.
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.
 
 
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Additional details regarding specific benefits and risks for subjects participating in this 
clinical trial may be found in the accompanying approved labeling and Informed Consent 
documents.
5.0 METHODOLOGY
Entry Criteria
5.1
Diagnosis/Condition for Entry into the Trial
5.1.1
Male or female Japanese subjects with T2DM at least 20 years of age who are have 
inadequate glycemic control on insulin monotherapy with or without single oral AHA 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 (ICF)
3) Meet all of following criteria for Group A or B at Visit 1/Screening:
Group A (pre-treatment period is 10 weeks)
(1) Are currently treated with diet and exercise therapy, AND
(2) Have been on a stable dosage and administration of insulin (8 to 40 units/day) 
for 4 weeks or longer, AND
<Note> Insulin will be administered during the trial as monotherapy of pre-
mixed insulin/fixed ratio combination of insulin (content percentage of rapid-
acting or ultra rapid-acting insulin is lower than or equal to 30%), 
intermediate or long-acting insulin.  If a subject is treated with the insulin 
monotherapy on the consent date, but the dosage of insulin was modified 
within 4 weeks before on the consent date, it can be allowed to postpone 
Visit 1/Screening until the subject meets the requirement.  In this case, the 
type of insulin, and the dosage and administration should not be 
changed/modified from those on the consent date.
(3) Have been on a single oral AHA, AND
<Note> Wash-out from multiple oral AHAs is not allowed in the trial.
(4) Are not on any injectable AHA, except insulin monotherapy, AND
(5) HbA1c ≥7.0% and ≤9.0%
Group B (pre-treatment period is 2 weeks)
(1) Are currently treated with diet and exercise therapy, AND
 
 
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(2) Have been on a stable dosage and administration of insulin (8 to 40 units/day) 
for 10 weeks or longer, AND
<Note> Insulin will be administered during the trial as monotherapy of pre-
mixed insulin/fixed ratio combination of insulin (content percentage of rapid-
acting or ultra rapid-acting insulin is lower than or equal to 30%), 
intermediate or long-acting insulin.
If a subject is treated with the insulin 
monotherapy on the consent date, but the dosage of insulin was modified 
within 10 weeks before on the consent date, it can be allowed to postpone 
Visit 1/Screening until the subject meets the requirement.  In this case, the 
type of insulin, and the dosage and administration should not be 
changed/modified from those on the consent date.
(3) Have not been on any additional AHAs (except for insulin monotherapy) in 
the past 8 weeks, AND
(4) HbA1c ≥7.5% and ≤10.0%
4) Have a body mass index (BMI) >18 kg/m2 and <40 kg/m2
5) Meets one of the following criteria:
(1) Subject is a male
(2) Subject 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/Screening.
(3) Subject 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 
21 days after the last dose of study medication. Acceptable methods of 
contraception include:
(a) Use of double-barrier methods; diaphragm with spermicide and 
a condom.
(b) Use of hormonal contraception (any registered and marketed 
contraceptive agent
that contains an estrogen and/or a 
progestational agent [including oral, subcutaneous, intrauterine 
and intramuscular agents, and cutaneous patch]) with one of 
the 
following: 
diaphragm 
with 
spermicide; 
condom; 
vasectomy; or intrauterine device (IUD).
(c) Use of an IUD with one of the following: condom; diaphragm 
with spermicide; vasectomy; or hormonal contraception (see 
above).
 
 
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(d) Vasectomy with one of the following: diaphragm with 
spermicide; condom; IUD; or hormonal contraception (see 
above).
6) Understand the study procedures, alternative treatments available, and risks involved 
with the study, and voluntarily agrees to participate by giving written informed 
consent. The subject may also provide consent for Future Biomedical Research
(FBR). However, the subject may participate in the main trial without participating in 
FBR.
At Visit 3/Week -2
7) Be treated with diet and exercise therapy ≥39 days (6 weeks -3 days)
<Note> See Section 6.0 trial flow chart for scheduling Visit 3/Week -2.  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].
8) Be on a stable dosage and administration of insulin ≥67 days (10 weeks -3 days)
9) Not be on other AHAs except for insulin monotherapy ≥53 days (8 weeks -3 days)
10) Meet all following glycemic criteria at Visit 3/Week -2
(1) HbA1c ≥7.5% and ≤10.0%
<Note> If subjects in Group B performed the procedures of Visit 3/Week -2
within 2 weeks after Visit 1/Screening, HbA1c measurement is not needed at 
Visit 3/Week -2.  The subject may be deemed to meet the HbA1c criterion of 
Visit 3/Week -2 by HbA1c value of Visit 1/Screening
(2) FPG ≥126 mg/dL and ≤230 mg/dL
<Note> FPG may be re-tested once upon the investigators discretion if he/she 
believes that the value does not reflect the subject’s recent glycemic control.
At Visit 4/Day 1/Randomization
11) Be treated with diet and exercise therapy ≥53 days (8 weeks -3 days)
<Note> See Section 6.0 trial flow chart for scheduling Visit 4/Day 1/Randomization.  
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].
12) Be on a stable dosage and administration of insulin ≥81 days (12 weeks -3 days)
13) Not be on AHAs except for insulin monotherapy ≥67 days (10 weeks -3 days)
14) Have 100% compliance with study medication (placebo) which is confirmed by 
counting remaining tablets at the trial site, and Have ≥85% compliance with insulin
during the single-blind placebo run-in period (From the day at Visit 3/Week -2 to the 
day before Visit 4/Day 1/Randomization).
 
 
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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.
At Visit 1/Screening
Criteria related to Diabetes
1) Has type 1 DM or has a history of diabetic ketoacidosis.
2) Has a history of being administered any of the following AHAs including fixed 
dose combination (FDC) containing the following ingredients:
(1) TZD: within 12 weeks prior to Visit 1/Screening
(2) GLP-1 receptor agonists: within 12 weeks prior to Visit 1/Screening
(3) Omarigliptin (including placebo for treatment period): any time
<Note> Subjects who have previously participated in clinical studies with 
omarigliptin but were not enrolled into the active treatment period (i.e., only 
took single-blinded placebo during the observation period) may be eligible 
to participate in the trial.
3) Has history of severe hypoglycemia with coma or loss of consciousness, or for 
whom hypoglycemia was observed greater or equal to two times per week within 
8 weeks prior to Visit 1/Screening.
Requiring Specific Treatments
4) Is currently participating in or has participated in another study with an 
investigational
compound 
or 
device 
within 
the 
prior 
12 weeks 
of 
Visit 1/Screening and does not agree to refrain from participating in any other 
study while participating in this study.
<Note> A subject who has participated in a non-interventional study may be 
enrolled.
5) Has undergone a surgical procedure within 8 weeks prior to Visit 1/Screening or 
has planned major surgery during the study.
<Note> A subject who has undergone minor surgery within the prior 8 weeks and 
is fully recovered or a subject who has planned minor surgery may participate. 
Minor surgery is defined as a surgical procedure involving local anesthesia.
 
 
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6) Receives a following medication at unstable dosage and administration:
(1) Lipid-lowering medication: within 4 weeks prior to Visit 1/Screening
(2) Thyroid hormone replacement therapy : 
within 
6 weeks 
prior 
to 
Visit 1/Screening
7) Is currently on or likely to require treatment with a prohibited medication (refer to 
5.5.1), and/or subject has unstable complication such as he/she is likely to require 
a new treatment and/or adjustment with a limited concomitant medication.
Concomitant Disease of Organs and Systems
8) Has poorly controlled hypertension defined as systolic blood pressure of 
≥160 mmHg or diastolic blood pressure of ≥90 mmHg and blood pressure is 
unlikely to be within these limits by Visit 3/Week -2 with an adjustment in anti-
hypertensive medication (See section 5.5.2).
<Note> Investigators are encouraged to maximize blood pressure control. 
Subject may have blood pressure medications adjusted and be enrolled if repeat 
blood pressure measurement no longer meets exclusion criterion.
9) Has a medical history of active liver disease (other than non-alcoholic hepatic
steatosis), including chronic active hepatitis B or C (assessed by medical history),
primary biliary cirrhosis, or symptomatic gallbladder disease.
10) Has human immunodeficiency virus (HIV) as assessed by medical history.
11) Has had new or worsening signs or symptoms of coronary heart disease or 
congestive heart failure within the past 3 months, or has any of the following 
disorders within the past 3 months:
(1) Acute coronary syndrome (e.g., myocardial infarction or unstable angina)
(2) Coronary artery intervention (e.g., coronary artery bypass grafting or 
percutaneous transluminal coronary angioplasty)
(3) Stroke or transient ischemic neurological disorder
12) Has severe peripheral vascular disease (e.g., claudication with minimal activity, a 
nonhealing ischemic ulcer, or disease which is likely to require surgery or 
angioplasty).
13) Has a history of malignancy ≤ 5 years prior to Visit 1/Screening, except for 
adequately treated basal cell or squamous cell skin cancer, or in situ cervical 
cancer.
<Note> The following subjects should be excluded;
(1) A subject with a history of malignancy >5 years prior to Visit 1/Screening 
should have evidence of residual or recurrent disease
(2) A subject with any history of melanoma, leukemia, lymphoma, or renal cell
carcinoma.
 
 
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14) Has a clinically important hematological disorder (such as aplastic anemia,
myeloproliferative or myelodysplastic syndromes, thrombocytopenia).
Laboratory Abnormalities
15) Have any exclusionary laboratory values as listed in Table 1 below.
Table 1 Laboratory Exclusion Criteria (Visit 1/Screening)
Parameter
Population
Study Limit for Exclusion
Estimated glomerular filtration rate (eGFR)1
<35 mL/min/1.73 m2
Alanine aminotransferase (ALT)
>two times upper limit of normal (ULN)
Aspartate aminotransferase (AST)
>two times ULN
Thyroid-stimulating hormone (TSH)
Outside central laboratory normal range
Hemoglobin
Male
Female
<11 g/dL
<10 g/dL
Triglyceride
>600 mg/dL 
C-peptide
<0.6 ng/mL
1
eGFR (mL/min/1.73 m2) = 194 x serum creatinine (Cr) -1.094 x age (years) -0.287 (x 0.739 for female).
Insulin therapy-Specific Criterion
16) Meets any contraindication or warning listed on the package insert of each insulin 
products and which do not be contained in the exclusion criteria of this study 
protocol.
Other Criteria
17) (For women of childbearing potential) has a positive urine pregnancy test.
18) Meets any following criteria regarding pregnant, breast-feeding or donate eggs;
(1) Be pregnant or breast-feeding
(2) Is expecting to conceive during the study, including 21 days following the 
last dose of study medication.
(3) Subject is expecting to undergo hormonal therapy in preparation to donate 
eggs during the period of the trial, including 21 days following the last dose 
of study medication.
19) Is a user of recreational or illicit drugs or has had a recent history of drug abuse.
20) Meets any following criteria regarding alcohol consumption; 
(1) Routinely consumes >14 alcoholic drinks per week
(2) Engages in binge drinking ["Binge drinking" is defined as a pattern of 5 or 
more alcoholic drinks (male), or 4 or more alcoholic drinks (female) in 
about 2 hours].
<Note> One alcoholic drink is defined as 5 oz (150 mL) of wine, or 12 oz 
(350 mL) of beer, or 1.5 oz (45 mL) of 80 proof liquor.
 
 
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21) Meets any following criteria regarding donated blood products, phlebotomy or 
receive of blood products
(1) Has had phlebotomy of >300 mL or donated blood products of >300 mL 
within 8 weeks of Visit 1/Screening 
(2) Has intends to have phlebotomy or donated blood products within the 
projected duration of the study
(3) Has received, or is anticipated to receive, blood products within 12 weeks of 
Visit 1/Screening or within the projected duration of the study.
22) Is disqualified from the study by the investigator for any reasons other than those 
given above.
Example: Subject has a history or current evidence of any condition, therapy, lab
abnormality or other circumstance as follows, 
(1) Makes participation not in the subject's best interest, 
(2) Might interfere with the subject’s participation for the full duration of the
study, 
(3) Might confound the results of the study.
23) 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.
At Visit 2/Week -10 (Only for Group A)
Other Criterion
24) Is disqualified from the study by the investigator for any reasons other than those 
given above.
At Visit 3/Week -2
Concomitant Disease of Organs and Systems
25) Has poorly controlled hypertension defined as systolic blood pressure of 
≥160 mmHg or diastolic blood pressure of ≥90 mmHg.
Laboratory Abnormalities
26) Has any exclusionary laboratory values as listed in Table 2 below.
Table 2 Laboratory Exclusion Criteria (Visit 3/Week -2)
Parameter
Population
Study Limit for Exclusion
eGFR1
<35 mL/min/1.73 m2
ALT
>two times ULN
AST
>two times ULN
Triglyceride
>600 mg/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
27) (For women of childbearing potential) have a positive urine pregnancy test.
 
 
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28) Be disqualified from the study by the investigator for any reasons other than those 
given above.
At Visit 4/Day 1/Randomization
Criteria related to Diabetes
29) Is difficult to continue stable dosage and administration of insulin during Phase A 
(double-blind period, 16 weeks)
30) Received rapid-acting or ultra rapid-acting insulin within 10 weeks prior to 
Visit 4/Day 1/Randomization.
31) Received pre-mixed insulin/fixed ratio combination of insulin with a greater than 
30% 
rapid 
or 
ultra
rapid-acting 
insulin
within 
10 weeks 
prior 
to 
Visit 4/Day 1/Randomization.
32) Has history of severe hypoglycemia with coma or loss of consciousness, or for 
whom hypoglycemia was observed greater or equal to two times per week from 
Visit 1/Screening to Visit 4/Day 1/Randomization.
Other Criteria
33) (For women of childbearing potential) have a positive urine pregnancy test.
34) Be disqualified from the study by the investigator for any reasons other than those 
given above.
Trial Treatment(s)
5.2
The treatment(s) to be used in this trial are outlined below in Table 3.
Table 3 Trial Treatments
Drug
Dose/Potency
Dose 
Frequency
Route 
of 
Administration
Regimen/Treatment 
Period
Use
Placebo run-in period (Single-Blind Pre-Treatment Period)
Omarigliptin 
Matching 
Placebo
Placebo 
tablet
Once 
a 
week
Oral
2 weeks
Run-in 
medication
Phase A (Double-Blind Treatment Period)
Omarigliptin
or
matching 
placebo
25 mg tablet 
or 
placebo 
tablet
Once 
a 
week
Oral
16 weeks
Experimental 
or 
experimental 
placebo
Phase B (Open-label Treatment Period)
Omarigliptin
25 mg tablet
Once 
a 
week
Oral
36 weeks
Experimental
 
 
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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
Administration of study medication
5.2.2.1
Omarigliptin or omarigliptin placebo
1) Single-blind, placebo run-in period
•
At Visit 3/Week -2 (beginning of the single-blind run-in period), subjects will 
take one tablet of study medication (omarigliptin 25 mg matching placebo) as 
a witnessed dose in the trial site and take 1 subsequent dose of single-blind 
placebo run-in study medication at home etc. the following week on their 
scheduled day of dosing.  Subjects will be instructed to take study medication 
on the same day of the week at approximately the same time of day. Study 
medication may be taken with or without regard to meals or time of day.
2) Phase A (Double-blind period) and Phase B (Open-label period)
•
At Visit 4/Day 1/Randomization (beginning of the double-blind period), each 
subject will take one tablet of study medication (omarigliptin 25 mg or 
matching placebo) as a witnessed dose in the clinic and take subsequent doses 
of double-blind study medication at home etc. the following weeks on their 
scheduled day of dosing. Subjects will be instructed to take study medication 
on the same day of the week at approximately the same time of day. Study 
medication may be taken with or without regard to meals or time of day.
<Note> "The day of the week of the scheduled dosing" is the first day of the 
week 
when 
this
study
medication 
is 
administered 
(i.e., 
Visit 4/Day 1/Randomization). Since then, the subject should take study drug 
on every same day (i.e., Scheduled day of Dosing) throughout the trial
[including Phase B (open-label period)].
The investigator will instruct the subject to contact the site if they vomit within 6 hours of 
taking their weekly dose of omarigliptin or matching placebo. The investigator will 
determine whether the subject should take another dose of study medication.
 
 
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Timing of Dosing of Pre-Treatment Period, and Treatment Period Medication 
5.2.2.2
on Days of Study Visits
1) The 
first 
dose 
of 
each 
medication 
(Visit 3/Week -2
and
Visit 4/Day 1/Randomization)
The first dose of each medication on a day of Visit 3/Week -2
and
Visit 4/Day 1/Randomization [Visit 3/Week -2: Medication for placebo run-in 
period 
(matching 
placebos 
for 
omarigliptin 
25 mg)
and
Visit 4/Day 1/Randomization: Medication for Phase A (double-blind period, 
omarigliptin 25 mg or matching placebos)] must be taken as a witnessed dose at 
the trial site visit after completion of all procedures and collection of all fasting 
blood samples.
2) Except for the first dose of each medication (Except of Visit 3/Week -2 and
Visit 4/Day 1/Randomization)
If this is the subject's scheduled day of dosing, study medication should only be 
taken after completion of all study visit procedures and collection of all fasting
blood samples.  Otherwise, the next dose should be taken on the next scheduled 
day. [Same as first dose for Phase B (open-label period) at Visit 8/Week 16]
Handling of Missed Doses
5.2.2.3
Omarigliptin or omarigliptin placebo
The missed one dose of study medication should be taken as soon as the subject 
remembers. The missed dose can be taken at any day of the 7-day dosing period up to 
the day before the next scheduled dose. The day of the week of the scheduled dosing 
should not change as a result of the missed dose.
Example: If a subject has a scheduled day of dosing each Monday, the subject can 
take a missed dose up to Sunday. The next scheduled dose is still taken the following 
Monday, even if the missed dose was taken the day before "the day of the week of the 
scheduled dosing" (Sunday).
Details of each procedure are provided in Section 7 – Trial Procedures
Trial Blinding 
5.2.3
A double-blinding technique with in-house blinding will be used (Phase A).  Omarigliptin 
and placebo will be packaged identically so that blind/masking is maintained.  The subject, 
the investigator and Sponsor personnel or delegate(s) who are involved in the treatment or 
clinical evaluation of the subjects are unaware of the group assignments.
See Section 7.1.4.2, Blinding/Unblinding, for a description of the method of unblinding a 
subject during the trial, should such action be warranted.
Randomization or Treatment Allocation
5.3
Treatment allocation/randomization will occur centrally using an interactive voice response 
system / integrated web response system (IVRS/IWRS).
There are 2 treatment arms.  
 
 
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Subjects will be assigned randomly in a 2:1 ratio to omarigliptin 25 mg q.w. or placebo, 
respectively.
Stratification
5.4
Treatment allocation/randomization will be stratified according to the following factors:
1. Use of oral AHA at Visit 1/Screening (insulin + oral AHA or insulin monotherapy)
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
(1) All AHAs (Except for omarigliptin for the trial and insulin agents which will be 
administered during the trial)
a)
Insulin agents [rapid-acting, ultra rapid-acting insulin or pre-mixed insulin/fixed 
ratio combination of insulin (content percentage of rapid-acting or ultra rapid-
acting insulin is greater than 30%)]
b)
SUs (sulfonylureas, sulfonamides)
c)
Glinides (nateglinide, mitiglinide, repaglinide, etc.)
d)
BGs
e)
TZD
f)
α-GIs
g)
DPP-4 inhibitors
h)
SGLT2 inhibitors
i)
GLP-1 receptor agonists (Such as exenatide or liraglutide)
j)
FDC products containing the above active ingredient(s) (Except for insulin 
agents which will be administered during the trial)
<Note> The subject in Group A can continue single oral AHA taken at 
Visit 1/Screening thorough to Visit 2/Week -10.
(2)
Other investigational drugs
(3) Systemic corticosteroids ≥14 consecutive days or repeated courses
<Note> Inhaled, nasal, and topical corticosteroids which don’t have systemic effect 
are permitted.
 
 
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Within 10 hours before the visit
(1) Intravenous fluids (other than those having a volume <50 mL without any glucose 
content)
(2) Glucagon
Limited Concomitant Medications
5.5.2
Medications for complication, which are used prior to Visit 1/Screening 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 investigator judges that it is necessary to 
change the regimen considering the individual subject's condition and safety.
In addition, subjects can use lipid-lowering medication, anti-hypertension medication or 
thyroid hormone replacement agents during the trial period.  It's preferable that those dosages 
of medications are stable during the trial period  
<Note> Based on section 5.1.3, subjects receive unstable dosage of lipid-lowering 
medication within 4 weeks prior to Visit 1/Screening, or subjects receive unstable dosage of 
thyroid hormone replacement therapy within 6 weeks prior to Visit 1/Screening will be 
excluded from the trial.
Rescue Medications & Supportive Care
5.6
Rescue treatment (up-titration of insulin)
5.6.1
The subject who meets the following glycemic rescue criteria in Table 4 should initiate
rescue therapy with up-titration of the insulin that they are receiving during the trial 
(continuing from Visit 1/Screening).
Table 4 Rescue criteria
Application Timing
Criteria
Administration 
Timing
After
Visit 4/Day 1/Randomization
to Visit 10/Week 24
FPG (as reported by the central lab) is
repeatedly * confirmed >240 mg/dL two
times
At the next
scheduled or
unscheduled Visit
(= Rescue Visit)
After Visit 10/Week 24
FPG (as reported by the central lab) is
repeatedly * confirmed >200 mg/dL two
times
*
Repeatedly at the scheduled visit (or at unscheduled visit as needed).  
After initiation of rescue therapy, insulin can be adjusted by judgment of the investigator even if the FPG does not show 
"repeatedly" the above criteria.
Subjects that meet rescue criteria will have their insulin dose adjusted as determined 
clinically appropriate by the investigator to manage glycemic control.  The maximum dosage 
of insulin should follow the maximal approved dose based on its package insert.  
 
 
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During Phase A, up-titration of insulin relative to the dose at Visit 4/Day 1/Randomization 
may be performed only if the subject has glucose measurements meeting rescue criteria,
during Phase B, up-titration will be determined by investigator’s assessment of subject’s 
need for glycemic control.
Subjects will continue on study medication after initiation of rescue therapy or down-titration 
of insulin until completion unless they meet discontinuation criteria (See Section 5.8).
Down-titration of insulin
5.6.2
Subjects who meet the following down-titration criteria (hypoglycemia criteria) may have 
their insulin down-titrated upon discretion of investigators (i.e., the insulin dose that they 
were receiving during the trial, which they were continuing from Visit 1/Screening, may be 
reduced).
1. The subject has hypoglycemic episode with hypoglycemic symptoms, and with an 
FPG (central lab) ≤70 mg/dL or an SMBG of ≤70 mg/dL
2. The subject has repeated (more than and equal to two times of) FPG (central lab) 
<80 mg/dL or an SMBG of <80 mg/dL per week, and if the subject is considered at 
high risk for hypoglycemia by the investigators.
Subjects that meet hypoglycemia criteria will have their insulin dose adjusted as determined 
clinically appropriate by the investigator to manage glycemic control.  There are no 
restrictions on the number of units the insulin dosage may be reduced.  Investigators should 
decide insulin dosage for each subject based on the package insert for the specific insulin 
being used.  
Subjects will continue on study medication after initiation of rescue therapy or down-titration 
of insulin until completion unless they meet discontinuation criteria (See Section 5.8).
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/Screening.  Diet therapy is mandatory and should remain stable throughout the study.
Exercise therapy
5.7.2
The subject will be instructed to continue the exercise therapy which was undergone at 
Visit 1/Screening.  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 event (e.g., arthritis in a lower limb).
Insulin therapy
5.7.3
Insulin will be administered during the trial as monotherapy of pre-mixed insulin/fixed ratio 
combination of insulin (content percentage of rapid-acting or ultra rapid-acting insulin is 
lower than or equal to 30%), intermediate or long-acting insulin and type of insulin agents 
should not be changed during the trial.  In addition, the dosage and administration of insulin 
will be required to follow each package insert.
 
 
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Insulin dosage must remain unchanged from the Visit 1/Screening dose throughout Phase A 
(double-blind period, 16 weeks), unless hypoglycemia or hyperglycemia rescue criteria are 
met [Down-titration, see Section 5.6.2 "Down-titration of insulin" or Up-titration, see Section 
5.6.1 "Rescue treatment (up-titration of insulin)"].
While during Phase B (open-label period, 36 weeks), dosage adjustments of insulin will be 
allowed as clinically appropriate to manage the subject’s glycemic control. During Phase A
(double-blind period) and also Phase B (open-label period), dosage changes are required if 
subject meets rescue criteria [Up-titration, see Section 5.6.1 "Rescue treatment (up-titration 
of insulin)"] or hypoglycemia criteria [Down-titration, see Section 5.6.2 "Down-titration of 
insulin"]. 
At morning at the each study visit, the subjects should visit the trial site before administrating 
insulin.  The subject should administer insulin according to its package insert for each insulin 
agent after completion of all study visit procedures and collection of all fasting blood 
samples.  
The missing dose should be administered in accordance with the package insert for each 
insulin agents.
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; including specific details regarding 
withdrawal from Future Biomedical Research, are provided in Section 7.1.4 – Other 
Procedures.
A subject must be discontinued from the trial if:
o
The subject withdraws consent.
A subject must be discontinued from treatment for any of the following reasons:
o
Lack of efficacy
The effect of the study medication is not sufficient and study continuation is judged 
inappropriate by the investigator.  If the following case occurs, the investigator should 
consider the discontinuation from the trial:
a)
After Visit 4/Day 1/Randomization to Visit 10/Week 24, FPG consistently 
>240 mg/dL (as reported by the central lab) ≥4 weeks after maximal 
adjustment of insulin [Up-titration, see Section 5.6.1 "Rescue treatment (up-
titration of insulin)"].
 
 
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b)
After Visit 10/Week 24, FPG consistently >200 mg/dL (as reported by the 
central lab) ≥4 weeks after maximal adjustment of insulin [Up-titration, see 
Section 5.6.1 "Rescue treatment (up-titration of insulin)"].
<Note> The investigator should instruct the subject to visit the trial site as 
soon as possible to perform the repeat test once he/she meets the threshold of 
FPG criteria.  If result of re-test does not meet the threshold of FPG criteria, 
the subject can continue to attend the trial.
o
Adverse event
In the case that the investigator assesses that administration of the study medication 
should be discontinued due to the occurrence of adverse events.  When subjects meet 
the following criteria, they should discontinue the study, regardless of the 
investigator’s assessment (except for hypoglycemia).
a)
Hypoglycemia
Subject meets any one of the following criteria without a reasonable 
explanation (such as increased physical activity or skipped meal)
(1) Repeated (2 or more episodes since the prior study visit) FPG (as 
reported by the central lab) or finger stick glucose (FSG) <50 mg/dL 
with or without symptoms of hypoglycemia, which persists despite 
progressive down-titration of insulin agents.
(2) Repeated (2 or more episodes since the prior study visit) FPG (as 
reported by the central lab) or FSG ≤70 mg/dL with symptoms of 
hypoglycemia, which persists despite progressive down-titration of 
insulin agents.
<Note>The subject must be discontinued from the trial if the subject is 
meeting above criteria despite down-titration of insulin, or the 
investigator judges administrating of insulin have to be discontinued
(There are no limit for down-titration of insulin. The investigator will 
decide dose of insulin when insulin is down-titrated, based on each 
package insert of insulin agents.).
b)
Increased ALT or AST
(1) Elevation in ALT and/or AST ≥three times the ULN as specified in
Appendix 12.5,OR
(2) Elevations in ALT and/or AST ≥three times the ULN with concurrent
total bilirubin ≥two times the ULN and alkaline phosphatase (ALP)
<two times the ULN (See "Event of Clinical Interest (ECI) Guidance for
Potential Drug-Induced Liver Injury (DILI) in Clinical Trials guidance 
document").
c)
Reduction in eGFR
If the repeat measurement performed as early as possible meets the criteria in 
Table 5, the subject must be discontinued from the trial.
 
 
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Table 5 Discontinuation criterion of eGFR
Parameter
Study Limit for Discontinuation
eGFR 1
<30 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).
d)
Pancreatitis
If a subject is suspected of having pancreatitis, study medication should be 
interrupted and if pancreatitis is confirmed, study medication should be 
discontinued.
o
Protocol Violation
It becomes inappropriate to continue study treatment as a result of a significant 
protocol deviation.
o
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.
o
Subject moved
When the subject has either moved or relocated and is no longer able to participate in 
the study.
o
Pregnancy
<Note> A positive urine pregnancy test requires immediate interruption of study
medication until serumβ-human chorionic gonadotropin (β-hCG) can be performed 
and found to be negative. Subject must be permanently discontinued and followed per 
Section 7.2.2 if pregnancy is confirmed by a positive serum pregnancy test.
o
In addition, investigator's decision that subject should discontinue for any other
reason.
Example: Requirement for one of the excluded medications listed in Section 5.5.
If a subject discontinues study medication, he/she should complete all 
Discontinuation Visit procedures as listed in the Trial Flow Chart (see Section 6.0).  
All subjects will be followed until resolution (i.e., return to baseline values, diagnosis 
determined or new stable state established, based upon investigator and the Sponsor) 
for any adverse events or any laboratory safety test abnormality resulting in 
discontinuation from study medication.  
Discontinuation from treatment is “permanent.” Once a subject is discontinued, he/she shall 
not be allowed to restart treatment.
Subject Replacement Strategy
5.9
A subject who discontinues from the trial will not be replaced.
 
 
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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
(2 weeks or 10 weeks)2
Treatment period (52 weeks)
Rescue visit4
Discontinuation visit
Telephone contact
(8 weeks)
Placebo 
run-in
(2 weeks)
Phase A (Double-blinded period, 
16 weeks)
Phase B (Open-label period, 36 weeks)
Screening Wk-103
Wk-6 3
Wk-2
Day1
Wk4
Wk8
Wk12 Wk16 Wk20 Wk24 Wk28 Wk32 Wk36 Wk44
Wk52
Visit 1
Visit 23
Tele-
phone 
contact3 Visit 3
Visit 4
Visit 5 Visit 6 Visit 7 Visit 8 Visit 9 Visit 10Visit 11Visit 12Visit 13Visit 14 Visit 15
Allowed 
range of visit1
Screening period
0
≤ 
2wks(A)
≤ 
2wks(B)
Wash-out period (Group A)
0
±7days
±3days
Placebo run-in period
0
+3days
Treatment period
0
±7 days ±7 days±7 days -6 days ±7 days ±7days ±7 days±7 days±7 days±7 days
±3days
General Study Procedure
Informed Consent 5
X13
Informed Consent for FBR
X
Providing Subject Identification Card
X
Inclusion/Exclusion Criteria evaluation
X
A
X
X
Medical History evaluation
X
Prior/Concomitant Medication Review
X
A
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Instruction to discontinue oral AHA (except for 
insulin agents)
A
Diet/exercise therapy counseling
X
A
X
X
X
X
X
X
X
X
X
X
X
X
X
Instruction for recording of patient’s log and 
dispensing
X
A
X
X
X
X
X
X
X
X
X
X
X
X
Collection and Review of Patient’s Log
A
X
X
X
X
X
X
X
X
X
X
X
X
X
X14
X
Providing SMBG devise and instruction
A
B
Instructions on hypoglycemic symptoms, 
management, and recording of hypoglycemic
assessment log (HAL)
A
B
Dispensing HAL
A
X
X
X
X
X
X
X
X
X
X
X
X
Patient Registration
X
A
X
X
X
X
X
X
X15
Assignment of Treatment/Randomization 
Number
X
Clinical Procedures/Assessments
Confirmation of Diet and exercise therapy
X
A
X
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
X
Vital Sign (height)
X
SMBG at each visits
A
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Review of HAL and assessment of hypoglycemia
A
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse event monitoring
A
A
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
 
 
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Protocol/Amendment No.: 039-01
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Screening 
period
(≤ 2 weeks)
Pre-treatment period
(2 weeks or 10 weeks)2
Treatment period (52 weeks)
Rescue visit4
Discontinuation visit
Telephone contact
(8 weeks)
Placebo 
run-in
(2 weeks)
Phase A (Double-blinded period, 
16 weeks)
Phase B (Open-label period, 36 weeks)
Screening Wk-103
Wk-6 3
Wk-2
Day1
Wk4
Wk8
Wk12 Wk16 Wk20 Wk24 Wk28 Wk32 Wk36 Wk44
Wk52
Visit 1
Visit 23
Tele-
phone 
contact3 Visit 3
Visit 4
Visit 5 Visit 6 Visit 7 Visit 8 Visit 9 Visit 10Visit 11Visit 12Visit 13Visit 14 Visit 15
Allowed 
range of visit1
Screening period
0
≤ 
2wks(A)
≤ 
2wks(B)
Wash-out period (Group A)
0
±7days
±3days
Placebo run-in period
0
+3days
Treatment period
0
±7 days ±7 days±7 days -6 days ±7 days ±7days ±7 days±7 days±7 days±7 days
±3days
12-lead ECG Locally
X
X
X
X
Assessment for necessity of rescue treatment (up-
titration of insulin agents) 4
X
X
X
X
X
X
X
X
X
X
Laboratory Procedures/Assessments
HbA1c
X
X6
X
X
X
X
X
X
X
X
X
X7
X7
Glucose
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
1,5-AG8
X
X
X8
X8
Hematology
X
X
X
X
X
X
X
X
Blood chemistry
X
X
X
X
X
X
X
X
X
Endocrinological9
X
Urinalysis
X
X
X
X
X
X
Urine Pregnancy Test 10
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Blood (deoxyribonucleic acid, DNA) for FBR 11
X
Plasma and serum sample for FBR11
X
X
X
X
X11
Study Medication
Witness Dose 12
X
X
Single-blinded study medication dispensing
X
Phase A (Double-blinded) study medication 
dispensing
X
X
X
X
Phase B (Open-label) study medication 
dispensing
X
X
X
X
X
X
X
Medication compliance monitoring (Study 
medication and insulin)
X
X
X
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
1.
Origination of Visit 2/Week -10 allowance is based on Visit 1/Screening, origination of Visit 3/Week -2 allowance is based on Visit 2/Week -10, origination of Visit 4/Day 1/Randomization 
allowance is based on Visit 3/Week -2 and origination after Visit 4/Day 1/Randomization allowance is based on Visit 4/Day 1/Randomization, respectively. 
2.
For a subject who needs wash-out of oral AHA, the duration of the pre-treatment period is 10 weeks (Group A).  For a subject who does not need wash-out of oral AHA, the duration of the pre-
treatment period is 2 weeks (Group B).
3.
For subjects in Group A.  A subject in Group B proceeds to Visit 3/Week -2 after Visit 1/Screening, skipping Visit 2/Week -10.
4.
See Section 7.1.5.3 for procedures to be performed at Rescue Visit.
5.
Informed consent must be obtained before any study procedures of Visit 1/Screening.
6.
If a subject in Group B performed the procedures of Visit 1/Screening within 2 weeks before Visit 3/Week -2, HbA1c measurement is not needed at Visit 3/Week -2. The subject may be deemed 
 
 
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Screening 
period
(≤ 2 weeks)
Pre-treatment period
(2 weeks or 10 weeks)2
Treatment period (52 weeks)
Rescue visit4
Discontinuation visit
Telephone contact
(8 weeks)
Placebo 
run-in
(2 weeks)
Phase A (Double-blinded period, 
16 weeks)
Phase B (Open-label period, 36 weeks)
Screening Wk-103
Wk-6 3
Wk-2
Day1
Wk4
Wk8
Wk12 Wk16 Wk20 Wk24 Wk28 Wk32 Wk36 Wk44
Wk52
Visit 1
Visit 23
Tele-
phone 
contact3 Visit 3
Visit 4
Visit 5 Visit 6 Visit 7 Visit 8 Visit 9 Visit 10Visit 11Visit 12Visit 13Visit 14 Visit 15
Allowed 
range of visit1
Screening period
0
≤ 
2wks(A)
≤ 
2wks(B)
Wash-out period (Group A)
0
±7days
±3days
Placebo run-in period
0
+3days
Treatment period
0
±7 days ±7 days±7 days -6 days ±7 days ±7days ±7 days±7 days±7 days±7 days
±3days
to meet the HbA1c criterion of Visit 3/Week -2 by HbA1c value of Visit 1/Screening.
7.
HbA1c should not be drawn if Discontinuation Visit or the Rescue Visit occurs within 4 weeks after Visit 4/Day 1/Randomization
8.
1,5-AG will be only collected at Phase A (double-blinded period).
9.
Endocrinological: C-peptide and TSH
10. Pregnancy test: Urinary hCG. Pregnancy test will be performed at the site only for females of childbearing potential. Subjects with a positive urine pregnancy test from taking study medication 
for the treatment period will have a confirmatory serum β-hCG test performed in the central laboratory as a pregnancy test
11. Informed consent for FBR samples must be obtained to collect the DNA, plasma, and serum samples.  The FBR sample for DNA analysis should be obtained pre-dose, at 
Visit 4/Day 1/Randomization, as the last sample drawn, and on subjects who qualify for randomization. The sample may be obtained at a later date during the study after the FBR informed 
consent is obtained. The plasma and serum samples for FBR should be collected at Visit 4/Day 1/Randomization [pre-dose of study medication for Phase A (double-blind period)], 
Visit 8/Week 16 [pre-dose of study medication for Phase B (open-label period)], Visit 15/Week 52 or Discontinuation Visit, and the visit when the rescue therapy is initiated (pre-dose of up-
titrated insulin) (if applicable). For the FBR serum and plasma, samples should be collected at all-time points, even if the pre-dose or other time point was not collected.
12. The witnessed dose will be taken after completion of all procedures for the study visit (See Section 5.2.2.2 for details) 
13. Visit 1/Screening can be conducted separately from the consent date.
14. Patient’s Log will be confirmed, but it will not be collected at rescue visit.
15. Patient registration at discontinuation will be conducted during only Phase A (double-blind period)
 
 
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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 or Future Biomedical Research. 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.
7.1.1.1.2 Consent and Collection of Specimens for Future Biomedical Research
The investigator or qualified designee will explain the Future Biomedical Research consent 
to the subject, answer all of his/her questions, and obtain written informed consent before 
 
 
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performing any procedure related to the Future Biomedical Research sub-trial.  A copy of the 
informed consent will be given to the subject.
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.
7.1.1.2.1 Contraception
Non-pregnant, non-breast-feeding women may be enrolled if they are considered highly
unlikely to conceive. Highly unlikely to conceive is defined as the relevant part of 
Section 5.1.2 –Subject Inclusion Criteria.
Subjects should be informed that taking the study medication may involve unknown risks to
the fetus (unborn baby) if pregnancy were to occur during the study and agree that in order to
participate in the study they must adhere to the contraception requirement (See Section 5.1.2)
for the duration of the study and for 21 days after the last dose of study medication. If there is 
any question that a subject will not reliably comply with the requirements for contraception, 
she should not be entered into the study.
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. At the time of treatment allocation/randomization, site 
personnel will add the treatment/randomization number to the Subject Identification Card.
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 wash-out requirement, and record any prior medication taken by the 
subject below;
1. Omarigliptin (including placebo for treatment period): any time
2. AHAs other than omarigliptin: within 12 weeks prior to Visit 1/Screening.
3. Prior medications other than AHAs: within 6 weeks prior to Visit 1/Screening.
 
 
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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.
Assignment of Treatment/Randomization Number
7.1.1.7
All eligible subjects will be randomly allocated 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
Interruptions from the protocol specified treatment plan of the study medication for 
compliance (treatment period) <75% require consultation between the investigator and the 
Sponsor and written documentation of the collaborative decision on subject management.
Administration of trial medication at Visit 3/Week -2 and Visit 4/Day 1/Randomization will 
be witnessed by the investigator and/or trial staff.
Diet and exercise therapy counseling
7.1.1.9
From Visit 1/Screening, the subject will be instructed to continue the diet and exercise 
therapy which was undergone at Visit 1/Screening with reference to “Treatment Guidance for 
Diabetes” [1].  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/Screening, if the subject’s physical activity changed or he/she became unable to 
adhere to the exercise therapy instructed at Visit 1/Screening due to an adverse event and so 
on.
Example:
1)
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.
2)
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.
 
 
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Patient Registration
7.1.1.10
The investigator or trial staff will register the subjects via the system of the patient 
registration center at each scheduled visit.  Patient registration will be done during Phase A 
(double-blind period).
Instruction for recording of patient’s log and dispensing
7.1.1.11
The subject will be instructed to record diet and exercise therapy compliance and insulin 
compliance in the patient’s log from Visit 1/Screening.  From Visit 2/Week -10 (Group A) or 
from Visit 3/Week -2 (Group B), the subject will be instructed to record SMBG data in the 
patient’s log in addition to diet and exercise therapy compliance and insulin compliance.  In 
addition, the subject will be instructed to record study medication compliance in the patient’s 
log from Visit 3/Week -2.
The patient’s log will be dispensed at Visit 1/Screening.  The subject will be instructed to 
bring the subject-completed patient’s log to the trial site at each visit.
Collection and review of patient’s log
7.1.1.12
The patient’s log dispensed at the previous visit will be collected, and the investigator should 
check the diet and exercise therapy compliance, insulin compliance, study medication 
compliance, and SMBG value.  The investigator should make effort to prevent the 
reoccurrence of non-compliance by an instruction to the subject, if the non-compliance with 
diet and exercise therapy, taking insulin therapy and/or taking study medication were found.  
If SMBG value ≤70 mg/dL is in patient’s log, the investigator should check that its 
information is also in the HAL.
Providing SMBG devise and instruction
7.1.1.13
Glucose meters will be supplied to all subjects at Visit 2/Week -10 (Group A) or 
Visit 3/Week -2 (Group B) in order to perform SMBG.  The subjects will be instructed on the 
procedure to perform FSG measurements.  The subjects will monitor their FSG 
concentrations with a frequency determined appropriate by the investigator with a minimum 
of 2 fasting (without taking insulin and study medication) determinations per week (2 or 
more frequency may be set based upon his/her assessment of the subject’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 trial site since it is necessary that the 
investigator assesses an adverse event and a need for rescue therapy and judges the 
continuation of the study for the subjects.
1)
FSG ≤70 mg/dL throughout the duration of the entire study
2)
Fasting FSG >230 mg/dL before Visit 4/Day 1/Randomization
3)
Fasting FSG >240 mg/dL after Visit 4/Day 1/Randomization through Visit 10/Week 24
4)
Fasting FSG >200 mg/dL after Visit 10/Week 24
 
 
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Instructions on hypoglycemic symptoms, management, and recording of HAL
7.1.1.14
The subject will be informed that there is a possibility of developing hypoglycemic 
symptoms (e.g., weakness, dizziness, shakiness, increased sweating, palpitations, or 
confusion) after administration of the study medications.  The subject will be instructed to 
complete the HAL for any symptomatic episodes he or she believes may represent 
hypoglycemia.  If a symptom that may be considered hypoglycemia occurs, hypoglycemia 
for which assistance was required (i.e., severe hypoglycemia) occurs and/or FSG ≤70 mg/dL 
with or without symptoms, the subject will be instructed to;
1. Promptly take countermeasures, such as the ingestion of glucose (5 - 10 g) or glucose 
supplement
2. If a symptom that may be considered hypoglycemia occurs: Immediately (before 
taking glucose or within 2-3 minutes after taking glucose) perform a FSG
measurement
3. Complete all symptoms which occurred in HAL
4. Contact the investigational site and 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.)
5. Bring HAL completed by the subjects at the next visit.
Dispensing HAL
7.1.1.15
The patient’s log will be dispensed from Visit 2/Week -10 (Group A) or from Visit 3/Week -2 
(Group B).  The subject will be instructed to bring the HAL to the trial site at each visit.
Instruction to discontinue oral AHA (except for insulin agents)
7.1.1.16
Subject of Group A will be instructed to discontinue oral AHA (except for insulin agents) 
after Visit 2/Week -10.
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.
Confirmation of Diet and exercise therapy
7.1.2.1
From Visit 1/Screening, subject will be confirmed to continue the diet and exercise therapy 
which was undergone at Visit 1/Screening with reference to “Treatment Guidance for 
Diabetes” [1].  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).
Measuring of Vital signs
7.1.2.2
Blood pressure, weight and height will be measured according to the procedures in Section
12.4.
 
 
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SMBG at each visits
7.1.2.3
Subjects will be instructed to measure SMBG by FSG at each scheduled visit from 
Visit 2/Week -10 (Group A) or Visit 3/Week -2 (Group B).
Review of HAL and assessment of hypoglycemia
7.1.2.4
HAL will be reviewed to record symptoms that subjects believe are related to hypoglycemia 
and/or FSG measurements on the HAL. Each episode should be evaluated by the investigator 
and recorded on the Hypoglycemia Assessment (HA) electronic case report form (eCRF). If 
the event is considered by the Investigator to be an adverse event of hypoglycemia or 
asymptomatic hypoglycemia, the event should also be reported on the adverse event eCRF as 
an adverse event of hypoglycemia or asymptomatic hypoglycemia, respectively (see Section 
7.2.4). 
12 lead ECG
7.1.2.5
12-lead ECG will be measured in each site and the investigator will read it.
Assessment for necessity of rescue treatment (up-titration of insulin agents)
7.1.2.6
FPG (as reported by the central lab) will be assessed whether it meet rescue criteria which is 
shown in Table 4 after Visit 4/Day 1/Randomization.
If the FPG meets rescue criteria, 
rescue therapy will be started to up-titrate of insulin agents that is administered from 
Visit 1/Screening.  Details are described at Section 5.6.1.
Laboratory Procedures/Assessments
7.1.3
Details regarding specific laboratory procedures/assessments to be performed in this trial are 
provided below. 
Laboratory efficacy Evaluations (Hematology and blood chemistry)
7.1.3.1
Laboratory efficacy tests are specified in Table 6.  
Table 6 Laboratory Efficacy Tests (Hematology, Blood chemistry)
Hematology
Blood chemistry
HbA1c
1, 5-AG
Glucose
Laboratory fating tests other than HbA1c will be performed after at least a 10-hour fast.
Laboratory safety tests (Hematology, blood chemistry, urinalysis and other)
7.1.3.2
Laboratory safety tests are specified in Table 7.  
 
 
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Table 7 Laboratory Safety Tests (Hematology, Blood Chemistry, Urinalysis and Other)
Hematology
Chemistry
Urinalysis
Other
Hematocrit
Albumin
Blood
Serum β-hCG, (if
urine pregnancy 
test is positive)
Hemoglobin
Alkaline phosphatase 
Ketones
TSH
Platelet count
ALT
pH
C-Peptide
Erythrocytes
AST
Protein
White 
blood
cell 
(WBC 
, 
total)
Blood Urea Nitrogen
Urobilinogen
WBC 
(differential)
Calcium
Chloride
Creatinine/Glomerular
Filtration Rate Estimation
Creatine Kinase
Direct bilirubin (if total bilirubin is 
over upper limit normal)
Gamma Glutamyl Transferase
High-density lipoprotein cholesterol
Lactate Dehydrogenase
Low-density lipoprotein cholesterol
Magnesium
Phosphorus
Potassium
Sodium
Total Bilirubin
Total Cholesterol
Total protein
Triglycerides
Uric acid
Laboratory safety tests other than hematology tests and serum β-hCG will be performed after 
at least a 10-hour fast.
Pregnancy test
All pre-menopausal women who are not surgically sterilized participating in the study will
have a urine pregnancy test at each study visit indicated on the Study Flow Chart.  Urine 
pregnancy test will be performed at each trial 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.  
A positive urine pregnancy test requires immediate interruption of study medication until 
serum β-hCG is performed and found to be negative. A subject must be permanently 
 
 
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discontinued and followed (see Section 5.8) if pregnancy is confirmed by a positive serum 
pregnancy test.
Future Biomedical Research Samples
7.1.3.3
The following specimens are to be obtained as part of Future Biomedical Research:
1) DNA for future research
2) Plasma for future research
3) Serum for future research
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 Visit 15/Week 52 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.
7.1.4.1.1 Withdrawal From Future Biomedical Research
Subjects may withdraw their consent for Future Biomedical Research.  Subjects may 
withdraw consent at any time by contacting the principal investigator for the main trial.  If 
medical records for the main trial are still available, the investigator will contact the Sponsor 
using the designated mailbox (clinical.specimen.management@merck.com).  Subsequently, 
the subject's consent for Future Biomedical Research will be withdrawn.  A letter will be sent 
from the Sponsor to the investigator confirming the withdrawal. It is the responsibility of the 
investigator to inform the subject of completion of withdrawal.  Any analyses in progress at 
the time of request for withdrawal or already performed prior to the request being received 
by the Sponsor will continue to be used as part of the overall research trial data and results.  
No new analyses would be generated after the request is received.
In the event that the medical records for the main trial are no longer available (e.g., if the 
investigator is no longer required by regulatory authorities to retain the main trial records) or 
the specimens have been completely anonymized, there will no longer be a link between the 
subject’s personal information and their specimens.  In this situation, the request for 
specimen withdrawal cannot be processed.
Subject Blinding/Unblinding
7.1.4.2
When the investigator or delegate needs to identify the drug used by a subject and the dosage 
administered in case of emergency e.g., the occurrence of serious adverse experiences, he/she 
will contact the emergency unblinding call center by telephone and make a request for 
emergency unblinding.  As requested by the investigator or delegate the emergency 
unblinding call center will provide the information to him/her promptly and report unblinding 
to the sponsor.  Prior to contacting the emergency unblinding call center to request 
unblinding of a subject’s treatment assignment, the investigator or delegate must enter the 
 
 
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intensity of the adverse experiences observed, the relation to study drug, the reason thereof, 
etc., in the medical chart etc. Subjects whose treatment assignment has been unblinded by the 
investigator/delegate and/or non-study treating physician must be discontinued from study 
drug.
In the event that unblinding has occurred, the circumstances around the unblinding (e.g., 
date, reason and person performing the unblinding) must be documented promptly, and the 
Sponsor Clinical Director notified as soon as possible. Only the principal investigator or 
delegate and the respective subject’s code should be unblinded. Other trial site personnel and 
Sponsor personnel directly associated with the conduct of the trial should not be unblinded.
Subjects whose treatment assignment has been unblinded by the investigator/delegate and/or 
non-study treating physician must be discontinued from study drug.
At the end of the trial, random code/disclosure envelopes or lists and unblinding logs are to 
be returned to the Sponsor or designee.
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:
Not applicable in this study.
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.
1 Scheduling Visit and Study Duration
At the end of each study visit, the next study visit should be scheduled. Every effort should
be made to adhere to the visit schedule (refer to Study Flow Chart – Section 6.0). 
Prior to each visit, subjects should be contacted and reminded of:
1) The date and time of appointment.
Note: Subject should visit the trial site in the morning.
2) The requirement to fast for at least 10 hours prior to the trial site visit (no food or 
drink except for water).
3) The requirement not to take intravenous fluids (other than those having a volume 
<50 mL without any sugar content) and/or glucagon within 10 hours of the visit to the 
trial site.
 
 
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4) The requirement not to take study medication and insulin agents at home the morning 
of the visit.  Subject should bring any unused study drugs prescribed, without disposal 
and intake.
Note: Non-study medications that are not AHA medications should be taken as
directed by the prescribing physician. 
5) The requirement to bring study medication (including containers), blood glucose 
meter, HAL and Patient's Log to the study visit.
Screening
7.1.5.1
Up to 12 weeks prior to randomization, potential subjects will be evaluated to determine that
they fulfill the entry requirements as set forth in Section 5.1. The subject will be identified as 
Group A (pre-treatment period is 10 weeks) or Group B (pre-treatment period is 2 weeks) 
based on their pre-treatments for T2DM (use of oral AHA) at Visit 1/Screening (See 
Figure 2).
For the subject who meets all the eligibility criteria of Visit 1/Screening, patient’s log will be 
dispensed and they will be instructed for recording of patient’s log. The subject will be 
instructed to bring the subject-completed patient’s log to the trial site at each visit.  In 
addition, the subject will be instructed to continue the diet and exercise therapy which was 
undergone at Visit 1/Screening.  
For subject in Group A, Visit 2/Week -10
is scheduled
within 2 weeks after 
Visit 1/Screening. For subject in Group B, Visit 3/Week -2 is scheduled within 2 weeks after 
Visit 1/Screening (Visit 2/Week -10 will be skipped). The subject who meets laboratory 
criteria of Visit 1/Screening can proceed to the next visit.
 
 
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Figure 2  Selection of subject group (Visit 1/Screening)
Pre-Treatment Period
7.1.5.2
1)
Visit 2/Week -10 (only for subject in Group A)
The subject, who meets the enrollment criteria of Visit 2/Week -10 and can continue the 
study based on the review of concomitant medications and the monitoring of adverse 
events and implementation status of diet/exercise therapy, will undergo all study 
procedures of Visit 2/Week -10 including the following instructions:
(1) SMBG instruction
(2) Instructions on hypoglycemic symptoms, management of hypoglycemic symptoms
and recording of HAL and subject’s log
(3) Instructions on discontinuation of an oral AHA other than insulin
After the above procedures have been completed, a SMBG meter will be dispensed. Next 
visit (Visit 3/Week -2) is arranged 8 weeks (± 3 days) after Visit 2/Week -10.
 
 
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2)
Telephone Contact/Week -6 (only for subject in Group A)
Investigators or trial staff contacts the subjects by phone at Week -6 (between 
Visit 2/Week -10 and Visit 3/Week -2) to confirm developments of any adverse events.  
If adverse events are confirmed, investigator will make a decision for continuing the 
subject on trial.
3)
At Visit 3/Week -2
(1) For the subject in Group A: The subject, who meets the enrollment criteria of 
Visit 3/Week -2 and can continue the study based on the review of concomitant 
medications and the monitoring of adverse events and implementation status of 
diet/exercise therapy, will undergo all study procedures of Visit 3/Week -2.
(2) For the subject in Group B: The subject, who meets the enrollment criteria of 
Visit 3/Week -2 and can continue the study based on the review of concomitant 
medications and the monitoring of adverse events and implementation status of 
diet/exercise therapy, will undergo all study procedures of Visit 3/Week -2 including 
the following instructions:
a)
SMBG instruction
b)
Instructions on hypoglycemic symptoms, management of hypoglycemic 
symptoms and recording of HAL and subject's log
After the above procedures have been completed, a SMBG meter will be dispensed.
(3) For all subjects: After the above procedures have been completed, the study drugs 
will be dispensed in single-blinded manner to the subject and his/her will take them 
as a witnessed dose in the trial site. Next visit (Visit 4/Day 1/Randomization) is 
arranged 2 weeks (+ 3 days) after Visit 3/Week -2. The subject who meets
laboratory criteria of Visit 3/Week -2 can proceed to Visit 4/Day 1/Randomization.
Treatment Period
7.1.5.3
1)
At Visit 4/Day 1/Randomization
The subject, who meets the enrollment criteria of Visit 4/Day1/Randomization and can 
continue the study based on the review of concomitant medications, the monitoring of 
adverse events, implementation status of diet/exercise therapy, compliance of insulin and 
compliance 
of 
study 
medications, 
will
undergo 
all 
study 
procedures 
of 
Visit 4/Day 1/Randomization (except for taking study medication, patient registration 
and dispensing of study medication).  For subjects who meet the enrollment criteria of 
Visit 4/Day 1/Randomization and are judged as eligibility, subjects are registered via the 
subject registration center to be assigned the randomization number. The subjects will 
be randomized in a 2:1 ratio to receive either omarigliptin 25 mg q.w. or placebo, and 
stratified by use of oral AHA. After patient registration of Visit 4/Day 1/Randomization
is completed, the study drugs will be dispensed in double-blinded manner to the subject 
and his/her will take them as a witnessed dose in the trial site.
 
 
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2)
From Visit 5/Week 4 to Visit 14/Week 44
The subject, who can continue the study based on the review of concomitant medications 
and the monitoring of adverse events, will undergo all study procedures of each visit
(except for patient registration and dispensing of study medication).
After the above procedures have been completed, the study drugs will be dispensed to 
the subject in double-blinded manner from Visit 5/Week 4 to Visit 7/Week 12 and in 
open manner from Visit 8/Week 16, and his/her will take them if the visit is subject's 
scheduled day of dosing.  After registration [subject registration will be done during 
Phase A (double-blind period)], study medication will be dispensed.  
3)
At Visit 15/Week 52 or Discontinuation Visit
The subject will conduct all study procedure of Visit 15 (± 3 days of scheduled visit) or 
the discontinuation visit.
4)
At Rescue Visit
Subjects meeting rescue criteria (See Section 5.6.1 Table 4) will continue in the study 
until completion unless they meet discontinuation criteria (See Section 5.8). Rescue 
therapy must be initiated at either a scheduled or unscheduled visit at the investigational 
site, and not by a telephone visit. Immediately prior to initiation of rescue therapy,
subjects meeting rescue criteria must undergo the Rescue Visit procedures as referenced 
in section 6.0.
Note: FBR (plasma and serum) samples should be collected at the Visit before initiating 
rescue therapy (administration of up-titrated insulin agents) before administration of 
insulin agents as possible.
Post trial
7.1.5.4
Twenty one days after the last dose of study drug for the treatment period or later, a follow
up contact will be conducted by having subject visit or contacting the subject via telephone to
collect any serious adverse events and any events of clinical interest (ECI) information that 
might have occurred within the 21 days. 
Note: In the event any serious drug-related adverse events occurred later than 21 days after 
the last dose of study drug, it will be subjected to the follow-up evaluation.
Assessing and Recording Adverse 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 adverse change 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 (including study medication for placebo run-in period) 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 (including study medication for placebo run-in period) through 21 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 any dose higher than defined below. 
1)
Dosing with higher than a total of 25 mg of omarigliptin or matching placebo at once.
2)
Dosing with higher than a total of 50 mg omarigliptin or matching placebo within 8 days.
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.”
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).
 
 
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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 (including study medication for placebo run-in period) 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 (including study medication for placebo run-in 
period) through 21 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.
●
Is a cancer;
●
Is associated with an overdose.
Refer to Table 8 for additional details regarding each of the above criteria.
For the time period beginning when the consent form is signed until taking study medication 
(including study medication for placebo run-in period), 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 
 
 
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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 (including study medication for 
placebo run-in period) through 21 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 
(including study medication for placebo run-in period), 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 (including study medication for 
placebo run-in period) through 21 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).
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.*
 
 
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*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).
Guidance on Adverse Events Related to Glycemia
7.2.4
Hyperglycemia
7.2.4.1
An adverse event of hyperglycemia requires that a subject have 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 ma y be
reported as an adverse event of "increased blood glucose. "General guidance regarding the
determination as to whether an event is considered to be an adverse event should be followed
(see Section 7.2.5).
Hypoglycemia
7.2.4.2
1)
Documentation
Regardless of whether an episode is considered an adverse event, the HA eCRF must be
completed for the following:
(1) all episodes determined by the investigator to be hypoglycemia (symptomatic or
asymptomatic)
(2) all glucose values ≤70 mg/dL
2)
Guidance
All episodes considered as likely to represent symptomatic hypoglycemia by the 
investigator should be captured as an adverse event of "symptomatic hypoglycemia." 
This diagnosis may be supported by, but does not require, confirmatory blood glucose 
results (such as those measured using a finger stick or from a clinical laboratory sample). 
Further, at the discretion of the investigator, an asymptomatic blood glucose value 
≤70 mg/dL may be reported as an adverse event of "asymptomatic hypoglycemia." 
General guidance regarding the determination as to whether an event is considered to be 
an adverse event should be followed (see Section 7.2.5).
Evaluating Adverse Events
7.2.5
An investigator who is a qualified physician will evaluate all adverse events with respect to 
the elements outlined in Table 8. The investigator’s assessment of causality is required for 
each adverse event.  Refer to Table 8 for instructions in evaluating adverse events.
 
 
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Table 8 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
7.2.6
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.
TRIAL GOVERNANCE AND OVERSIGHT
7.3
Clinical Adjudication Committee
7.3.1
A Clinical Adjudication Committee (CAC) will evaluate the following events for the 
purposes of confirming them according to the criteria in Section 8.0 – Statistical Analysis 
Plan, as well as evaluating the presence of confounding factors.
1) Pancreatitis - There have been post-marketing reports of acute pancreatitis, including
non-fatal and fatal hemorrhagic or necrotizing pancreatitis, in subjects with T2DM
treated with incretin based therapies (DPP-4 inhibitors and GLP-1 receptor agonists).
When an eligible event is identified, the SPONSOR or its delegate will request copies of
additional source documentation related to the event (e.g., hospital records, death certificates,
etc.) from the investigator.
In some cases, it may be necessary for the investigator to request permission from the subject
or his/her legally acceptable representative to obtain these documents. The investigator
agrees to make every effort to obtain the necessary documentation. If any key source
documents are not available, the investigator will be expected to document his/her attempts
to obtain this information and to provide a narrative summarizing what is known regarding
the event.
Details regarding procedures for the collection and submission of additional documentation
for eligible cases can be found in separate instruction documents provided to the investigator.
All personnel involved in the adjudication process will remain blinded to treatment allocation 
throughout the trial.  Specific details regarding endpoint definitions can be found in the
Adjudication Charter.
8.0 STATISTICAL ANALYSIS PLAN
This section outlines the statistical analysis strategy and procedures for the study. If, after the 
study has begun, but prior to unblinding, changes are made to the primary and/or key 
secondary hypothesis, or the statistical methods related to those hypotheses, then the protocol 
will be amended (consistent with ICH Guideline E-9). Changes to exploratory or other non-
confirmatory analyses made after the protocol has been finalized, but prior to unblinding, 
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.
 
 
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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 to 8.12.
Study Design Overview
Omarigliptin Phase IV Study -Omarigliptin Add-on to Insulin in Japanese 
T2DM 
Treatment Assignment
Subjects will be randomized to omarigliptin and placebo in a 2:1 ratio. 
The study will be conducted as a double-blind study up to Week 16 and 
following extension part up to Week 52 will be conducted as an open-
label study.
Analysis Populations
Efficacy
Full Analysis Set (FAS) population, defined as all randomized subjects 
who:

received at least one dose of treatment period study medication

have at least one measurement of the outcome variable (baseline or 
post-randomization)
Safety
All Subject as Treated (ASaT) population, defined as all randomized 
subjects who received at least one dose of treatment period study 
medication.
Primary Endpoint
Change from baseline in HbA1c at Week 16
Secondary Endpoint
Change from baseline in FPG at Week 16
Statistical 
Methods 
for 
Key 
Efficacy Analyses
Change from baseline in HbA1c at Week 16 will be analyzed using a 
constrained longitudinal data analysis (cLDA) model proposed by Liang 
and Zeger [12]. The model will include terms for treatment, prior AHA 
therapy status (yes/no), time and the interaction of time by treatment, 
time by prior AHA therapy status and time by treatment by prior AHA 
status. The primary hypothesis which is the superiority of omarigliptin to 
placebo, will be evaluated by using the cLDA model.
Statistical 
Methods 
for 
Key 
Safety Analyses
Safety will be assessed following a tiered-approach by clinical review of 
all relevant parameters including AEs, PDLCs, laboratory tests, vital 
signs, body weight and ECG. AEs of symptomatic hypoglycemia will be 
pre-specified as Tier 1 events.
The percentage of subjects experiencing Tier 1 events will be analyzed 
using the Miettinen and Nurminen method [13]. P-Values for treatment 
comparisons and 95% confidence intervals (CIs) for treatment differences 
will be provided.
Interim Analyses
No interim analysis is planned.
Multiplicity
Given a single primary hypothesis, no multiplicity adjustment is required.
Sample Size and Power
A sample size of 180 subjects in a 2:1 ratio (i.e., 120 and 60 subjects for 
omarigliptin and placebo, respectively) will provide 97% power to detect 
a treatment difference of 0.50% in HbA1c reduction from baseline at 
Week 16 (α=0.05, two-sided test) based on the conditional standard 
deviation of 0.82% and the correlation matrix and subject attrition 
assumptions specified in Section 8.9. The half-width of the 95% CI is 
expected to be 0.26%.  In addition, the sample size is expected to provide 
100 or more subjects exposed for one year (omarigliptin group only), 
assuming 15% discontinuation rate for 52 weeks.
 
 
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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 
SPONSOR.
This study will be conducted as a double-blind study for first 16-weeks [Phase A (double-
blind period)] under in-house blinding procedures with following 36-weeks extension part
[Phase B (Open-label period)], i.e. total of 52-weeks study.  With regard to Week 16, the 
official, final database for Week 16 will not be unblinded until medical/scientific review has 
been performed, protocol violators have been identified, and data have been declared final 
and complete.  With regard to Week 52, the official, final database will not be frozen until 
medical/scientific review has been performed and data have been declared final and complete.  
The Clinical Biostatistics department in Merck will generate the randomized allocation 
schedule for study treatment assignment. 
Hypotheses/ Estimation
8.3
Objectives and hypotheses of the study are stated in Section 3.0.
Analysis Endpoints
8.4
Efficacy and safety endpoints that will be evaluated for within- and/or between-treatment 
differences are listed below.
The baseline value will be defined as the Visit 4/Day 1/Randomization measurement.  If this 
measurement is not available, the Visit 3/Week -2 measurement will be used as the baseline 
value.  If neither measurement is available, the baseline value will be treated as missing. The 
primary time point is Week 16.
Efficacy Endpoints
8.4.1
The efficacy measurements and time points at which they are measured are provided in 
Section 6.0 (the Trial Flow Chart).
The primary efficacy endpoint in the study is the change from baseline in HbA1c at Week 16.
The secondary efficacy endpoints in the study are the change from baseline in Fasting Plasma 
Glucose (FPG) and 1,5-anhydroglucitol (1,5-AG) at Week 16, and the percentages of 
subjects at HbA1c goals (<7.0% and <6.5%) at Week 16.
The other secondary efficacy endpoints in the study are the change from baseline in HbA1c 
and FPG at Week 52 and the percentages of subjects at HbA1c goals (<7.0% and <6.5%) at 
Week 52.
The insulin dose and percentages of subjects with up-titration and down-titration of insulin 
dose at Week 16 and Week 52 are other efficacy endpoints.
In describing the efficacy variables of interest below, the description is restricted to the 
primary time point of interest (Week 16).  However, many variables are measured at 
additional time points, as indicated in the Trial Flow Chart (Section 6.0), and will be 
summarized at other time points.
 
 
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Table 9 Efficacy Endpoints
Primary Endpoint
Change from baseline in HbA1c at Week 16
Secondary Endpoint
Change from baseline in FPG at Week 16
Percentages of subjects at HbA1c goals (<7.0% and <6.5%) at Week 16
Change from baseline in 1,5-AG at Week 16
Change from baseline in HbA1c at Week 52
Change from baseline in FPG at Week 52
Percentages of subjects at HbA1c goals (<7.0% and <6.5%) at Week 52
Safety Endpoints
8.4.2
The primary safety endpoint (i.e. Tier 1 safety endpoint) is the percentage of subjects 
experiencing one or more adverse events of symptomatic hypoglycemia, regardless of 
glucose value. 
Other safety endpoints include adverse events, percentages of subjects meeting predefined 
limits of change in laboratory parameters (including blood chemistry and hematology), 
change (or percent change) from baseline at Week 16 and Week 52 in laboratory parameters, 
ECG, vital signs and body weight, and the numbers and percentages of subjects experiencing 
one or more of each the following:  

Adverse events of hypoglycemia (symptomatic or asymptomatic)

Documented symptomatic hypoglycemia: An episode with clinical symptoms 
attributed to hypoglycemia with a documented glucose level of ≤70 mg/dL.

Severe hypoglycemia, defined as adverse events of symptomatic hypoglycemia that 
required assistance, either medical or non-medical, regardless of whether such 
assistance was obtained. These events will be further sub-classified as: 

Those that required medical assistance. Adverse events of symptomatic 
hypoglycemia that included a markedly depressed level of consciousness, loss of 
consciousness, or seizure will be classified as having required medical assistance, 
whether or not medical assistance was obtained. 

Those that did not require medical assistance. (i.e., those episodes that required 
non-medical assistance to treat).

Asymptomatic hypoglycemia:  An episode with a documented glucose level of 
≤70 mg/dL but without clinical symptoms attributed to hypoglycemia.
 
 
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Analysis Populations
8.5
Efficacy Analysis Populations
8.5.1
The Full Analysis Set (FAS) population will serve as the primary population for the analysis 
of efficacy endpoints in this study. The FAS population consists of all randomized subjects 
who:

receive at least one dose of study treatment.

have at least one measurement (baseline or post-randomization).
A secondary population for analyzing efficacy endpoints will be the Per-Protocol (PP) 
population. The PP population consists of all randomized subjects who have a baseline (Visit 
4/Day 1/Randomization) measurement and a measurement at Week 16, without the following 
protocol violations. 
Protocol violations are not just a repetition of the exclusion and inclusion criteria in the 
protocol, but a clinical assessment of deviations from the protocol-specified criteria that will 
either affect or confound the measures of efficacy. Subjects meeting any of the following 
criteria will be excluded from the per-protocol population (at all time points).

Study drug compliance <75%, with compliance based on prime therapy records using 
the formula provided in Section 8.11.

Use of prohibited medications, based on the list of prohibited medications in 
Section 5.5, as follows:

Prohibited anti-hyperglycemic medications after randomization (Visit 4/Day 
1/Randomization) for a total of ≥14 days or ≥7 consecutive days.

Pharmacologic doses of corticosteroid use ≥2 consecutive weeks during the study 
period of interest.

Incorrect double-blind study medication for a total of ≥14 days (two times) during the 
study period of interest. 
The final determination on protocol violations, and thereby the composition of the PP 
population, will be made prior to unblinding of the database for week 16 and will be 
documented in a separate memo.
Any substantial differences between conclusions based on the FAS population and the PP 
population will be investigated. The number of subjects included in the FAS and PP 
populations may vary across endpoints due to the degree of missing data for each endpoint.
Subjects will be included in the treatment group to which they are randomized for all 
analyses of efficacy data. 
To avoid the confounding influence of rescue therapy on efficacy comparisons at Week 16, 
efficacy analyses in the FAS and PP populations will treat data as missing after the initiation 
of rescue therapy.  Outlines on the approach to handling missing data are provided in 
Section 8.6, Statistical Methods. Sensitivity analysis to assess the impact of missing data will 
be described in sSAP.
 
 
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Safety Analysis Populations
8.5.2
The All-Subjects-as-Treated (ASaT) population will be used for the analysis of safety data in 
this study.  The ASaT population consists of all randomized subjects who received at least 
one dose of study treatment. Subjects will be included in the treatment group corresponding 
to the study treatment they actually received for the analysis of safety data using the ASaT 
population.  This will be the treatment group to which they are randomized for all subjects 
except for those who take incorrect study treatment for the entire treatment period.  Such 
subjects will be included in the treatment group corresponding to the study treatment actually 
received.
At least one laboratory or vital sign measurement obtained subsequent to at least one dose of 
study treatment is required for inclusion in the analysis of each specific parameter.  To assess 
change (or percent change) from baseline, a baseline measurement is also required.
All safety endpoints analyses will be based on the observed data (i.e., with no imputation of 
missing data).
Statistical Methods
8.6
Statistical testing and inference for efficacy and safety analyses are described in 8.6.1 and 
8.6.2, respectively. Nominal p-values may be computed for other efficacy analyses as a 
measure of strength of association between the endpoint and the treatment effect rather than 
formal tests of hypotheses. All statistical tests will be conducted at α=0.05, two-sided.
Efficacy Analysis
8.6.1
This section describes the statistical methods that address the primary and secondary 
objectives. 
The estimand for the primary analysis approach for HbA1c and FPG consists of the 
following elements:
•
Target population: Japanese patients with T2DM who have inadequate glycemic 
control on insulin monotherapy.
•
Endpoints:  mean change from baseline at Week 16 in HbA1c and in FPG.
•
Measure of intervention effect: Difference in means in the effect of randomized 
treatments if all subjects followed the randomized treatment (without the addition 
of any other AHAs) through Week 16.
For the analysis of the primary endpoint (i.e., change from baseline in HbA1c at Week 16) in 
the FAS population, a constrained longitudinal data analysis (cLDA) method proposed by 
Liang and Zeger [12] will be used. This model assumes a common mean across treatment 
groups at baseline and a different mean for each treatment at each of the post-baseline time 
points. In this model, the response vector consists of baseline values and the values observed 
at each post-baseline time point. Time is treated as a categorical variable so that no restriction 
is imposed on the trajectory of the means over time. The analysis model will adjust for 
treatment, prior AHA therapy status (yes/no), time and the interaction of time by treatment, 
time by prior AHA therapy status and time by treatment by prior AHA status. The primary 
hypothesis which is the superiority of omarigliptin to placebo on mean HbA1c change from 
 
 
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baseline at Week 16 will be demonstrated using above cLDA model. The Kenward-Roger 
adjustment will be used with restricted (or residual) maximum likelihood (REML) to make 
proper statistical inference. An unstructured covariance matrix will be used to model the 
correlation among repeated measurements and hence avoids the potential bias that could 
result from the use of specific structured covariance models. If the unstructured covariance 
model fails to converge with the default Newton-Raphson algorithm, the Fisher scoring 
algorithm or other appropriate methods can be used to provide initial values of the covariance 
parameters. In the rare event that none of the above methods yield convergence, a structured 
covariance such as Toeplitz can be used to model the correlation among repeated 
measurements. In this case, the empirical option will be used because the sandwich variance 
estimator is asymptotically unbiased while the model-based variance estimator can grossly 
overestimate or underestimate the true variance. The cLDA model uses the maximum 
likelihood principle to estimate the parameters and account for missing data in an implicit 
fashion.
To avoid the confounding influence of rescue therapy on efficacy comparisons at Week 16, 
efficacy analyses in the FAS and PP populations will treat data as missing after the initiation 
of rescue therapy. Sensitivity analyses will be performed to assess the robustness of the 
results to the assumptions about missing data. The details will be described in sSAP. 
Secondary efficacy endpoint of FPG at Week 16 will be analyzed using the above cLDA 
method described for HbA1c in the same fashion. 
Analyses in the PP population for the primary and secondary efficacy endpoints at Week 16 
will be performed using a repeated measures analysis of covariance (RM ANCOVA), in 
which the response vector consists of change from baseline at each of the post-baseline time 
points. The model will include the same terms for the cLDA model above, and baseline value 
as a covariate.
For the analysis of percentages of individuals at the HbA1c goals of <7.0% and <6.5% at 
Week 16, the constrained longitudinal data analysis (cLDA) model that is used for the 
analysis of HbA1c will also be used to impute Week 16 missing data on HbA1c.  Imputations 
of the missing data will be based on the marginal univariate normal distributions with means 
equal to the predicted values and variances equal to the squared standard errors for the 
predicted values from the cLDA model. Ten sets of imputations of each missing value will be 
constructed from the cLDA model.  The seed for the random number generator will be 
3102039.  Observed data will not be imputed.  Subjects will be categorized as a responder 
(satisfying the HbA1c specific goal of <7.0% or <6.5%) or non-responder at Week 16 after 
imputations.  
To estimate the within-group response rates and between-group rate difference, each of the 
10 imputed data sets will be summarized to obtain the proportion of responders within each 
group. The estimated proportions of responders from the 10 imputed data sets will be 
combined using the standard multiple imputation (MI) techniques [14] to yield an overall 
estimate of response rate and associated variance for each group. The estimated response 
rates and effective sample sizes [15] will then be used to obtain the confidence intervals for 
within-group response rates via the Wilson score method [16], and the confidence interval 
and p-value for between-group rate difference via Miettinen & Nurminen (M&N) method 
[13].
 
 
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Other efficacy secondary endpoint of change from baseline in 1,5-anhydroglucitol at 
Week 16 will be analyzed using the above cLDA method described for HbA1c in the same 
fashion.
Table 10 summarizes the key efficacy analyses. The strategy to address multiplicity issues 
with regard to multiple endpoints is described in Section 8.8, Multiplicity.
Table 10 Analysis Strategy for Key Efficacy Variables
Endpoint
Approach
Statistical 
Method
Analysis Population
Missing Data 
Approach
Primary
Change from baseline in HbA1c 
at Week 16
P
cLDA
FAS
Model-based
S
RM ANCOVA
PP
N/A
S
Missing Data 
Methods§
§
§
Secondary
Change from baseline in FPG at 
Week 16
P
cLDA
FAS
Model-based
S
RM ANCOVA
PP
N/A
Percentages 
of 
subjects 
at 
HbA1c 
goals 
(<7.0% 
and 
<6.5%) at Week 16
P
M&N
FAS
MI
Change from baseline in 1,5-AG
at Week 16
P
cLDA
FAS
Model-based
Change from baseline in HbA1c
at Week 52
P
Summary 
Statistics
FAS
N/A
Change from baseline in FPG at 
Week 52
P
Summary 
Statistics
FAS
N/A
Percentages 
of 
subjects 
at 
HbA1c 
goals 
(<7.0% 
and
<6.5%) at Week 52
P
Summary 
Statistics
FAS
N/A
P=Primary; S=Secondary.
§ Sensitivity analyses will be performed to assess the impact of missing data. Details will be provided in the sSAP.
For long-term efficacy data up to Week 52, the mean change and the 95% confidence 
intervals will be calculated by treatment groups of double-blind period to assess the long-
term efficacy of omarigliptin. The mean change will be computed relative to baseline (Visit 
4/Day 1/Randomization). Between-groups comparisons and/or estimation of between-group 
difference will not be performed.
For the HbA1c goals of <7.0% and <6.5% at Week 52, the percentage of individuals and the 
95% confidence intervals will be calculated using Wilson score method [16] by treatment 
groups of double-blind period.
For long-term efficacy analyses, all data will be included in the analysis regardless of 
initiating the rescue therapy since insulin dose during extension period are allowed to down 
or up –titrate if clinically required.
The summary statistics for the insulin dose, percentages of subjects with up-titration and 
down-titration of insulin dose will be generated by treatment group of double-blind period at 
Week 16 and Week 52.
 
 
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Safety Analysis
8.6.2
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
adverse events (AEs), laboratory tests, ECG, vital signs and body weight.
The ASaT population will be employed for safety analyses. Data after the initiation of rescue 
therapy will be excluded from the safety analyses for primary safety approach for double-
blind period but those data will be included for the secondary safety approach for double-
blind period. For long-term safety analyses, all data will be included in the analysis 
regardless of initiating the rescue therapy, since insulin dose during Phase B (open-label 
period) are allowed to down or up –titrate if clinically required .
Double-Blind Safety Assessment
The analysis of safety results in the double-blind period will follow a tiered approach 
(Table 11).  The tiers differ with respect to the analyses that will be performed.  Safety 
parameters or adverse events of special interest that are identified a priori constitute “Tier 1” 
safety endpoints that will be subject to inferential testing for statistical significance with p 
values and 95% CIs provided for between-group comparisons. Between-group comparisons 
will be made between active treatment groups versus placebo.  Other safety parameters will 
be considered Tier 2 or Tier 3.  Tier 2 parameters will be assessed via point estimates with 
95% CIs provided for between-group comparisons; only point estimates by treatment group 
are provided for Tier 3 safety parameters.
Adverse events (overall summary, specific terms, system organ class terms, confirmed 
adjudicated pancreatitis) and predefined limits of change (PDLC) in laboratory parameters 
that are not pre-specified as endpoints of special interest will be classified as belonging to 
"Tier 2" or "Tier 3", based on the number of events observed. Membership in Tier 2 requires 
that at least 4 subjects in any treatment group exhibit the event or meet the PDLC criterion.  
All other adverse events and PDLCs will belong to Tier 3.
Because many 95% CIs may be provided without adjustment for multiplicity, the CIs should 
be regarded as a helpful descriptive measure to be used in review, and not as a formal method 
for assessing the statistical significance of the between-group differences in adverse events 
and PDLC. 
Change from baseline in body weight at Week 16 will belong to Tier 2 and will be analyzed 
using a cLDA method described for HbA1c where imputation of missing data is model-based
(i.e., accounting for missing data in an implicit fashion).
Continuous measures such as changes (or percent change) from baseline in laboratory, ECG, 
vital signs and body weight parameters that are not pre-specified as Tier-1 endpoints will be 
considered Tier 3 safety parameters.  Summary statistics for baseline, on-treatment, and 
change (or percent change) from baseline values will be provided by treatment group in table 
format.  Mean change (or Mean percent change) from baseline over time will be plotted.  For 
safety endpoints except for body weight, all analyses will be based on the observed data (i.e., 
with no imputation of missing data).
Table 11 summarizes the analysis strategy for safety endpoints.  P-Values and 95% CIs for 
between-treatment differences (vs placebo) in the percentage of subjects with AEs of 
symptomatic hypoglycemia identified by the investigator (Tier 1), will be calculated using 
 
 
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M&N method [13].  For Tier 2 endpoints, 95% CIs for between-treatment differences will be 
provided using the M&N method.
Table 11 Analysis Strategy for Safety Parameters
Tier
Safety Endpoint
p-
Value
95% CI for 
Treatment 
Comparison
Descriptiv
e 
Statistics
Tier 1
Any AE of symptomatic hypoglycemia
X
X
X
Tier 21
AE overall summary
X
X
Specific AEs2, SOCs, confirmed pancreatitis and 
PDLCs
X
X
Any AE of hypoglycemia
X
X
  Documented symptomatic
X
X
  Severe hypoglycemia
X
X
    Requiring medical assistance
X
X
    Not requiring medical assistance
X
X
  Asymptomatic hypoglycemia
X
X
Change from baseline in body weight at Week 16
X
X
Tier 3
All endpoints listed under Tier 2 (above) that have 
incidence <4 subjects in all treatment groups
X
Additional hypoglycemia adverse event endpoints
X
Change and percent change from baseline results 
(laboratory measurements, ECG and vital signs)
X
1 Endpoints listed here will qualify for Tier 2 only if the incidence is ≥4 subjects in at least one of the treatment 
groups.
2 Among those endpoints not prespecified as Tier 1 endpoints.
SOC=System Organ Class; PDLC=Pre-Defined Limit of Change; X = results will be provided.
Hypoglycemia
The Tier 1 and Tier 2 hypoglycemia endpoints defined in Section 8.4.2 will be analyzed in 
the same ways described above. The Tier 3 summary of hypoglycemia will include the 
following, based on episodes classified by the investigator as adverse events:

The numbers and percentages of subjects with each of the following, overall and by
lowest reported glucose category (<50 mg/dL, ≤70 mg/dL, >70 mg/dL, or unknown).
A subject's lowest glucose category will be classified as unknown only if no glucose 
measurements are available for that subject.
1.
any episodes (symptomatic or asymptomatic)
2.
symptomatic episodes
3.
asymptomatic episodes

The numbers and percentages of subjects with episodes having precipitating factors,
overall and separately by factor.

The number of episodes per subject.
 
 
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
The number of each of the following (summed across all subjects). The overall 
summary will include an indication of whether precipitating factors were present.
1.
all episodes (symptomatic or asymptomatic)
2.
symptomatic episodes
3.
asymptomatic episodes
A summary of subjects with episodes that were reported on the hypoglycemia assessment
eCRF but were not classified by the investigator as adverse events, will also be provided. If a 
substantial number of subjects had episodes that were not classified as adverse events, then 
additional summaries may be provided for the Tier 3 analyses above, including all episodes 
reported on the hypoglycemia assessment eCRF (i.e., not restricted to adverse events). It is 
expected that all symptomatic hypoglycemia episodes will be classified by the investigator as 
adverse events and, thus, that any episodes that are not classified as adverse events will be 
asymptomatic episodes.
Long-Term Safety Assessment
For safety parameters at Week 52, the incidence rates of adverse or PDLC events and/or 
summary statistics on the continuous safety parameters will be calculated separately based on 
treatment received in the double-blind period. However, the safety results will only include 
the period that subjects are treated with omarigliptin. For subjects who were randomized to 
omarigliptin in the double-blind period, who continued to be administered omarigliptin in the 
open-label period (referred to as the omarigliptin/omarigliptin group), the results will be 
reported for whole duration of the study, Phase A and Phase B (i.e., 52-weeks). For subjects 
who were randomized to placebo in the double-blind period, who were switched to 
omarigliptin in the open-label period (referred to as the placebo/omarigliptin group), the 
results will be reported for the duration of omarigliptin administration in Phase B (i.e., 36-
weeks). The between-groups comparisons and/or estimation of between-group difference will 
not be performed. Mean change from baseline in body weight up to Week 52 will be 
calculated by treatment group of double-blind period. The mean change will be computed 
relative to baseline (Visit 4/Day 1/Randomization).
Interim Analyses
8.7
No interim analyses is planned for the study.
The statistical analysis for double-blind data will be performed at Week 16 and then the final 
analysis for long-term data will be performed at Week 52.
Multiplicity
8.8
The primary evaluation of the glycemic efficacy in this study will be based on testing the
primary hypotheses for HbA1c at Week 16. Since there is only one primary hypothesis, no 
multiplicity adjustment will be needed. 
Comparisons involving other efficacy endpoints are considered supportive or exploratory and 
will be made at α=0.05 nominal level (two-sided) and 95% CIs will be provided. No 
multiplicity adjustment will be performed for these other comparisons.
 
 
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Sample Size and Power Calculations
8.9
Efficacy analyses
A sample size of 180 subjects in a 2:1 ratio (i.e., 120 and 60 subjects for omarigliptin and 
placebo, respectively) will be equivalent to an effective sample size of 176 at Week 16 in the 
power calculation for the primary hypothesis test using the cLDA model.  The effective 
sample size accounts for information loss due to missing data and the correlation among 
repeated measures, and is derived using the method proposed by Lu, et al. [17] under the 
assumptions of cumulative attrition rates and covariance matrix at Weeks 4, 8, 12, and 16
specified below. An effective sample size of 176 will provide 97% power to detect a 
treatment difference of 0.5% at Week 16 (α=0.05, two-sided test) assuming the conditional 
standard deviation is 0.82%. In addition, it will provide 90% (80%) power to detect a 
treatment difference of 0.43% (0.37%). The half-width of the 95% CI is expected to be 
0.26%. These calculations were based upon the following assumptions: 
•
Cumulative attrition rates, which include HbA1c data considered missing after 
rescue, at Weeks 4, 8, 12, and 16 are 0.0125, 0.0250, 0.0375, 0.0500, respectively
•
A conditional correlation matrix at Weeks 4, 8, 12, and 16 is 
The cumulative attrition rates and correlation assumptions above are based on data from MK-
0431 PN106.  
Given the effective sample size above, the treatment difference of 25.0 mg/dL (21.6 mg/dL) 
can be detected with 90% (80%) power for the secondary efficacy endpoint, change from 
baseline in the fasting plasma glucose (FPG) at Week 16, assuming the conditional standard 
deviation is 48 mg/dL.
Safety analyses
The sample size is expected to provide 100 or more subjects exposed for one year 
(omarigliptin group only), assuming 15% discontinuation rate for 52 weeks.
The probability of observing at least one specific adverse event in this study depends on the 
number of subjects and the underlying percentage of subjects with a specific adverse event in 
the study population. If the underlying incidence of a specific adverse event is 1%, there is a 
70% and 45% chance of observing at least one specific adverse event among 120 and 60 
subjects, respectively. If no adverse events are observed among the 120 and 60 subjects, this 
study will provide 95% confidence that the underlying percentage of subjects with an adverse 
event is <2.5% and <4.9%, respectively.
 
 
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Subgroup Analyses and Effect of Baseline Factors
8.10
To assess whether the treatment effect at Week 16 is consistent across various subgroups, the 
estimate of the between-group treatment effect (with a nominal 95% CI) against placebo for 
the primary efficacy endpoint will be estimated within each category of the following 
classification variables. The consistency of the treatment effect will be assessed in the 
context of the primary efficacy analysis model (i.e. cLDA model).  Formal statistical testing 
of these interactions will not be performed.

Baseline HbA1c levels: by categories: <8%, ≥8%

Age: by categories: <65 years, ≥65 years

Gender (female, male)

BMI: by categories: <25 kg/m2, ≥25 kg/m2

Duration of diabetes (≤10 years, >10 years)

Prior AHA status (yes, no)
Results from the subgroup analyses should be reviewed cautiously.  Because sample sizes 
within subgroups will be smaller than the overall study sample size, estimation may not be 
precise and 95% CIs will usually be wide in the subgroup analyses.
To assess whether the mean HbA1c change from baseline at Week 52 is consistent across 
subgroups, the summary statistics will be generated by subgroup in each treatment group.
Compliance (Medication Adherence)
8.11
The computation of compliance will be based on the study medication case report form.  
Both the assigned treatment and any matching placebo tablets will be encompassed in the 
compliance calculation.
The compliance will be based on the compliance week for once-weekly omarigliptin or 
matching placebo.  According to trial design, study medication is recommended to be taken 
on the scheduled day of dosing, although it is acceptable for the dose to be taken at any day 
of 7-day dosing period up to the day before the next scheduled dose.  Therefore, the week of 
7-day dosing period will be considered a compliant week provided that the subject reports 
taking one tablet of omarigliptin or matching placebo on any day of the week. Otherwise, the 
week will be non-compliant. Any day within a compliant week is a compliant day for 
omarigliptin or matching placebo. Any day within a non-compliant week is a non-compliant 
day for omarigliptin or matching placebo.
For Phase A (double-blind period), compliance will be summarized for both treatment groups 
in Phase A, For Phase B (open-label period), compliance will be summarized for only the 
placebo group of the double-blind period.  For Phase A+B (whole study period), compliance 
will be summarized for only the omarigliptin group of the double-blind period.  Compliance 
in Phase B alone will not be summarized for the omarigliptin group of the double-blind 
period, and compliance in Phase A+B will not be summarized for the placebo group of the 
double-blind period to be consistent with safety assessments. 
 
 
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Summary statistics for each relevant period will be provided on percent compliance by 
treatment group of double-blind period. For each subject, the percent compliance for the 
relevant duration will be calculated using the following formula:
Compliance  =
Number of Compliant Days
× 100%.
Number of Days in the Respective Study Period
The "Number of Days in the Respective Study Period" is defined for each subject as the total 
number of days from the first day to the final day as defined in Table 12 below.
Table 12 Definitions of Study Periods
Study Period
Treatment Groups  
First Day
Final Day
Phase A
(double-blind 
period)
Omarigliptin and 
Placebo groups
The first dose of double-
blind study medication
The last scheduled day 
of study medication 
+ 6 days
Phase B
(open-label period)
Placebo group of 
double-blind period
The first dose of 
omarigliptin in Phase B
The last scheduled day  
of omarigliptin 
+ 6 days
Phase A+B
(whole study period)
Omarigliptin group 
of double-blind 
period
The first dose of double-
blind study medication
The last scheduled day 
of study medication 
+ 6 days
Extent of Exposure
8.12
The extent of exposure to study treatment will be summarized by treatment group.
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 13.
Table 13 Product Descriptions
Product Name & 
Potency
Dosage Form
Source/Additional Information
Omarigliptin (MK-3102)
25 mg 
or 
matching 
placebo
Tablet
Provided centrally by the Sponsor 
All placebos were created by the Sponsor to match the active product.
 
 
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Packaging and Labeling Information
9.2
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements.
In the placebo run-in period, subjects will receive one single-blinded bottle of Omarigliptin
25 mg matching placebo. In the Phase A (Double-blind period), subjects will receive one 
blinded bottle of Omarigliptin 25 mg or matching placebo every four (4) weeks. In the Phase 
B (Open-label period), subjects will receive sufficient supplies of open label bottle of 
Omarigliptin 25 mg to support a period between visits. No kitting is required.
Clinical Supplies Disclosure
9.3
The emergency unblinding call center will use the treatment allocation/randomization 
schedule for the trial to unblind subjects and to unmask treatment identity Phase A (Double-
blind period) of this trial. The Sponsor will not provide random code/disclosure envelopes or 
lists with the clinical supplies.
Treatment identification information is to be unmasked ONLY if necessary for the welfare of 
the subject.  Every effort should be made not to unblind the subject unless necessary. 
In the event that unblinding has occurred, the circumstances around the unblinding (e.g., 
date, reason and person performing the unblinding) must be documented promptly, and the 
Sponsor Clinical Director notified as soon as possible.  Only the principal investigator or 
delegate and the respective subject’s code should be unblinded.  Trial site personnel and 
Sponsor personnel directly associated with the conduct of the trial should not be unblinded to 
treatment assignment. Subjects whose treatment assignment has been unblinded (by the 
investigator, Merck subsidiary, or through the emergency unblinding call center) must be 
discontinued from study drug.
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.  
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.
 
 
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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, 
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.
 
 
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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.
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.
 
 
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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 
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.
 
 
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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 Protocol/CSR 
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 Amendments Act (FDAAA) of 2007 
and the European Medicines Agency (EMA) clinical trial Directive 2001/20/EC, the Sponsor 
of the trial is solely responsible for determining whether the trial and its results are subject to 
the 
requirements 
for 
submission 
to 
http://www.clinicaltrials.gov, 
www.clinicaltrialsregister.eu or other local registries.  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 FDAAA or the EMA clinical trial directive 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 
FDAAA, the EMA clinical trials directive or other locally mandated registries are that of the 
Sponsor and agrees not to submit any information about this trial or its results to those 
registries.
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.
 
 
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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 
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 
 
 
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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.
11.0 LIST 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. Seventh
edition. 2015
Executive Summary. International Diabetes Federation. 2015.
4.
Heath Service Bureau, Ministry of Health, Labor and Welfare. National Health and 
Nutrition Examination Survey in 2012. December-2012. Japanese
5.
Japan Diabetes Clinical Data Management Study Group. Summarized data in fiscal 2013. 
2014. Japanese
6.
Drucker DJ. The biology of incretin hormones. Cell Metab 2006;3(3):153-65.
7.
Drucker DJ, Sherman SI, Gorelick FS, Bergenstal RM, Sherwin RS, Buse JB. 
Incretinbased therapies for the treatment of type 2 diabetes: evaluation of the risks and 
benefits. Diabetes Care 2010;33(2):428-33.
8.
Parker HE, Reimann F, 
Gribble FM. 
Molechular mechanisms 
underlying 
nutrientstimulated incretin secretion. Expert Rev Mol Med 2010 Jan 5;12:e1, dol 
10.1017, S146239940900132X.
9.
Hare KJ, Vilsbøll T, Asmar M, Deacon CF, Knop FK, Holst JJ. The glucagonostatic and 
insulinotropic effects of glucagon-like peptide 1 contribute equally to its 
glucoselowering action. Diabetes 2010;59(7):1765-70.
10. Nauck MA, Meininger G, Sheng D, Terranella L, Stein PP. Efficacy and safety of the
dipeptidyl peptidase-4 inhibitor, sitagliptin, compared with the sulfonylurea, glipizide, in 
patients with type 2 diabetes inadequately controlled on metformin alone: a randomized, 
double-blind, non-inferiority trial. Diabetes Obes Metab 2007 Mar;9(2):194-205.
11. Guideline on Clinical Evaluation Methods for Oral Hypoglycemic Agents (draft), 
MHLW PFSB, Draft, 19th May 2014
12. Liang K, Zeger, S. Longitudinal data analysis of continuous and discrete responses for 
pre-post designs. Sankhyā: The Indian Journal of Statistics. 2000; 62(Series B): 134-
148.
13. Miettinen O, Nurminen M. Comparative analysis of two rates: Stat Med. 1985; 4(2): 
213-226.
14. Rubin DB (1987). Multiple Imputations for Nonresponse in Surveys. Wiley, NewYork.
 
 
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15. Liu GF. A note on effective sample size for constructing confidence intervals for the 
difference of two proportions. Pharmaceutical Statistics 2012;11(2):163-9.
16. Wilson EB. Probable inference, the law of succession, and statistical inference. Journal 
of the American Statistical Association 1927;22(158):209-12.
17. Lu K, Mehrotra DV, Liu G. Sample size determination for constrained longitudinal data 
analysis. Statistics in Medicine 2009;15;28(4):679-99.
 
 
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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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Collection and Management of Specimens for Future Biomedical Research
12.2
1. Definitions
a.
Biomarker:  A biological molecule found in blood, other body fluids, or tissues that is a 
sign of a normal or abnormal process or of a condition or disease.  A biomarker may be 
used to see how well the body responds to a treatment for a disease or condition.1
b. Pharmacogenomics:  The investigation of variations of DNA and RNA characteristics as 
related to drug/vaccine response.2
c.
Pharmacogenetics:  A subset of pharmacogenomics, pharmacogenetics is the influence of 
variations in DNA sequence on drug/vaccine response.2
d. DNA:  Deoxyribonucleic acid.
e.
RNA:  Ribonucleic acid.
2. Scope of Future Biomedical Research
The specimens consented and/or collected in this trial as outlined in Section 7.1.3.3 –
Future Biomedical Research Samples will be used in various experiments to understand:
o
The biology of how drugs/vaccines work
o
Biomarkers responsible for how a drug/vaccine enters and is removed by the body
o
Other pathways drugs/vaccines may interact with
o
The biology of disease
The specimen(s) may be used for future assay development and/or drug/vaccine 
development.
It is now well recognized that information obtained from studying and testing clinical 
specimens offers unique opportunities to enhance our understanding of how individuals 
respond to drugs/vaccines, enhance our understanding of human disease and ultimately 
improve public health through development of novel treatments targeted to populations 
with the greatest need.  All specimens will be used by the Sponsor or those working for 
or with the Sponsor.
3. Summary of Procedures for Future Biomedical Research
a.
Subjects for Enrollment
All subjects enrolled in the clinical trial will be considered for enrollment in the 
Future Biomedical Research sub-trial.
b. Informed Consent
Informed consent for specimens (i.e., DNA, RNA, protein, etc.) will be obtained 
during screening for protocol enrollment from all subjects or legal guardians, at a trial 
visit by the investigator or his or her designate.  Informed consent for Future 
Biomedical Research should be presented to the subjects on the visit designated in the 
trial flow chart.  If delayed, present consent at next possible Subject Visit.  Consent 
forms signed by the subject will be kept at the clinical trial site under secure storage 
for regulatory reasons.  
 
 
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A template of each trial site’s approved informed consent will be stored in the 
Sponsor’s clinical document repository.
c.
eCRF Documentation for Future Biomedical Research Specimens
Documentation of subject consent for Future Biomedical Research will be captured in 
the electronic Case Report Forms (eCRFs). Any specimens for which such an 
informed consent cannot be verified will be destroyed.
d. Future Biomedical Research Specimen(s)
Collection of specimens for Future Biomedical Research will be performed as 
outlined in the trial flow chart. In general, if additional blood specimens are being 
collected for Future Biomedical Research, these will usually be obtained at a time 
when the subject is having blood drawn for other trial purposes.
4. Confidential Subject Information for Future Biomedical Research 
In order to optimize the research that can be conducted with Future Biomedical Research 
specimens, it is critical to link subject' clinical information with future test results. In fact 
little or no research can be conducted without connecting the clinical trial data to the 
specimen. The clinical data allow specific analyses to be conducted. Knowing subject 
characteristics like gender, age, medical history and treatment outcomes are critical to 
understanding clinical context of analytical results.
To maintain privacy of information collected from specimens obtained for Future 
Biomedical Research, the Sponsor has developed secure policies and procedures. All 
specimens will be single-coded per ICH E15 guidelines as described below. 
At the clinical trial site, unique codes will be placed on the Future Biomedical Research 
specimens.  This code is a random number which does not contain any personally 
identifying information embedded within it. The link (or key) between subject identifiers 
and this unique code will be held at the trial site.  No personal identifiers will appear on 
the specimen tube.  
5. Biorepository Specimen Usage
Specimens obtained for the Sponsor will be used for analyses using good scientific 
practices.  Analyses utilizing the Future Biomedical Research specimens may be 
performed by the Sponsor, or an additional third party (e.g., a university investigator) 
designated by the Sponsor. The investigator conducting the analysis will follow the 
Sponsor’s privacy and confidentiality requirements. Any contracted third party analyses 
will conform to the specific scope of analysis outlined in this sub-trial. Future Biomedical 
Research specimens remaining with the third party after specific analysis is performed 
will be reported to the Sponsor.
6. Withdrawal From Future Biomedical Research 
Subjects may withdraw their consent for Future Biomedical Research and ask that their 
biospecimens not be used for Future Biomedical Research.  Subjects may withdraw 
consent at any time by contacting the principal investigator for the main trial. If medical 
records for the main trial are still available, the investigator will contact the Sponsor 
using 
the 
designated 
mailbox 
(clinical.specimen.management@merck.com). 
 
 
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Subsequently, the subject's specimens will be flagged in the biorepository and restricted 
to main study use only. If specimens were collected from study participants specifically 
for Future Biomedical Research, these specimens will be removed from the biorepository 
and destroyed. Documentation will be sent to the investigator confirming withdrawal 
and/or destruction, if applicable. It is the responsibility of the investigator to inform the 
subject of completion of the withdrawal and/or destruction, if applicable.  Any analyses 
in progress at the time of request for withdrawal/destruction or already performed prior to 
the request being received by the Sponsor will continue to be used as part of the overall 
research trial data and results. No new analyses would be generated after the request is 
received.
In the event that the medical records for the main trial are no longer available (e.g., if the 
investigator is no longer required by regulatory authorities to retain the main trial 
records) or the specimens have been completely anonymized, there will no longer be a 
link between the subject’s personal information and their specimens. In this situation, the 
request for withdrawal of consent and/or destruction cannot be processed.
7. Retention of Specimens 
Future Biomedical Research specimens will be stored in the biorepository for potential 
analysis for up to 20 years from the end of the main study. Specimens may be stored for 
longer if a regulatory or governmental authority has active questions that are being 
answered. In this special circumstance, specimens will be stored until these questions 
have been adequately addressed.
Specimens from the trial site will be shipped to a central laboratory and then shipped to 
the Sponsor-designated biorepository. If a central laboratory is not utilized in a particular 
trial, the trial site will ship directly to the Sponsor-designated biorepository. The 
specimens will be stored under strict supervision in a limited access facility which 
operates to assure the integrity of the specimens.  Specimens will be destroyed according 
to Sponsor policies and procedures and this destruction will be documented in the 
biorepository database.
8. Data Security
Databases containing specimen information and test results are accessible only to the 
authorized Sponsor representatives and the designated trial administrator research 
personnel and/or collaborators. Database user authentication is highly secure, and is 
accomplished using network security policies and practices based on international 
standards to protect against unauthorized access.
9. Reporting of Future Biomedical Research Data to Subjects
No information obtained from exploratory laboratory studies will be reported to the 
subject, family, or physicians. Principle reasons not to inform or return results to the 
subject include: Lack of relevance to subject health, limitations of predictive capability, 
and concerns regarding misinterpretation.
If important research findings are discovered, the Sponsor may publish results, present 
results in national meetings, and make results accessible on a public website in order to 
rapidly report this information to doctors and subjects.  Subjects will not be identified by 
 
 
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name in any published reports about this study or in any other scientific publication or 
presentation.
10. Future Biomedical Research Study Population
Every effort will be made to recruit all subjects diagnosed and treated on Sponsor clinical 
trials for Future Biomedical Research.
11. Risks Versus Benefits of Future Biomedical Research 
For FBR, risks to the subject have been minimized. Risks include those associated with 
venipuncture to obtain the whole blood specimen.  This specimen will be obtained at the 
time of routine blood specimens drawn in the main trial.
The Sponsor has developed strict security, policies and procedures to address subject data 
privacy concerns.  Data privacy risks are largely limited to rare situations involving 
possible breach of confidentiality.  In this highly unlikely situation there is risk that the 
information, like all medical information, may be misused.
12. Questions
Any questions related to the future biomedical research should be e-mailed directly to 
clinical.specimen.management@merck.com.
13. References
1. National Cancer Institute: http://www.cancer.gov/dictionary/?searchTxt=biomarker
2. International Conference on Harmonization: DEFINITIONS FOR GENOMIC 
BIOMARKERS, PHARMACOGENOMICS, PHARMACOGENETICS, GENOMIC 
DATA 
AND 
SAMPLE 
CODING 
CATEGORIES 
-
E15; 
http://www.ich.org/LOB/media/MEDIA3383.pdf
3. Industry Pharmacogenomics Working Group. Understanding the Intent, Scope and 
Public Health Benefits of Exploratory Biomarker Research: A Guide for IRBs/IECs 
and Investigational Site Staff. Available at http://i-pwg.org/
4. Industry Pharmacogenomics Working Group. Pharmacogenomics Informational 
Brochure for IRBs/IECs and Investigational Site Staff. Available at http://i-pwg.org/
 
 
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List of Abbreviations
12.3
Abbreviations
Definition
1, 5-AG
1,5-anhydroglucitol
AE
adverse event
AHA
anti-hyperglycemic agent
ALP
alkaline phosphatase
ALT
alanine aminotransferase
AMA
american medical association
ASaT
all subject as treated
AST
aspartate aminotransferase
BG
biguanide
BMI
body mass index
CAC
clinical adjudication committee
CI
confidence interval
cLDA
constrained longitudinal data analysis
Cr
creatinine
CSR
clinical study report
DILI
drug-induced liver inury
DM
diabetes mellitus
DNA
deoxyribonucleic acid
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
EMA
European medicines agency
ERC
ethics review committee
EU
European Union
FAS
full analysis set
FBR
future biomedical research 
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Amendments Act
FDC
fixed dose combination
FPG
fasting plasma glucose
FSG
finger stick glucose
GCP
Good Clinical Practice
GIP
glucose-dependent insulinotropic peptide
GLP-1
glucagon-like peptide 1
HA
hypoglycemia assessment
HAL
hypoglycemic assessment log
HbA1c
hemoglobin A1c (glycosylated hemoglobin A1c)
HIV
human immunodeficiency virus
ICF
informed consend form
ICH
international conference on harmonisation of technical 
requirements for registration of pharmaceuticals for human use 
IEC
independent ethics committee
IgM
immunoglobulin M
IRB
institutional review board
 
 
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Abbreviations
Definition
IUD
intrauterine device
IVRS
interactive voice response system
IWRS
interactive web response system
M&N
Miettinen & Nurminen
MHLW
Ministry of Health, Labor and Welfare
MI
multiple imputation
PDLC
predefined limits of change
PFSB
Pharmaceutical and Food Safety Bureau
PP
per-protocol
REML
restricted (or residual) maximum likelihood
RM 
ANCOVA
repeated measures analysis of covariance
RNA
ribo nucleic acid
SAE
serious adverse event
SAP
statistical analysis plan
SGLT2
sodium glucose cotransporter 2
SMBG
self-monitoring blood glucose
sSAP
supplemental statistical analysis plan
SU
sulfonylurea
T2DM
type 2 diabetes mellitus
TSH
Thyroid-stimulating hormone
TZD
thiazolidinediones
ULN
upper limit of normal
WBC
white blood cell
α-GI
α-glucosidase inhibitors
β-hCG
β-human chorionic gonadotropin
 
 
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Measurement of blood pressure, body weight and height
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
Ensure subject has not had any caffeine or tobacco within 30 minutes.  Patients should be 
fasted (no food or drink except water) for at least 10 hours prior to blood pressure
measurements.  Blood pressure should be measured in the sitting position.  The subject will 
remain in the sitting position for at least 5 minutes before any blood pressure readings are 
recorded.  The same arm, preferably the non-dominant arm, should be used for all blood 
pressure determinations at each visit.  Systolic and diastolic blood pressure will be 
determined by obtaining two measurements, 1 to 2 minutes apart.  The consecutive systolic 
or diastolic blood pressure readings should be within 5 mmHg of each other.  The final blood 
pressure measurement must be recorded.
Body Weight
12.4.2
Weight will be measured using a standardized scale throughout the study.  
Subjects should be instructed to fast for at least 10 hours prior to the measurement of body 
weight.  Weight will be taken on a digital scale throughout the study, after voiding and while 
wearing only a gown and underwear (no street clothes, no shoes or socks).  Subjects should 
step gently onto the scale, place both feet together in the center of the scale and stand straight 
with eyes directed ahead.  Subjects should be instructed to stand still and not sway.  
Measurement will be recorded after the weight has stabilized.
Weight will be measured to the nearest 0.1 kg.  Measurements will be collected until 
2 consecutive measurements do not differ by more than 0.2 kg from each other.  The final 
weight measurement must be recorded.  The same digital scale must be used throughout the 
study.
Height
12.4.3
Height will be measured without shoes, using a stadiometer.
Standing height will be assessed through maximum vertical stature for persons who can stand 
unassisted.  Hair ornaments, barrettes, braids, jewelry, or cornrows should be moved or 
removed from the top of the head before the measurement is taken.
 
 
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A fixed stadiometer with vertical backboard, fixed floorboard and movable headboard should 
be used.  Subjects should stand with the heels of their feet against the vertical backboard with 
feet pointing outward at approximately a 60-degree angle.  Body weight should be distributed 
evenly with both feet flat on the floor.  The examiner should check several contact points 
with the vertical backboard, including heels, buttocks, shoulder blades, and the back of the 
head.  This may be difficult for subjects with certain body shapes.  However, the head should 
be in the Frankfort plane (an imaginary line from the ear canal to just below the lower orbit 
of the eye should be parallel to the floor).  Subject should be looking straight ahead, and be 
asked to take a deep breath and stand tall.  Once the subject is positioned, the headboard or a 
flat ruler will be placed on top of the head, with sufficient pressure to compress the hair.  The 
measurement is recorded in cm, to the nearest mm.  Measurements will be collected until 
2 consecutive measurements do not differ by more than 2.5 cm from each other.  The final 
height measurement must be recorded.  Some people may have physical conditions that may 
limit the ability to measure height accurately (e.g., kyphosis).  In such cases, height should be 
measured to the best of the examiner’s ability, and a note should be made of the condition.
 
 
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Standard Operating Procedures for Liver Enzyme Elevations
12.5
Every increase in ALT, and/or AST, above the limits described in the protocol is defined as 
clinically significant (i.e., ALT or AST ≥three times the ULN). In addition, when ALT 
and/or AST levels are elevated beyond the clinical significant margin above, the 
investigators/trial staffs 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 ≥three times the 
ULN) with a total bilirubin lab value ≥two times ULN and, at the same time, the ALP lab 
value is <two times ULN, please follow the guidance document entitled " ECI Guidance 
for Potential DILI 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 ≥three times the ULN) but 
who do not also meet the above criteria for both total bilirubin and ALP, 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 ALP.
(6) Perform serologic tests including: (a) Hepatitis A (immunoglobulin M, IgM); (b) 
Hepatitis B (surface antigen and core IgM); (c) Hepatitis C (antibody).
(7) Based upon initial abnormal ALT/AST level:
a)
If ALT or AST levels are ≥three times ULN, but ≤five times ULN, consideration 
can be given to keeping subject on study medication until repeat determination.
b)
If ALT or AST levels are >five 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).
 
 
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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 <three 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 ≥three times ULN, subjects will be discontinued from 
study medication.
Note: If the repeat determination is still ≥three 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 three 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 
≥three 
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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Entry of Hypoglycemic Episode into eCRF
12.6
Report from Subject
Investigator’s Judgment
Enter into eCRF
Subjective 
symptom
SMBG
Hypoglycemic 
episode
Adverse 
event
HA
eCRF
FSG
eCRF
Adverse event eCRF
With
(e.g., 
headache, 
feeling 
hungry)
>70 mg/dL
or
No data
Yes
Yes
X
X 1
“hypoglycemia”
No
Yes
Relevant adverse event term 
(e.g., “headache”)
No
≤70 mg/dL 
-
Yes
X
X
“hypoglycemia”
No
X
X
Without
≤70 mg/dL
-
Yes
X
X
“asymptomatic 
hypoglycemia”
No
X
X
-
: 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
12.7
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
 
 
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