Conditions: Type 2 Diabetes Mellitus
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 458
Healthy volunteers: no

Brief summary:
This trial is designed to evaluate, in adult participants with Type 2 diabetes mellitus (T2DM) and inadequate glycemic control on sub-maximal metformin mono-therapy (1000 mg/day), the effect of up-titration of metformin plus the addition of sitagliptin compared to up-titration of metformin alone on glycemic control. The primary hypothesis of this study is that up-titration of metformin to 2000 mg/day (1000 mg/twice a day) plus the addition of sitagliptin 100 mg/day provides greater reduction in hemoglobin A1C (A1C) compared to metformin up-titration alone. Another primary objective of this study is to evaluate the safety and tolerability of this treatment.

Detailed description:

Arms:
arm 1: Participants will receive sitagliptin 100 mg once daily for 20 weeks. They will also receive immediate-release metformin (Met-IR), which will be titrated from a baseline dose of 1000 mg/day (500 mg/twice a day \[b.i.d.\]) up to 2000 mg/day (1000 mg/b.i.d.) by Day 15. Participants will also receive glycemic rescue therapy as needed. arm 2: Participants will receive placebo matching sitagliptin once daily for 20 weeks. They will also receive Met-IR, which will be titrated from baseline dose of 1000 mg/day (500 mg/b.i.d.) up to 2000 mg/day (1000 mg/b.i.d.) by Day 15. Participants will also receive glycemic rescue therapy as needed.

Interventions: intervention 1: Sitagliptin intervention 2: Placebo intervention 3: Metformin IR
Intervention descriptions: intervention 1: Oral tablet, 100 mg, once daily at approximately the same time each day intervention 2: Oral tablet, once daily at approximately the same time each day intervention 3: All participants will take Met-IR as background medication. Initially, they will take 1 x 500 mg tablet Met-IR b.i.d. (1000 mg/day). After randomization, all participants will be titrated to 2 x 500 mg tablets of Met-IR b.i.d. (2000 mg/day).

Protocol document:
Prot_SAP_000.pdf: 
Official Protocol Title:  A Phase III, Multicenter, Randomized, Double-Blind, Placebo-
Controlled Clinical Trial to Study the Safety and Efficacy of the 
Addition of Sitagliptin During Metformin Up-titration Compared 
with Metformin Up-titration Alone in Subjects with Type 2 
Diabetes Mellitus
NCT number: 
NCT02791490 
Document Date: 
08-Mar-2016


Product:  MK-0431 
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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 III, Multicenter, Randomized, Double-Blind, Placebo-Controlled Clinical Trial to 
Study the Safety and Efficacy of the Addition of Sitagliptin During Metformin Up-titration
Compared with Metformin Up-titration Alone in Subjects with Type 2 Diabetes Mellitus
IND NUMBER:  65,495
EudraCT NUMBER:  2015-004224-59
 
 
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TABLE OF CONTENTS
1.0
TRIAL SUMMARY.................................................................................................... 9
2.0
TRIAL DESIGN.......................................................................................................... 9
Trial Design ............................................................................................................. 9
2.1
Trial Diagram........................................................................................................ 13
2.2
3.0
OBJECTIVE(S) & HYPOTHESIS(ES).................................................................. 13
Primary Objective(s) & Hypothesis(es) .............................................................. 13
3.1
Secondary Objective(s) & Hypothesis(es)........................................................... 14
3.2
4.0
BACKGROUND & RATIONALE.......................................................................... 14
Background ........................................................................................................... 14
4.1
Pharmaceutical and Therapeutic Background .................................................... 14
4.1.1
Rationale................................................................................................................ 15
4.2
Rationale for the Trial and Selected Subject Population .................................... 15
4.2.1
Rationale for Dose Selection/Regimen/Modification ......................................... 17
4.2.2
Rationale for Metformin Dose..................................................................... 17
4.2.2.1
Rationale for Sitagliptin Dose...................................................................... 17
4.2.2.2
Glycemic Rescue ......................................................................................... 17
4.2.2.3
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 .................................................................................. 21
5.1.3
Trial Treatment(s) ................................................................................................ 25
5.2
Dose Selection/Modification .............................................................................. 26
5.2.1
Dose Selection (Preparation) ....................................................................... 26
5.2.1.1
Dose Modification (Escalation/Titration/Other).......................................... 26
5.2.1.2
 
 
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Dose Modification of Sitagliptin/Matching Placebo for Sitagliptin..... 26
5.2.1.2.1
Dose Modification/Titration of Metformin........................................... 26
5.2.1.2.2
Glycemic Rescue Therapy.................................................................... 26
5.2.1.2.3
Timing of Dose Administration .......................................................................... 27
5.2.2
Trial Blinding/Masking....................................................................................... 27
5.2.3
Randomization or Treatment Allocation............................................................ 27
5.3
Stratification.......................................................................................................... 27
5.4
Concomitant Medications/Vaccinations (Allowed & Prohibited).................... 28
5.5
Rescue Medications & Supportive Care............................................................. 30
5.6
Diet/Activity/Other Considerations..................................................................... 30
5.7
Diet...................................................................................................................... 30
5.7.1
Alcohol, Caffeine and Tobacco .......................................................................... 30
5.7.2
Activity ............................................................................................................... 31
5.7.3
Subject Withdrawal/Discontinuation Criteria................................................... 31
5.8
Follow-up for Subjects Who Discontinue Blinded Study Drug ......................... 32
5.8.1
Withdrawal of Consent ................................................................................ 32
5.8.1.1
Discontinuation from Blinded Study Therapy............................................. 33
5.8.1.2
Subject Replacement Strategy............................................................................. 33
5.9
Beginning and End of the Trial ........................................................................... 34
5.10
Clinical Criteria for Early Trial Termination ................................................... 34
5.11
6.0
TRIAL FLOW CHART ........................................................................................... 35
7.0
TRIAL PROCEDURES ........................................................................................... 39
Trial Procedures ................................................................................................... 39
7.1
Administrative Procedures.................................................................................. 39
7.1.1
Informed Consent......................................................................................... 39
7.1.1.1
General Informed Consent.................................................................... 39
7.1.1.1.1
Consent and Collection of Specimens for Future Biomedical 
7.1.1.1.2
Research................................................................................................ 40
Inclusion/Exclusion Criteria ........................................................................ 40
7.1.1.2
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
 
 
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Prior Medications.................................................................................. 40
7.1.1.5.1
Concomitant Medications..................................................................... 40
7.1.1.5.2
Assignment of Screening Number............................................................... 40
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 Counseling............................................................... 41
7.1.1.8.1
Dispense Hypoglycemia Assessment Log and Instruct on 
7.1.1.8.2
Hypoglycemia Symptoms and Management ........................................ 41
Dispense Glucose Meter and Self-Monitoring Blood Glucose 
7.1.1.8.3
(SMBG) Instructions............................................................................. 42
Witness Dosing..................................................................................... 42
7.1.1.8.4
Dispense Single-Blind Placebo Run-in................................................. 42
7.1.1.8.5
Dispense Double-Blind Study Drug ..................................................... 42
7.1.1.8.6
Medication Compliance Monitoring..................................................... 43
7.1.1.8.7
Clinical Procedures/Assessments........................................................................ 43
7.1.2
Vital Signs (Sitting Blood Pressure and Pulse Rate) ................................... 43
7.1.2.1
Height and  Weight.................................................................................... 43
7.1.2.2
Physical Examination ................................................................................ 43
7.1.2.3
12-Lead Electrocardiogram ...................................................................... 44
7.1.2.4
Laboratory Procedures/Assessments .................................................................. 44
7.1.3
Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis) .. 45
7.1.3.1
Future Biomedical Research Sample Collection ......................................... 45
7.1.3.2
Other Procedures................................................................................................. 46
7.1.4
Withdrawal/Discontinuation........................................................................ 46
7.1.4.1
Withdrawal From Future Biomedical Research ................................... 46
7.1.4.1.1
Blinding/Unblinding .................................................................................... 46
7.1.4.2
Calibration of Critical Equipment................................................................ 47
7.1.4.3
Visit Requirements.............................................................................................. 47
7.1.5
Assessing 
and 
Recording 
Adverse 
EventsAdverse 
Events 
and 
7.2
Patient/Device Events ........................................................................................... 47
Definition of an Overdose for This Protocol and Reporting of Overdose to 
7.2.1
the Sponsor.......................................................................................................... 48
Reporting of Pregnancy and Lactation to the Sponsor ....................................... 48
7.2.2
Immediate Reporting of Adverse Events to the Sponsor.................................... 49
7.2.3
 
 
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Serious Adverse Events ............................................................................... 49
7.2.3.1
Events of Clinical Interest............................................................................ 50
7.2.3.2
Evaluating Adverse Events ................................................................................. 51
7.2.4
Sponsor Responsibility for Reporting Adverse Events ...................................... 54
7.2.5
8.0
STATISTICAL ANALYSIS PLAN ........................................................................ 54
Statistical Analysis Plan Summary ..................................................................... 54
8.1
No interim analyses are planned for this study........................................................... 55
Responsibility for Analyses/In-House Blinding ................................................. 55
8.2
Hypotheses/Estimation ......................................................................................... 55
8.3
Analysis Endpoints ............................................................................................... 55
8.4
Efficacy Endpoints.............................................................................................. 55
8.4.1
Safety Endpoints ................................................................................................. 56
8.4.2
Analysis Populations............................................................................................. 56
8.5
Efficacy Analysis Populations ............................................................................ 56
8.5.1
Safety Analysis Populations ............................................................................... 57
8.5.2
Statistical Methods................................................................................................ 57
8.6
Statistical Methods for Efficacy Analyses .......................................................... 57
8.6.1
Statistical Methods for Safety Analyses ............................................................. 62
8.6.2
Demographic and Baseline Characteristics ........................................................ 64
8.6.3
Interim Analyses ................................................................................................... 64
8.7
Multiplicity ............................................................................................................ 64
8.8
Sample Size and Power Calculations .................................................................. 65
8.9
Sample Size and Power for Efficacy Analyses ................................................... 65
8.9.1
Subgroup Analyses and Effect of Baseline Factors ........................................... 66
8.10
Compliance (Medication Adherence).................................................................. 67
8.11
Extent of Exposure................................................................................................ 68
8.12
9.0
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES ................................................................................................................. 68
Investigational Product ........................................................................................ 68
9.1
Packaging and Labeling Information ................................................................. 68
9.2
Clinical Supplies Disclosure................................................................................. 68
9.3
Storage and Handling Requirements.................................................................. 69
9.4
 
 
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Discard/Destruction/Returns and Reconciliation .............................................. 69
9.5
Standard Policies................................................................................................... 69
9.6
10.0
ADMINISTRATIVE AND REGULATORY DETAILS....................................... 70
Confidentiality....................................................................................................... 70
10.1
Confidentiality of Data ....................................................................................... 70
10.1.1
Confidentiality of Subject Records ..................................................................... 70
10.1.2
Confidentiality of Investigator Information........................................................ 70
10.1.3
Confidentiality of IRB/IEC Information............................................................. 71
10.1.4
Compliance with Financial Disclosure Requirements....................................... 71
10.2
Compliance with Law, Audit and Debarment ................................................... 71
10.3
Compliance with Trial Registration and Results Posting Requirements ........ 73
10.4
Quality Management System............................................................................... 73
10.5
Data Management................................................................................................. 73
10.6
Publications ........................................................................................................... 74
10.7
11.0
LIST OF REFERENCES......................................................................................... 75
12.0
APPENDICES........................................................................................................... 77
Merck Code of Conduct for Clinical Trials........................................................ 77
12.1
Collection and Management of Specimens for Future Biomedical 
12.2
Research................................................................................................................. 79
Understanding the Intent, Scope and Public
Health Benefits of 
12.3
Exploratory Biomarker Research: A Guide for IRBs/IECs and 
Investigational Site Staff ...................................................................................... 83
Management of Subjects with Elevated Liver Enzymes (ALT or AST ≥3X 
12.4
ULN)....................................................................................................................... 94
Predefined Limits of Change (PDLC)................................................................. 96
12.5
13.0
SIGNATURES........................................................................................................... 97
Sponsor's Representative ..................................................................................... 97
13.1
Investigator............................................................................................................ 97
13.2
 
 
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LIST OF TABLES
    
Table 1  Pre-Randomization Management ............................................................................. 11
Table 2  Laboratory Exclusion Criteria .................................................................................. 23
Table 3  Trial Treatment ......................................................................................................... 25
Table 4  Glycemic Thresholds for Rescue.............................................................................. 30
Table 5  Laboratory Tests ....................................................................................................... 45
Table 6  Evaluating Adverse Events....................................................................................... 52
Table 7  Efficacy Endpoints.................................................................................................... 56
Table 8  Analysis Strategy for Key Efficacy Variables.......................................................... 61
Table 9  Analysis Strategy for Safety Parameters .................................................................. 63
Table 10  Power (%) for the Analysis of A1C Goal < 7.0% at Week 20 ............................... 66
Table 11  Power (%) Under Various FPG Assumptions ........................................................ 66
Table 12  Product Descriptions............................................................................................... 68
 
 
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LIST OF FIGURES
          
Figure 1  Trial Design............................................................................................................. 13
 
 
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1.0 TRIAL SUMMARY
Abbreviated Title
Sitagliptin Addition during Metformin Up-titration
Sponsor Product Identifiers
Sitagliptin
Trial Phase
III
Clinical Indication
Treatment of Type 2 Diabetes Mellitus (T2DM)
Trial Type
Interventional
Type of control
Placebo
Route of administration
Oral
Trial Blinding
Double-blind
(Select Groups)
Metformin 1000 mg/b.i.d + Sitagliptin 100 mg
Metformin 1000 mg/b.i.d + Sitagliptin-matching Placebo
Number of trial subjects
Approximately 380 subjects will be enrolled.
Estimated duration of trial
The Sponsor estimates that the trial will require approximately 17
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 approximately 35
weeks, from the time the subject signs the Informed Consent Form 
(ICF) through the final contact.  This will include an approximately 
1-week screening period (not to exceed an approximately 2 weeks)
(Visit 1 to Visit 2); a metformin initiation/dose stabilization period of 
up to 10 weeks (Visit 2 to Visit 3); a 2-week single-blind placebo run-
in period (Visit 3 to Visit 4); a 20-week double-blind, placebo-
controlled treatment period (Visit 4 to Visit 7); and a post-treatment 
telephone contact 14 days after the last dose of blinded study drug.
2.0 TRIAL DESIGN
Trial Design
2.1
This trial is designed to evaluate, in adult subjects with T2DM and inadequate glycemic 
control on sub-maximal metformin mono-therapy (1000 mg/day), the effect of up-titration of
metformin plus the addition of sitagliptin compared to up-titration of metformin alone on 
glycemic control.  
Randomization Ratio
1:1
 
 
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This is a multicenter, randomized, double-blind, placebo-controlled, 2-parallel-arm clinical 
trial.  In one arm, subjects will be randomized to receive 100mg/day of sitagliptin while in 
the other, subjects will receive placebo to sitagliptin.  All subjects will receive metformin as 
background therapy.  At randomization, all subjects will undergo up-titration of immediate-
release metformin (Met-IR) from 1000 mg/day (500 mg b.i.d.) to 2000 mg/day (1000 mg 
b.i.d.). Approximately 380 subjects ≥18 years of age with T2DM diagnosed in accordance 
with American Diabetes Association (ADA) guidelines [1] who have inadequate glycemic 
control on monotherapy with metformin 1000 mg per day, as defined below, and who 
otherwise meet study enrollment criteria, will be randomized.   This trial will be conducted in 
conformance with Good Clinical Practices.
The duration of the trial will be up to approximately 35 weeks (with 7 scheduled clinic visits) 
for each subject.  This will include a 1 to 2 week screening period (Visit 1 to Visit 2); a
period of up to 10 weeks for metformin dose stabilization (Visit 2 to Visit 3); a 2-week 
placebo run-in period (Visit 3 to Visit 4); a 20-week double-blind, placebo-controlled 
treatment period (Visit 4 to Visit 7 [with telephone contact at Day 9]); and a post-treatment  
telephone contact 14 days after the last dose of blinded study drug.
Management of Subjects Prior to Randomization
Pre-randomization management of subjects is summarized in Table 1 below.  At Visit 
1/Screening, subjects who meet criteria for one of the four groups presented in Table 1, based 
on their anti-hyperglycemic agent (AHA) status and A1C, and also meet other study 
eligibility criteria detailed in Section 5.0, will be eligible for enrollment.  At Visit 2, all 
subjects will receive diet and exercise counseling and initiate/transition to AHA mono-
therapy of Met-IR 1000mg/day (500mg b.i.d), if necessary.  After lifestyle +/- AHA 
modification, subjects will enter a stabilization period of approximately 6-10 weeks prior to 
initiation of the placebo run-in.  At Visit 3/Week-2, subjects will enter a two week placebo 
run-in period and randomization will occur at Visit 4/Day 1.  
Eligibility for continued study participation will be assessed at Visits 1, 3, and 4 based on the 
criteria detailed in Section 5.1.  This includes the requirement at Visit 3/Week -2 that A1C be
≥7.5% and ≤11.0% (≥58 mmol/mol and ≤97 mmol/mol).  The placebo run-in may be 
initiated at Visit 3/Week -2 while laboratory data, including A1C, are pending, but 
randomization may not occur until all eligibility criteria are confirmed.  If a subject has 
initiated the placebo run-in but screen fails due to A1C or other laboratory data collected at 
Visit 3, they should be contacted and told to discontinue the placebo run-in.  
 
 
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Table 1  Pre-Randomization Management
AHA Regimen at Screening
Eligible A1C
at Screening 
(Visit 1)
Subject Management Between Visit 2     
and Visit 4
Metformin Dose  
and Duration at 
Screening
Other AHA
Met-IR 1000 
mg/day at stable 
dose for ≥8 weeks
none
≥7.5 and 
≤11.0%
Start stabilization period at Visit 2. After a 
minimum 6 week period between Visit 2 and 
Visit 3 (while continuing Met-IR
1000
mg/day), proceed to Visit 3 and initiate placebo 
run-in as appropriate.  Randomize at Visit 4 if 
subject continues to be eligible.            
Met-XR 1000 
mg/day at stable 
dose for ≥8 weeks
none
≥7.5 and 
≤11.0%
Switch to Met-IR 1000 mg/day (500 mg b.i.d.) 
at Visit 2. After a minimum 6 week period on 
Met-IR 1000 mg/day, proceed to Visit 3 and 
initiate 
placebo 
run-in
as 
appropriate.  
Randomize at Visit 4 if subject continues to be 
eligible.      
None
On monotherapy 
with the following 
AHAs  at a stable 
dose for ≥8 weeks
•Sulfonylurea
•Glinides 
•α-glucosidase 
inhibitors
≥7.5 and 
≤11.0%
Discontinue AHA at Visit 2 and initiate Met-
IR 1000 mg/day (500 mg b.i.d.).  
After a 
minimum 8 week stabilization period, proceed 
to Visit 3 and initiate placebo run-in as 
appropriate.   Randomize at Visit 4 if subject 
continues to be eligible.             
NOTE: At the discretion of the study 
investigator, Met-IR may be initiated at 500
mg/day and then increased to 1000 mg/day 
(500 mg b.i.d.) after up to 4 weeks.  The
subject must be on   Met-IR at 500 mg b.i.d. 
for at least 8 weeks prior to Visit 3.  
None for ≥8 weeks
None for ≥8 weeks 
(≥12 weeks for 
thiazolidinediones)
≥8.5 and 
≤12.0% 
Initiate Met-IR 1000 mg/day (500 mg b.i.d.) at 
Visit 2. After 10 week period on Met-IR 1000
mg/day, proceed to Visit 3 and initiate placebo 
run-in as appropriate.  Randomize at Visit 4 if 
subject continues to be eligible.  
NOTE: At the discretion of the study 
investigator, Met-IR may be initiated at 500
mg/day and then increased to 1000 mg/day 
(500 mg b.i.d.) after up to 4 weeks.  The 
subject must be on Met-IR at 500 mg b.i.d. for 
at least 10 weeks prior to Visit 3.  
 
 
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Management of Randomized Subjects
At Visit 4/Randomization (Day 1), subjects will enter the 20-week, double-blind, placebo-
controlled treatment period.  They will be randomized in a 1:1 ratio to once-daily sitagliptin 
100 mg or matching sitagliptin placebo, administered on a background of open-label Met-IR 
1000 mg twice daily (b.i.d.). At Visit 4/Day 1, all subjects will be up-titrated to Met-IR 1500
mg (1000 mg daily in AM and 500 mg daily in PM) from the 1000 mg/day (500 mg b.i.d.)
dose taken prior to randomization.  Subjects will again be up-titrated approximately 7 days 
(Day 8) post-randomization to Met-IR 2000 mg/day (1000 mg b.i.d.) and continue on this 
dose of Met-IR for the duration of study participation.   Dose escalation of Met-IR to 1000
mg b.i.d. may occur more gradually at the discretion of the investigator.  Every effort should 
be made to have subjects taking Met-IR 1000 mg b.i.d. by approximately 2 weeks after Visit 
4/Day 1.  If a subject is unable to tolerate 1000 mg b.i.d. Met-IR by Visit 5/Week 6, they 
should continue on the highest dose of Met-IR they have previously tolerated for the 
remainder of the study.  
Every appropriate effort should be made to support subject study completion on the AHA 
regimen to which they are randomized.  If a subject meets criteria for glycemic rescue 
therapy (see Section 5.6), rescue therapy will be initiated and taken in addition to blinded 
sitagliptin/placebo to sitagliptin and metformin.  Subjects discontinued from blinded study 
therapy for personal or other reasons (see Section 5.8), should continue to return to the study 
site for all study visits, and undergo all scheduled safety and efficacy evaluations.  If they are 
unwilling to do so, alternative efforts should be made to collect safety and efficacy 
information as summarized in Sections 5.8.1 and 7.1.4.  Withdrawal of consent will result in 
discontinuation of all study procedures. Subjects withdrawing consent should be encouraged 
to complete procedures for the Discontinuation Visit.
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
Met-IR 2000 mg/day (1000 mg b.i.d.) 
+ 
placebo to sitagliptin q.d. (N=190)
Met-IR 2000 mg/day (1000 mg b.i.d.) 
+ 
sitagliptin 100 mg q.d. (N=190)
R
Visit 4
Day 1
Randomization2
Visit 1
Screening
Visit 7
Week 20
Screening 
Period 
(≤ 2 weeks)
Visit 2
Placebo
Run-in Period             
(2 weeks)
Visit 3
Week -2
Pbo Run-In
AHA switch/metformin 
dose stabilization period      
(6-10 weeks)
Metformin            
immediate-release (IR) 
1000 mg/day                     
≥8 weeks                    
w/ A1C ≥ 7.5%- ≤11.0%
Single Blind 
Placebo 
A1C  ≥ 7.5% ≤11.0%;
FPG  ≤270 mg/dL
On monotherapy with 
allowed AHA1
≥8 weeks                      
w/ A1C ≥ 7.5% - ≤11.0%
Double-blind Treatment Period
Visit 5
Week 6
Visit 6
Week 14
Metformin  
up-titration2
Not on AHA for ≥8 weeks                   
w/ A1C ≥ 8.5% - ≤12.0%
Metformin              
extended-release (XR) 
1000 mg/day                     
≥8 weeks                    
w/ A1C ≥ 7.5%- ≤11.0%
Switch to Met-IR at 
Visit 2,  then ≥ 6
week stabilization
Period
Start Met-IR at 
Visit 2, then ≥ 10
week stabilization
Period
Switch to Met-IR at 
Visit 2, then 
stabilization period 
of ≥ 8 weeks
1. Allowable AHAs at Visit 1/Screening: α-glucosidase inhibitors, glinides or sulfonylureas.
2. Begin  Metformin-IR 1000 mg qAM and 500 mg qPM at Visit 4/Randomization. Metformin-IR up-titration to 1000 mg b.i.d. to occur at approximately 7days (Day 8) after randomization
Post Treatment 
Period
14-Day 
Post Treatment 
Telephone Contact
Follow up
At Visit 2, start  
a ≥ 6 week 
stabilization
Period. 
FFSG <120 or 
> 270mg/dL
Telephone Call
Day 9 
All subjects taking 
Met-IR 1000 mg/day
(500 mg b.i.d.) 
Figure 1  Trial Design
3.0 OBJECTIVE(S) & HYPOTHESIS(ES)
Primary Objective(s) & Hypothesis(es)
3.1
In subjects with T2DM and inadequate glycemic control on treatment with metformin
1000 mg/day, after 20 weeks:
(1)
Objective:  To assess the effect of up-titration of metformin plus the addition of 
sitagliptin compared with the up-titration of metformin alone on reduction from 
baseline in A1C.
Hypothesis:  Up-titration of metformin to 2000 mg/day (1000 mg b.i.d.) plus the 
addition of sitagliptin 100mg/day provides greater reduction in A1C compared to
metformin up-titration alone. 
 
 
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(2)
Objective:  To assess the overall safety and tolerability of up-titration of metformin 
plus the addition of sitagliptin compared to up-titration of metformin alone.
Secondary Objective(s) & Hypothesis(es)
3.2
In subjects with T2DM and inadequate glycemic control on treatment with metformin 
1000 mg/day, after 20 weeks:
(1)
Objective: To assess the proportion of subjects at the A1C goal of <7% (<53
mmol/mol) with up-titration of metformin plus the addition of sitagliptin compared 
with the up-titration of metformin alone.
Hypothesis: Up-titration of metformin plus the addition of sitagliptin results in a greater 
proportion of subjects at the A1C goal of <7.0% (<53 mmol/mol) relative to up-
titration of metformin alone.
(2)
Objective:  To assess the effect of up-titration of metformin plus the addition of 
sitagliptin compared to up-titration of metformin alone on reduction from baseline in 
fasting plasma glucose.
Hypothesis: Up-titration of metformin plus the addition of sitagliptin provides greater 
reduction in fasting plasma glucose compared to metformin up-titration alone.
(3)
Objective: To assess the proportion of subjects with baseline A1C ≥ 8.5% that are at 
the A1C goal of <7% (<53 mmol/mol) with up-titration of metformin plus the 
addition of sitagliptin compared with the up-titration of metformin alone.
(4)
Objective: To assess the proportion of subjects receiving glycemic rescue therapy 
with up-titration of metformin plus the addition of sitagliptin compared with the up-
titration of metformin alone.
4.0 BACKGROUND & RATIONALE
Background
4.1
Refer to approved labeling for detailed background information on sitagliptin and metformin
Pharmaceutical and Therapeutic Background
4.1.1
There has been a steady increase in the global prevalence of T2DM, largely attributed to 
rising rates of excess body weight and obesity. In 2011, diabetes was estimated to affect 
more than 365 million people worldwide between the ages of 20-79 years, and the prevalence 
of diabetes is projected to reach more than 550 million by the year 2030 [2]. T2DM also 
represents one of the largest medical burdens in the United States, resulting in direct medical 
costs of $176 billion and $69 billion in loss of productivity in 2012 [3]. At present, it is 
estimated that 25.8 million people in the US have diabetes (8.3% of the population), of which 
7 million remain undiagnosed [4]. T2DM accounts for approximately 90-95% of all cases of 
diabetes. Individuals with T2DM have an increased risk of developing both microvascular 
and macrovascular complications, including nephropathy, neuropathy, retinopathy, and 
cardiovascular disease, and are 2 to 4 times more likely to die from cardiovascular disease 
than adults who do not have diabetes [5].
 
 
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In recent years, diabetes experts have reached a consensus that glycemic targets and glucose-
lowering therapies should be individualized [6]. Important comorbidities and adverse effects 
of anti-hyperglycemic agents (AHAs) are among the subject factors that should be 
considered. Diet, exercise, and education remain the foundation of treatment for T2DM, but 
most patients will eventually require AHA therapy. Hence, it is essential to understand the 
relative efficacy and safety/tolerability of available AHA therapies and treatment paradigms. 
Metformin: Metformin is a well-established treatment for patients with T2DM which has 
been used in Europe for ~40 years and in the U.S. since 1995.  Its antihyperglycemic effects 
are mediated via decreased hepatic glucose output, decreased peripheral insulin resistance, 
and delay in gastrointestinal absorption of glucose.  It tends not to cause weight gain, may be 
associated with modest weight loss, and can be safely combined with other agents including 
dipeptidyl peptidase IV (DPP-4) inhibitors, sulfonylureas, sodium glucose co-transporter 2 
(SGLT2) inhibitors, and TZDs.  Its use has been associated with long-term benefit including 
decreased mortality.  Metformin is contraindicated in patients with advanced renal 
dysfunction, hypersensitivity to metformin, and acute or chronic metabolic acidosis.    
Sitagliptin: Sitagliptin is an orally active and highly-selective dipeptidyl peptidase IV (DPP-
4) inhibitor indicated for the treatment of patients with T2DM.  The therapeutic 
improvements in glycemic control associated with sitagliptin are mediated by increases in the
active incretin hormones, glucagon-like peptide-1 (GLP-1) and glucose-dependent 
insulinotropic polypeptide (GIP), which result from inhibition (by sitagliptin) of DPP-4, the
enzyme responsible for inactivation of these peptide hormones.  GLP-1 and GIP are released 
by enteroendocrine L- and K-cells respectively in response to a meal, and result in enhanced 
glucose-dependent insulin secretion from pancreatic β-cells.  In addition, GLP-1 suppresses 
glucagon release from pancreatic α-cells and slows gastric emptying.  These effects work in 
concert to lower both fasting and post-prandial glucose concentrations.  Clinical studies have 
shown that sitagliptin (as monotherapy and in combination with other AHAs) is generally 
well-tolerated, effectively reducing blood glucose concentrations in patients with T2DM.  
Rationale
4.2
Rationale for the Trial and Selected Subject Population
4.2.1
In light of its long-established favorable safety and glycemic efficacy profiles, potential 
cardiovascular benefits, and low cost, metformin is widely used as the first-line 
pharmacologic anti-hyperglycemic agent (AHA) for patients with T2DM.  Maximum 
approved doses of metformin for adults with T2DM are 2550mg (US) and 3000mg (EU).  To 
mitigate gastrointestinal tolerance and permit use of the lowest effective dose, metformin
treatment is typically initiated at a lower dose and increased periodically, guided by 
tolerability and glycemic response.  
 
 
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Unless contraindicated, metformin is typically initiated at or soon after diagnosis of T2DM, 
especially in individuals who have not or are unlikely to achieve glycemic targets with 
lifestyle intervention alone [6].  Metformin is commonly initiated at a dose 500-850 mg once 
daily, followed by up-titration to a sub-maximal dose (i.e., 1000 mg/day) and A1C re-
assessment after a period (≥ 3 months) of stable dosing.  For patients who are tolerating 
metformin well but have not achieved their glycemic target (typically A1c ≤7.0%), the 
metformin dose is increased in increments up to a final dose of ~ 2000 mg/day.  If glycemic 
targets are still not achieved, a second AHA is then added.  
Mean A1C decreases of -0.37 to 0.71% have been reported with a dose increase from 1000
mg/day metformin to 2000 mg/day metformin, with higher baseline A1C associated with 
greater response [7-9].  In patients with relatively high A1Cs already on sub-maximal 
metformin, the incremental glycemic benefit of maximizing the dose of metformin is 
unlikely to result in A1C goal achievement in more than a modest proportion of patients.  
Consistent with this, in T2DM subjects not at A1C goal with diet and exercise, treatment 
with 2000 mg/day metformin was only marginally more successful than 1000 mg/day 
metformin in achieving an A1C < 7.0% after 24 Weeks of treatment (38% vs. 23%) [10].  
Therefore, for many T2DM patients not at A1C goal on a sub-maximal dose of metformin, 
up-titration of metformin alone does not result in successful A1C goal attainment.  For these 
individuals, successful A1C goal attainment is substantially delayed by a treatment paradigm 
in which a second-line AHA is added only after metformin maximization is confirmed to be 
unsuccessful. 
The goal of this study is to assess A1C response with a treatment paradigm in which patients 
who are not at A1C goal on a sub-maximal dose of metformin receive simultaneous 
metformin maximization plus initiation of sitagliptin in comparison to the more traditional 
paradigm of metformin maximization only.  When used in combination with metformin, 
sitagliptin lowers A1C ~0.6-0.8% and is well tolerated [11].  Therefore, initiating sitagliptin
in parallel with metformin maximization is anticipated to provide a greater reduction in A1C 
and thus substantially increase the proportion of individuals achieving an A1C ≤7.0% 
compared to metformin maximization alone.  A population of male and female T2DM 
subjects with A1C ≥7.5 % and ≤11.0% (≥58 mmol/mol and ≤97 mmol/mol) while on a stable 
sub-maximal dose of metformin, will be randomized to make this comparison.
 
 
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Rationale for Dose Selection/Regimen/Modification
4.2.2
Rationale for Metformin Dose
4.2.2.1
As summarized above, the population of interest for this study is individuals with T2DM not 
at glycemic target on sub-maximal metformin monotherapy. The required pre-randomization 
Met-IR dose of 1000 mg/day (500 mg b.i.d.) was selected as it reflects the clinical scenario 
of interest in which many clinicians would routinely complete up-titration of metformin
before initiating a second AHA.  After randomization, Met-IR will be up-titrated in all 
subjects from 1000 mg to a top dose of 2000 mg/day in 500 mg increments, an approach that 
is routinely used and well tolerated in clinical practice. If a subject is unable to tolerate 1000
mg b.i.d. Met-IR by Visit 5/Week 6, they will be continued on the highest dose of Met-IR 
they have previously tolerated well for the remainder of the study as this would be the 
clinically appropriate approach. 
Met-IR will be administered to both treatment arms in a manner consistent with routine 
clinical practice.  Therefore, it is considered background medication for this study (12).    
Rationale for Sitagliptin Dose
4.2.2.2
Sitagliptin 100 mg q.d. has been shown to provide effective improvements across glycemic 
endpoints and to be well tolerated. Sitagliptin 100 mg q.d. is the approved treatment dose.  
Though patients with moderate or severe renal insufficiency require a dose reduction, they 
will be excluded from this study.  Therefore, 100mg sitagliptin will be appropriate for all 
enrolled subjects.   
Glycemic Rescue
4.2.2.3
During the double-blind treatment period, subjects who meet progressively more stringent 
glycemic rescue criteria (see Table 4) will receive glycemic rescue therapy at the discretion
of the study investigator.  These glycemic rescue thresholds are above standard treatment 
targets.  However, the degree of hyperglycemia permitted over the relatively short study 
timeframe is not expected to have any long-term health consequence as complications related 
to chronic hyperglycemia (i.e. retinopathy, nephropathy, neuropathy, macrovascular disease) 
develop over much longer timeframes [13].  Permitting some degree of hyperglycemia 
without rescue is necessary to meet the scientific goals of this study with regard to comparing 
the glycemic efficacy of the two treatment paradigms being evaluated.  This is consistent 
with recent National Research Council guidance emphasizing the importance of study 
designs that maximize the number of participants who are maintained on the protocol-
specified intervention until the outcome data are collected to best address the scientific goals 
of a clinical trial [14].      
 
 
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Rationale for Endpoints
4.2.3
Efficacy Endpoints
4.2.3.1
Glycemic efficacy endpoints will be A1C and FPG. A1C reflects average glucose 
concentrations in the past 3-4 months and, therefore, will provide a useful index of glycemic 
control at the end of the 20 week treatment period. It is a standard efficacy endpoint used to 
assess the glycemic efficacy of AHAs, and improvement in A1C correlates with reduction of 
risk of diabetic complications [6]. Assessment of FPG will provide useful insight into the
time course of glucose control in this trial.
Safety Endpoints
4.2.3.2
Safety assessment will include collection of adverse events (AEs), a hypoglycemia 
assessment log (HAL) to collect information on each potential hypoglycemia episode 
(including concurrent fingerstick glucose value) and physical examination including vital 
signs. Laboratory safety studies will include blood chemistry, lipid panel, hematology, and 
urine pregnancy testing (performed in women of childbearing potential). Refer to Section 8.0 
for further details.
Future Biomedical Research
4.2.3.3
The Sponsor will conduct Future Biomedical Research on specimens collected 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.
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 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.  Additional informational 
material for institutional review boards/ethics committees (IRBs/ERCs) and investigational 
site staff is provided in Section 12.3.
Benefit/Risk
4.3
Subjects in clinical trials generally cannot expect to receive direct benefit from treatment 
during participation.
Additional details regarding specific benefits and risks for subjects participating in this 
clinical trial may be found in the Informed Consent documents.
 
 
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5.0 METHODOLOGY
Entry Criteria
5.1
Diagnosis/Condition for Entry into the Trial
5.1.1
Male/female subjects with T2DM at least 18 years of age 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 in accordance with ADA guidelines [1] and be ≥18 years of age on the 
day of signing the ICF.
2. Understand and be willing to comply with the study procedures, scheduled visits, 
treatment plan, alternative treatments available, laboratory tests, risks involved with 
the study, and other study procedures and have personally signed and dated the ICF 
indicating that he/she has been informed of all pertinent aspects of the trial and 
voluntarily agrees to participate.  
NOTE: The subject may also provide consent for Future Biomedical Research.  
However, the subject may participate in the main trial without participating in Future 
Biomedical Research.
3. Meet one of the following criteria:
a.
Be on stable Met-IR monotherapy 1000 mg/day for ≥8 weeks with a Visit 
1/Screening A1C ≥7.5% and ≤11.0% (≥58 mmol/mol and ≤97 mmol/mol).
OR
b. Be on stable Met-XR monotherapy 1000 mg/day for ≥8 weeks with a Visit 
1/Screening A1C ≥7.5% and ≤11.0% (≥58 mmol/mol and ≤97 mmol/mol).
OR
c.
Not on any
AHA
for ≥8 weeks (≥12 weeks if previously taking 
thiazolidinediones) with a Visit 1/Screening A1C ≥8.5% and ≤12.0% (≥69
mmol/mol and ≤108 mmol/mol).
OR
d. Be on stable monotherapy with a sulfonylurea, a glinide, or an α-glucosidase 
inhibitor for ≥8 weeks with a Visit 1/Screening A1C ≥7.5% and ≤11.0% (≥58
mmol/mol and ≤97 mmol/mol).
4. Have a body mass index (BMI) ≥18.0 kg/m2.
 
 
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5. Meet one of the following criteria:
a.
Subject is a male.
b. Subject is a female not of reproductive potential defined as one who:
1) Is postmenopausal (defined as at least 12 months with no menses in 
women ≥45 years of age), or
2) Has had a hysterectomy and/or bilateral oophorectomy, bilateral 
salpingectomy, or had bilateral tubal ligation/occlusion at least 6 weeks 
prior to Visit 1/Screening.
3) Has a congenital or acquired condition that prevents childbearing.
c.
Subject is a female of reproductive potential and agrees to avoid becoming 
pregnant while receiving study drug and for 14 days after the last dose of 
study drug by complying with one of the following:
1. practice abstinence† from heterosexual activity 
OR
2. use (or have her partner use) acceptable contraception during 
heterosexual activity. 
Use of one of the following methods is 
acceptable‡:

intrauterine device (IUD)

vasectomy of a female subject’s male partner

contraceptive rod implanted into the skin

hormonal contraception including vaginal rings

condoms

diaphragm with spermicide

contraceptive sponge
† Abstinence (relative to heterosexual activity) can be used as the sole 
method of contraception if it is consistently employed as the subject’s 
preferred and usual lifestyle and if considered acceptable by local 
regulatory agencies and ERCs/IRBs.  Periodic abstinence (e.g., calendar, 
ovulation, sympto-thermal, post-ovulation methods, etc.) and withdrawal 
are not acceptable methods of contraception. 
‡If a contraceptive method listed above is restricted by local 
regulations/guidelines, then it does not qualify as an acceptable method of 
contraception for subjects participating at sites in this country/region.
 
 
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At Visit 3/Week -2
6. Be on stable Met-IR monotherapy 1000 mg/day as described in Section 2.1, Table 1
with a Visit 3/Week -2 A1C of 
≥7.5% and ≤11.0% (≥58 mmol/mol and ≤97 
mmol/mol)
Note: For subjects requiring confirmation of A1C as well as other laboratory testing 
at Visit 3, placebo run-in may initiate while these data are pending, but randomization 
will not occur until the results are confirmed to be appropriate for study inclusion 
including an A1C of ≥7.5% and ≤11.0% (≥58 mmol/mol and ≤97 mmol/mol).  
At Visit 4/Day 1
7. Be ≥80% compliant with the placebo run-in medication (as determined by site 
performed pill count)
Subject Exclusion Criteria
5.1.3
The subject must be excluded from participating in the trial if the subject:
At Visit 1/Screening
Diabetes Diagnosis and Prior Therapy Criteria
1. Has a history of type 1 diabetes mellitus or a history of ketoacidosis or subject is
assessed by the investigator as possibly having type 1 diabetes mellitus confirmed 
with a C-peptide <0.7 ng/mL (0.23 nmol/L) or has a history of secondary causes of 
diabetes of diabetes (e.g., genetic syndromes, secondary pancreatic diabetes, diabetes 
due to endocrinopathies, drug- or chemical-induced, and post-organ transplant).  
Note:  Only subjects assessed by the investigator as possibly having type 1 diabetes 
should have C-peptide measured at Visit 1/Screening.
2. Has a known hypersensitivity or intolerance to any DPP-4 inhibitor.
3. Has a known hypersensitivity or intolerance to metformin, including subjects who 
were previously unable to tolerate metformin at a dose >1000 mg/day or who have 
evidence of intolerance to the dose of metformin they are currently taking (for 
subjects who are taking metformin)
4. Has been treated with any of the following agents within 8 weeks (12 weeks for 
thiazolidinediones) of Visit 1/Screening:
a.
Insulin of any type (except for short-term use [i.e., ≤7 days] during 
concomitant illness or other stress)
b. Dipeptidyl-peptidase 4 inhibitors (DPP-4 inhibitor)
c.
Pioglitazone or rosiglitazone (thiazolidinediones)
d. GLP-1R agonists 
e.
SGLT2 inhibitors 
f.
Bromocriptine (Cycloset™)
 
 
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g. Colesevelam (Welchol™)
h. Any other AHA with the exception of protocol-approved agents
5. Subject is on a weight loss program and not in the maintenance phase, or has started a 
weight loss medication or has undergone bariatric surgery within 12 months prior to 
signing the informed consent.
Note: Saxenda™ (liraglutide 3.0mg/day) is approved as a weight loss medication.  
However, it contains the same active ingredient as the AHA Victoza™ (liraglutide 
1.2 and 1.8mg/day) at a higher dose.  Therefore, subjects taking Saxenda™ are not 
eligible for this study even if it was initiated >12 months prior to signing informed 
consent. 
Concomitant Disease of Organs and Systems 
6. Has a history of myocardial infarction, unstable angina, arterial revascularization, 
stroke, transient ischemic attack, NYHA functional class III-IV heart failure, or 
severe peripheral vascular disease (e.g., claudication with minimal activity, a non-
healing ischemic ulcer, or disease which is likely to require surgery or angioplasty) 
within 3 months of Visit 1/Screening. 
7. Has a history of malignancy ≤5 years prior to signing the ICF (i.e., the diagnosis 
occurred, or any evidence of residual or recurrent disease occurred, within the past 5 
years), except for adequately treated basal cell or squamous cell skin cancer, or in situ 
cervical cancer. 
Note: A patient with any history of melanoma, leukemia, lymphoma, or renal cell 
carcinoma is excluded. 
8. Has human immunodeficiency virus (HIV)
a.
with AIDS related complications, or 
b.
has not been on  a stable anti-retroviral regimen for >6 months, or
c.
has progressive disease, or 
d. using agents associated with glucose intolerance such as nucleoside reverse 
transcriptase inhibitors (NRTIs) such as azidothymidine (AZT), didanosine 
(ddI) and stavudine (d4T).
9. Is on or likely to require treatment for ≥14 consecutive days or repeated courses of 
pharmacologic doses of corticosteroids.
Note: Inhaled, nasal, ophthalmic, and topical corticosteroids and physiological 
replacement doses of adrenal steroids are permitted.
10. Has undergone a major surgical procedure within 12 weeks prior to signing the ICF 
or has major surgery planned during the trial.
Note:  A subject who has undergone minor surgery within the 4 weeks prior to Visit 
1/Screening 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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11. Has other medical, psychiatric condition, or laboratory abnormality that may increase 
the risk associated with study participation or may interfere with the interpretation of 
study results and, in the judgment of the investigator, would make the subject 
inappropriate for entry into this trial.  
Exclusion Criteria Based on Laboratory Abnormalities
12. Has an exclusionary laboratory value as listed in Table 2 below:
Table 2 Laboratory Exclusion Criteria
Parameter1
Population
(if applicable)
Trial Limit for Exclusion
eGFR2
<60 mL/min/1.73 m2
Alanine aminotransferase (ALT)
>2 times Upper Limit of Normal (ULN)
Aspartate aminotransferase (AST)
>2 times ULN
Thyroid-stimulating hormone (TSH)3
Outside central laboratory normal range
Hemoglobin
Male
Female
<11 g/dL (110 g/L)
<10 g/dL (100 g/L)
Triglycerides (TG)4
>600 mg/dL (6.78 mmol/L)
1 Subjects with an exclusionary laboratory value may have one repeat determination performed if the 
investigator considers the Visit 1/Screening result to be inconsistent with prior determinations.  Only the 
laboratory test not meeting entry criterion should be repeated (not the entire panel). The last laboratory 
draw/result should be used for inclusion.
2 Calculated by central laboratory using the 4- variable MDRD equation.
3 Subjects excluded due to the TSH criterion may be re-screened after being on a stable thyroid 
replacement therapy for at least 6 weeks.
4   Subjects with elevated TG levels may have lipid-lowering medication initiated or adjusted and continue 
in the trial if a repeat measurement (at Visit 3/Week -2) no longer meets the exclusion criterion.  
Subjects on lipid-lowering medication must be on a stable regimen for at least 4 weeks prior to Visit 
4/Randomization (Day 1).
Other Criteria
13. Subject is currently participating, or has participated, in a study in which the subject 
received an investigational compound or used an investigational device within the 
prior 12 weeks of signing informed consent or is not willing to refrain from
participating in another study.
Note: A subject who has participated in a non-interventional study may be enrolled.
14. Is pregnant or breast-feeding, has a positive urine pregnancy test, or is planning to 
conceive or donate eggs during the study, including 14 days following the last dose of 
blinded investigational product. 
15. Subject has a recent history of alcohol or drug abuse (within 3 years) or is a user of 
recreational or illicit drugs at the time of screening.
16. 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.
 
 
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At Visit 3/Week -2
17. Has a clinically significant ECG finding that requires further diagnostic evaluation or 
intervention (e.g., new, clinically significant arrhythmia or a conduction disturbance) 
which exposes the subject to risk by enrolling in the study.  
18. Has an FPG consistently (i.e., measurement repeated and confirmed within 7 days) 
>270 mg/dL (15.0 mmol/L).
19. Has a fasting TG level >600 mg/dL (6.8 mmol/L).
Note: This criterion applies to subjects who met the exclusion criterion for TG levels 
at Visit 1/Screening and who require evaluation of TG levels at Visit 3/Week -2 to 
assess eligibility following initiation or adjustment of lipid-lowering medication.   
At Visit 4/Randomization/Day 1
20. Has a site fasting fingerstick glucose (FFSG) of <120 mg/dL (6.7 mmol/L) or >270 
mg/dL (15.0 mmol/ L).
Note: If the subject meets this exclusion criterion AND the investigator believes that 
the value is not consistent with the subject’s current SMBG values and Visit 3/Week -
2 FPG value, the subject should not be excluded at this time.  This value can be 
repeated and the subject should be rescheduled for Visit 4/Day 1 within 7 days.
Additional single-blind placebo run-in medication should be dispensed if needed.
If the subject meets this FFSG exclusion criterion at the rescheduled Visit 4/Day 1, 
the subject MUST be excluded.
21. Has a positive urine pregnancy test. 
22. Blood pressure, lipid, hormone replacement and/or birth control medications are not 
at a stable dose or regimen as specified in Section 5.5 (at least four weeks for blood 
pressure, lipid, and hormone replacement medications and at least one cycle for birth 
control medications).
23. Has developed a new medical condition, suffered a change in status of an established 
medical condition, developed a laboratory abnormality, or required a new treatment 
or medication during the pre-randomization period which meets any previously 
described trial exclusion criteria or which, in the opinion of the investigator, exposes 
the subject to risk by enrolling in the study.
Note:  If at Visit 4/Day 1, a subject requires medication adjustment or initiation of a new 
medication to meet enrollment criteria, the subject should be rescheduled for a Visit 4/Day 1
to occur ≤2 weeks later.  If needed, additional single-blind placebo run-in medication should 
be dispensed.
 
 
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Trial Treatment(s)
5.2
The treatment(s) to be used in this trial are outlined below in Table 3.
During the placebo run-in and double-blind treatment periods, each subject will take 1 oral 
tablet of blinded study drug each day (sitagliptin or matching placebo tablet).  
All subjects will take Met-IR as background medication.  During the placebo run-in, they 
will take 1 x 500 mg tablet Met-IR twice daily (1000 mg/day).  After randomization, all 
subjects will be titrated to 2 x 500 mg tablets of Met-IR twice daily (2000 mg/day).  
Table 3  Trial Treatment
Treatment 
Group
Drug/Dose
Use
Dose Frequency/
Treatment 
Period
Route of 
Administration
placebo run-in
matching placebo for 
sitagliptin 100 mg tablet
Placebo
(trial drug)
Once daily (q.d.)
for 2 weeks
oral
sitagliptin 
100 mg
sitagliptin 100 mg tablet
experimental
(trial drug)
Once daily (q.d.)
for 20 weeks
oral
Placebo
Matching placebo to 
sitagliptin 100 mg tablet
experimental
(trial drug)
Once daily (q.d.) 
for 20 weeks
oral
The first dose of single-blind matching placebo for sitagliptin will be administered at the trial 
site as a witnessed dose at Visit 3/Week -2.  The first dose of double-blind 
sitagliptin/matching placebo will be administered at the trial site as a witnessed dose at Visit 
4/Day 1. Subsequent dosing will be performed once-daily by the subject at approximately the 
same time each day.
Background therapy with Met-IR will be up-titrated at Visit 4/Day 1 to 1500 mg and will be 
up-titrated again (at Day 8) to the target dose of 2000 mg/day (1000 mg b.i.d.).   A telephone 
contact will be made on Day 9 to assess the up-titration of Met-IR.  
Sitagliptin and matching placebo will be supplied by the Sponsor.  Met-IR will be sourced by 
the Sponsor’s (or designee’s) local subsidiary, the investigational site, or will be prescribed 
by the investigator, with the latter two options receiving reimbursement from the Sponsor. 
Glycemic rescue medication will be sourced by the investigational site or will be prescribed 
by the investigator receiving reimbursement from the sponsor. The trial investigator will be 
responsible for managing the initiation and maintenance of rescue medication in accordance 
to the local country label. 
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.
 
 
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Dose Selection/Modification
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.
Dose Modification (Escalation/Titration/Other)
5.2.1.2
Dose Modification of Sitagliptin/Matching Placebo for Sitagliptin
5.2.1.2.1
The dose of sitagliptin or matching placebo cannot be modified throughout the 20-week 
double-blind treatment period.
Dose Modification/Titration of Metformin
5.2.1.2.2
All subjects will undergo a period of stabilization, between Visits 2 and 3, prior to the 
initiation of single-blind placebo run-in at Visit 3.  During this time, all subjects will be 
taking Met-IR at a dose of 1000 mg/day (500 mg b.i.d.).  As discussed in section 2.1, the 
duration of this stabilization period will be between ≥6 and ≥10 weeks depending on the 
AHA status at the time of screening.  If an eligible subject is taking a stable dose of a 
permissible AHA (sulfonylurea, glinide, or α-glucosidase inhibitor) at screening, they will 
discontinue the AHA at Visit 2 and initiate Met-IR 1000 mg/day (500 mg b.i.d.). 
Met-IR will be up-titrated to 2000 mg/day (1000 mg b.i.d.) in all study subjects. Dose 
escalation of Met-IR to 1000 mg b.i.d. may occur more gradually at the discretion of the 
investigator.  Every effort should be made to have subjects taking Met-IR 1000 mg b.i.d. by 
approximately 2 weeks after Visit 4/Day 1.  If a subject is unable to tolerate 1000 mg b.i.d. 
Met-IR by Visit 5/Week 6, they should continue on the highest dose of Met-IR they have 
previously tolerated well for the remainder of the study.   
Glycemic Rescue Therapy
5.2.1.2.3
If the criteria for glycemic rescue (see Section 5.6) are met, the investigator should initiate 
what she/he considers to be appropriate glycemic rescue AHA therapy.  Note:
Rescue 
therapy is to be added to ongoing double-blind study drug and Met-IR 1000 mg b.i.d. 
Since double-blind study drug may be sitagliptin, rescue therapy must not be a DPP-4 
inhibitor.  Additionally, background Met-IR should not be used as a glycemic rescue 
medication.  Therefore, the dose of Met-IR should not be increased above the specified target 
dose of 2000 mg/day. Otherwise, the choice of the AHA agent, dose, regimen, and 
subsequent titration will be as directed by the investigator, as considered to be clinically 
appropriate. 
After initiation of rescue therapy, subjects will continue with all protocol-specified activities 
including all safety and efficacy evaluations.       
 
 
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Timing of Dose Administration
5.2.2
At Visit 4/Randomization (Day 1), subjects will enter the 20-week, double-blind, placebo-
controlled treatment period and be randomized in a 1:1 ratio to  sitagliptin 100 mg q.d. or 
matching sitagliptin placebo with all subjects on Met-IR 2000 mg/day (1000 mg b.i.d.).   
Subjects will take sitagliptin or matching placebo once-daily, at approximately the same time 
every day.  
Subjects will take Met-IR b.i.d. with meals.
On days without clinic visits, subjects should take Met-IR twice daily and blinded study 
medication (sitagliptin or matching placebo) once daily at approximately the same times each
day.  
Subjects will be instructed not to take Met-IR and blinded study medication (sitagliptin or 
matching placebo) the morning of clinic visits.  On clinic visit days, subjects will take Met-
IR and blinded study medication (sitagliptin or matching placebo) after all study procedures 
are completed.
If a subject misses a dose of Met-IR or blinded study medication (sitagliptin or matching 
placebo) during the trial, he/she should be instructed to take it as soon as they remember, 
unless it is time for the next dose.  Subjects should be instructed not to "make up" for the 
missed dose by taking two doses at the same time.
Trial Blinding/Masking
5.2.3
A double-blind/masking technique will be used.  Sitagliptin and matching 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.  
Subjects will be assigned randomly in a 1:1 ratio to either sitagliptin 100 mg q.d. or
sitagliptin 100 mg matching placebo, co-administered for all subjects with Met-IR 2000 mg/d 
(1000 mg b.i.d.).
Stratification
5.4
Treatment allocation/randomization will be stratified according to AHA status at screening 
based on the following levels:
1. Not on AHA at Visit 1/Screening
2. On Non-Metformin AHA at Visit 1/Screening
3. On Met-IR or Met-XR 1000 mg/day at Visit 1/Screening
 
 
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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.  
AHAs taken by the subject at any time prior to Visit 1/Screening, and any other medications 
taken within 8 weeks of Visit 1/Screening, should be recorded on the appropriate electronic 
case report form (eCRF).  The site may rely on subject report for this information.  
Concomitant medications taken during the trial must also be recorded.  
Subjects should be questioned about their use of concomitant medications at the time points 
indicated in the Trial Flow Chart (Section 6.0). Subjects should be instructed to contact the 
study investigator before initiating any prescription or non-prescription medications during 
study participation.  If medical necessity requires initiation of a medication prior to 
discussion with the study investigator, the subject should communicate with the study 
investigator as soon as possible.    
Prohibited Medications
Medications listed below are prohibited while subjects are receiving study medication during 
the double-blind treatment period:
NOTE: At the time points indicated in the Trial Flow Chart (Section 6.0), investigational 
sites should review the use of any prohibited medications, including AHAs with subjects.  At 
these time points, subjects should be instructed regarding the importance of not taking AHAs
other than metformin and blinded study medication (sitagliptin/placebo to sitagliptin) during 
study participation unless initiated by the study investigator as glycemic rescue.  
1. DPP-4 inhibitors (except blinded sitagliptin)
2. Any other AHA with exception of metformin and rescue therapy
Note: at Randomization/Day 1 subjects should be reminded to not to take any other 
AHA medications other than the trial treatments during their participation in the study
unless the AHA is initiated as glycemic rescue therapy by the study investigator.  
Subjects should be counseled that if another physician prescribes such a treatment (i.e., 
any AHA), the subject and/or the prescribing physician should immediately contact the 
investigational site prior to initiation of such therapy (unless alternative AHA therapy is 
considered clinically to be immediately required).  
Subjects who were switched from another AHA to Met-IR after screening and prior to 
randomization should be reminded to remain off this agent while participating in the 
current trial, and to not re-start this agent post-study unless advised by their diabetes care-
giver (whether the investigator or another physician).
 
 
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If a subject initiates another AHA (other than Met-IR and rescue therapy initiated per 
protocol specifications [see Section 5.6]) and is unwilling to discontinue this other AHA, 
they may continue to take Met-IR and double blind study medication if the other AHA is 
not a DPP-4 inhibitor and the study investigator considers continued administration of 
Met-IR and blinded study medication to be medically appropriate.  If the other AHA is a 
DPP-4 inhibitor, blinded study medication must be discontinued.
3. Corticosteroids: Treatment for ≥14 consecutive days or repeated courses of 
pharmacologic doses of systemic corticosteroids are prohibited.
Note: Inhaled, nasal, ophthalmic, and topical corticosteroids and physiological 
replacement doses of adrenal steroids are permitted.
4. Weight loss medications:  Initiation of weight loss medications after screening is 
prohibited.  If a subject is taking a weight loss medication which was initiated >12 
months prior to screening, this is not an exclusion (see Section 5.1.3).  However, it is 
preferable that the dose of weight loss medication remain stable during the double-blind 
treatment period.
Guidance for Other Medications
The investigator or subject’s physician/health care provider is permitted to make adjustments 
in the subject’s non-AHA therapies throughout the trial if clinically warranted.  Guidance for 
specific medications which are permitted during the study is provided below.
1. Blood Pressure and Lipid Medications: Concurrent lipid lowering and antihypertensive 
medications are permitted.  Subjects must be on a stable lipid and/or antihypertensive 
medication regimen for the 4 weeks prior to Visit 4/Day 1 (refer to Section 5.1.3, Table 
2).  It is preferable that doses of these medications remain stable during the double-blind 
treatment period.
2. Hormonal Replacement Therapy and Birth Control Medications: Hormone replacement 
therapy (HRT) and birth control medications are permitted.  Subjects on HRT must be on 
a stable dose for at least 4 weeks prior to Visit 4/Day 1.  Subjects on birth control 
medications must be using a single regimen for at least 1 cycle prior to Visit 4/Day 1.  It 
is preferable that HRT dose and birth control medication regimens remain stable during 
the double-blind treatment period and 14 days after the last dose of study medication.  
3. Thyroid Hormone Replacement Therapy:  Thyroid hormone replacement medication 
(e.g., thyroxine) is permitted.  Subjects who meet the TSH exclusion criterion specified in 
Table 2 may be re-screened after being on a stable thyroid replacement regimen for at 
least 6 weeks.
4. Supplements and/or Traditional Medicines: The use of herbal supplements and other 
natural products should be discouraged.  Subjects who do not discontinue the use of such 
supplements prior to Visit 3/Week -2 should be instructed not to change the use or dose 
of the supplement during the trial.  Subjects should be instructed not to initiate new 
supplements during the trial.
 
 
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Rescue Medications & Supportive Care
5.6
During the double-blind treatment period, subjects who meet progressively more stringent 
glycemic rescue criteria (see Table 4) will receive glycemic rescue therapy determined by the 
study investigator as summarized in Section 5.2.1.2.3.  Glycemic rescue medication will be 
initiated at either a scheduled visit or at the investigational site, and not by a telephone 
contact.  
Immediately prior to initiation of glycemic rescue therapy (at a scheduled visit), subjects 
must undergo the Rescue Visit procedures listed in the Trial Flow Chart –Section 6.0. 
Subjects requiring rescue medication are to continue to receive Met-IR plus double-blind 
sitagliptin/placebo to sitagliptin unless they meet any of the discontinuation criteria listed in 
Section 5.8.   
Table 4  Glycemic Thresholds for Rescue
Visit Intervals
Glycemic Thresholds
After Visit 4/Day 1 through Visit 5/Week 6:
FPG consistently >270 mg/dL (15.0 mmol/L)
After Visit 5/Week 6 through Visit 7/Week 20:
FPG consistently >240 mg/dL (13.3 mmol/L)
Note: A consistent value for FPG is defined as a repeat measurement performed within 7 days of notification 
from the central laboratory.  Site should reinforce diet/exercise counseling prior to repeat measurement.
Diet/Activity/Other Considerations
5.7
Diet
5.7.1
Subjects will be seen by a dietician or qualified healthcare professional for dietary and 
exercise counseling at Visit 2; follow-up at other visits may be done by other appropriate site 
personnel evaluating the subject.
The subject will receive counseling on diet consistent with the local guidelines of the country 
of the investigational site.  At each subsequent visit, the subject will be asked about their diet 
and exercise, and counseling should be provided, as appropriate. Detailed dietary information 
will not be captured. 
Alcohol, Caffeine and Tobacco
5.7.2

Subjects will be counseled to limit alcohol use to moderate amounts (i.e., ≤2 drinks per 
day and no more than 14 drinks per week).  

Ingestion of caffeine will be prohibited for at least 30 minutes prior to scheduled ECGs 
and blood pressure determinations.

Ingestion of nicotine-containing products will be prohibited for at least 30 minutes prior 
to the scheduled ECGs and blood pressure determinations.
 
 
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Activity
5.7.3
Subjects will be counseled to maintain a medically appropriate, routine exercise program and 
a consistent physical activity level during the trial.  Subjects should not engage in physically 
strenuous exercise (for example: heavy lifting, weight training, calisthenics, and aerobics) 
within 48 hours before each blood sample collection for clinical laboratory tests for the 
duration of participation in the trial.
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 for any of the following reasons:
●
The subject or legal representative (such as a parent or legal guardian) withdraws 
consent.
Note:  Withdrawal of consent should occur only in subjects who refuse to engage in any
trial-related activity including telephone contact.  Subjects unwilling to fully participate in 
the study should be discontinued from double-blind study therapy (sitagliptin/placebo to 
sitagliptin).  Appropriate management of their diabetes should be instituted by their personal 
physician or the study investigator.    Subjects should be encouraged to continue study 
participation on a more limited level to support the fullest evaluation of the treatment strategy 
being assessed.  See section 5.8.1 for discussion of the approach to subjects who are 
unwilling to fully participate in this study but agree to continue with more limited 
participation.
A subject must be discontinued from treatment (but may continue to be monitored in the 
trial) for any of the following reasons:
1. Subject develops a contraindication to either metformin or sitagliptin.  
2. Elevation in ALT and/or AST ≥3-times the upper limit of normal will require further 
evaluation in all cases.  Depending on results of this evaluation, interruption or 
discontinuation of randomized therapy may be required.  Refer to Appendix 12.4 for 
additional details on management and discontinuation of randomized therapy for 
subjects with elevated liver enzymes.
 
 
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3. Reduction of renal function:

eGFR persistently <50 mL/min/1.73m2 (MDRD formula)
Note: A persistent eGFR value is defined as a repeat measurement, performed 
within 2 weeks after notification from the central laboratory, that remains <50 
mL/min/1.73m2, despite correction of potential causative factors (e.g., 
correction of volume depletion, discontinuation of nonsteroidal anti-
inflammatory drugs [NSAIDs]).  If the eGFR value continues to meet the 
discontinuation criterion but demonstrates stability or improvement relative to 
the prior result, an additional repeat may be performed within 7 days.
4. Ongoing use of a DPP-4 inhibitor other than blinded study medication (see Section 
5.5).  
5. Pregnancy.
Note:  A positive urine pregnancy test requires immediate interruption of double-
blind study therapy (sitagliptin/placebo to sitagliptin) and metformin until serum β-
hCG can be performed and found to be negative.  Subject must be permanently 
discontinued from blinded study drug, and pregnancy should be reported and 
followed per Section 7.2.2 if pregnancy is confirmed by a positive serum pregnancy 
test. 
6. Any medical condition or personal circumstance which, in the opinion of the 
investigator, exposes the subject to risk by continuing in the trial or does not allow the 
subject to adhere to the requirements of the protocol.
7. Subject undergoes bariatric surgery.
8. The investigator or subject becomes unblinded to the subject’s treatment assignment.
The Sponsor should be notified as soon as possible when a subject is discontinued from 
blinded study drug or blinded study drug is interrupted because of an AE or a laboratory 
safety test abnormality.
Follow-up for Subjects Who Discontinue Blinded Study Drug
5.8.1
Withdrawal of Consent
5.8.1.1
If a subject indicates his or her intention to stop active participation in the trial (i.e., chooses 
to no longer attend visits at the investigational site, take blinded study drug, and have other 
study-related procedures conducted at the investigational site) or if the investigator has 
recommended withdrawal of the subject from active participation in the trial, the subject 
should be encouraged to complete procedures for the Discontinuation Visit.  Additionally, 
the investigator must clarify with the subject if he/she is willing to continue in the study with 
contact at intervals to provide a brief and focused update on health status (e.g., evaluate if the 
subject experienced any SAEs).  It will be important for the subject to understand the 
importance of complete collection of information, and also the limited requirements for 
continuing to provide this information (i.e., a brief telephone contact, occurring at the time of 
the originally planned study visits).  
 
 
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The sponsor may retain and continue to use any data collected before the subject’s 
withdrawal of consent.
Discontinuation from Blinded Study Therapy
5.8.1.2
If a subject discontinues randomized therapy for reasons other than withdrawn consent, the 
investigator should make every appropriate effort to maintain the subject in the ongoing 
study, implementing the study visit schedule (with efficacy and safety assessments) per study 
Trial Flow Chart, Section 6.0) It will be important for the subject to understand the 
importance of complete collection of information. Based upon this, subjects should be 
strongly encouraged to continue to participate in all scheduled clinic visits (which will 
continue as outlined in the Trial Flow Section 6.0, except those related to double-blind study 
drug).  
All subjects discontinuing study medication (either early discontinuation of study medication 
or at completion of the 20-week double-blind treatment period) should complete procedures 
for the Discontinuation Visit and have a 14-day post-last study drug dose telephone contact 
(see Section 6.0 for details).
A subject who discontinues study medication prematurely but does not withdraw consent 
should continue to be followed by the investigational site, attending scheduled study visits 
and undergoing study procedures (other than those related to study medication).  If subjects 
are not willing to return for on-site clinic visits, but agree to telephone contact follow-up, 
they should be followed by telephone contacts at the time of scheduled study visits until the 
end of the trial (Week 20).  The purpose of these telephone contacts, as well as the 14-day 
post-treatment telephone call, is to collect information about subjects’ health status.  
Subjects who discontinue treatment with blinded study drug but who continue to participate 
in the trial by providing follow-up information should receive medical and diabetes 
management by their managing physician or investigator, as appropriate.  These subjects may 
initiate any other therapy as needed (previously prohibited medications will not apply to 
them).  After discontinuation of blinded study drug, the Sponsor will continue to reimburse 
rescue medication (for those rescued) until trial completion (Week 20).
If the trial site loses contact with the subject, the site should make at least three attempts for a 
telephone contact.  If the three attempts of telephone contact are unsuccessful, the site should 
make at least one attempt to reach the subject via certified letter.  All attempts to contact a 
subject and information received during contact attempts must be documented in the 
subject’s medical record.  If attempts to contact the subject via telephone contacts and 
certified letters are unsuccessful, alternative measures should be implemented, which may 
include contacting family members and health care providers and, when applicable, using 
subject location services.  In any circumstance, every effort should be made to document 
subject outcome, if possible.
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
There are no pre-specified criteria for terminating the trial early.
 
 
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Trial Period:
Screening and Run-in Period
Randomization
Double-Blind Treatment
Post-Treatment
Visit Number/Title:
Visit 1
Visit 2
Visit 3
Visit 4
TC
Visit 5
Visit 6
Visit 7
Rescue
Discontinuation
Follow-up
Scheduled Day, Week: 
Week -2
Day 1
Day 9
Week 6
Week 14
Week 20
Rescue
At time of 
discontinuationa
14-Day Post 
Treatment 
Telephone 
Contact
Scheduling Window Days 
etc.:
± 5 days
± 5 days
± 1 day(s)
± 7 days
± 7 days
± 7 days
+3 days
Blood (DNA)for Future 
Biomedical Research b
X
a.
See section 5.8.1 for additional information regarding follow-up after premature discontinuation of study medication..
b.
Informed consent for future biomedical research samples must be obtained to collect the DNA, plasma, and serum sample.
c.
Subjects should be reminded to not to take any other AHA medications other than the trial treatments (background metformin and sitagliptin/placebo to 
sitagliptin) during their participation in the study.  They should be counseled that if another physician prescribes such a treatment (i.e., any AHA), the subject 
and/or the prescribing physician should immediately contact the investigational site prior to initiation of such therapy (unless alternative AHA therapy is 
considered clinically to be immediately required).  Subjects who were washed off of another AHA should be reminded to remain off this agent while participating 
in the current trial, and to not re-start this agent post-study unless advised by their diabetes care-giver (whether the investigator or another physician)
d.
Subjects will be seen by a dietician or qualified healthcare professional for dietary and exercise counseling at Visit 2; follow-up at other visits may be done by 
other appropriate site personnel evaluating the subject.
e.
Brief physical examination includes assessment of heart, lungs, abdomen, extremities and skin.
f.
Site fingerstick A1C is not mandatory, but may be used, at the discretion of the investigator, for screening a subject.  However, a fingerstick A1C cannot substitute 
for a central laboratory measured A1C to determine if a subject meets entry criteria
g.
FFSG values performed in the clinic will be used to assess exclusion criteria prior to randomization at Visit 4/Day 1.
h.
FPG values obtained at the central laboratory will be used to assess if the subject meets glycemic rescue criteria. Refer to Section 5.6 for further details.
i.
C-peptide test at Visit 1/Screening is only for subjects assessed by the investigator as possibly having Type 1 diabetes. 
j.
A patient excluded due to TSH criterion may be re-screened after being on a stable, adjusted thyroid replacement regimen for at least 6 weeks.
k.
Only subjects with TG meeting the exclusion criterion at Visit 1 should have a repeat test at Visit 3/Week-2, as described in exclusion criterion #12.
l.
Women of childbearing potential will have a urine pregnancy test (and serum pregnancy test if required by site's Institutional Review Board [IRB]/Ethics 
Committee [EC]).   Subjects with a positive urine pregnancy test during double-blind treatment period will interrupt blinded study drug and background therapy 
metformin, and undergo a serum pregnancy test.
m.
If dipstick (midstream urine specimen) is positive for blood, WBC (e.g., leukocyte esterase, nitrates), or protein, then a urine sample for a complete urinalysis 
(dipstick and microscopy) should be sent to the central laboratory
 
 
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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 or each subject’s legally acceptable representative 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. 
General Informed Consent
7.1.1.1.1
Consent must be documented by the subject’s dated signature or by the subject’s legally 
acceptable representative’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 or his/her legally acceptable 
representative 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 or 
by the subject’s legally acceptable representative’s dated signature.
Specifics about a trial and the trial population will be added to the consent form template at 
the protocol level.  
The informed consent will adhere to IRB/ERC requirements, applicable laws and regulations 
and Sponsor requirements.
 
 
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Consent and Collection of Specimens for Future Biomedical Research
7.1.1.1.2
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 
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.
Subject Identification Card
7.1.1.3
All subjects will be given a Subject Identification Card identifying them as participants in a 
research trial.  The card will contain trial site contact information (including direct telephone 
numbers) to be utilized in the event of an emergency.  The investigator or qualified designee 
will provide the subject with a Subject Identification Card immediately after the subject 
provides written informed consent.
The subject identification card also contains contact information for the emergency 
unblinding call center so that a health care provider can obtain information about trial 
medication/vaccination in emergency situations where the investigator is not available.
Medical History
7.1.1.4
A medical history will be obtained by the investigator or qualified designee. The use of 
tobacco should be collected as part of the medical history.
Prior and Concomitant Medications Review
7.1.1.5
Prior Medications
7.1.1.5.1
The investigator or qualified designee will review prior medication use. AHAs taken by the 
subject at any time prior to Visit 1/Screening and non-AHAs taken within 8 weeks prior to  
Visit 1/Screening should be recorded on the appropriate eCRF. The site may rely on subject 
report for this information.
Concomitant Medications
7.1.1.5.2
The investigator or qualified designee will record any medication taken by the subject during 
the trial on the appropriate eCRF.
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.
Any subject who is screened multiple times will retain the original screening number 
assigned at the initial screening visit.
 
 
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Please refer to the Trial Flow Chart (see Section 6.0) and the Trial File Binder for specific 
details on the screening/rescreening visit requirements
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
Adherence to both randomized double-blind therapy (sitagliptin/placebo to sitagliptin) and 
background therapy (Met-IR) will be assessed by subject report during the double-blind 
treatment period.  Every effort will be made to maintain adherence as close to 100% as 
possible.  Compliance will be documented in the source documentation and in the study 
medication eCRF.  
Interruptions from the protocol specified treatment plan for >7 days OR compliance <75%
require consultation between the investigator and the Sponsor and written documentation of 
the collaborative decision on subject management.
Diet and Exercise Counseling
7.1.1.8.1
Refer to Section 5.7 for further details.
Dispense Hypoglycemia Assessment Log and Instruct on Hypoglycemia 
7.1.1.8.2
Symptoms and Management
At Visit 2 the site will dispense the Hypoglycemia Assessment Log (HAL) and review the 
symptoms and management of hypoglycemia with the subject.  The site will counsel the 
subject to immediately perform a fingerstick glucose measurement if any symptoms occur 
that may be related to hypoglycemia (e.g., weakness, dizziness, shakiness, increased 
sweating, palpitations, or confusion), but also to avoid delay in treating these symptoms.
The subject will be instructed to complete the HAL for any symptomatic episodes he or she 
believes may represent hypoglycemia.  If a fingerstick glucose has been obtained before or 
shortly (i.e., within ≤5 minutes) after treating, the value should be recorded in the log.  In 
addition, subjects will be instructed to record in the log any fingerstick glucose values ≤70 
mg/dL (3.9 mmol/L) regardless of the presence of symptoms.
Subjects should be instructed to contact the investigational site to report:

any episode of hypoglycemia for which assistance was required (i.e., severe 
hypoglycemia),

any episode of fingerstick glucose ≤70mg/dL (≤3.9 mmol/L) with or without 
symptoms .
 
 
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Note:  As indicated, subjects will record symptoms and/or fingerstick glucose measurements 
that they believe are related to hypoglycemia on the HAL.  Each episode should be evaluated
by the investigator.  For episodes of documented 
symptomatic 
hypoglycemia 
with 
a 
concurrent glucose measurement of 70 mg/dL (3.9 mmol/L), and for all episodes of severe 
hypoglycemia regardless of biochemical documentation, the Hypoglycemia Assessment 
(HA) eCRF must also be completed.
Investigators should report any event of hypoglycemia they consider to be an adverse event 
on the appropriate AE eCRF.
Dispense Glucose Meter and Self-Monitoring Blood Glucose (SMBG) 
7.1.1.8.3
Instructions
Glucose meters will be supplied to all subjects at Visit 2 in order to perform SMBG. Subjects 
will be instructed on the procedure to perform fingerstick glucose measurements.  Subjects 
will monitor their fingerstick glucose concentrations with a frequency determined appropriate 
by the investigator.  
During the run-in period, subjects should be counseled to contact the trial site if fingerstick 
glucose levels are >270 mg/dL (15.0 mmol/L) ≥2 times per week.  Furthermore, in order to 
assess the need for rescue and/or discontinuation from blinded study drug, subjects should be 
instructed to contact the site for fingerstick glucose values that are >270 mg/dL (15.0
mmol/L) after Visit 4/Day 1 through Visit 5/Week 6, or >240 mg/dL (13.3 mmol/L) after 
Visit 5/Week 6 through Visit 7/Week 20. Subjects will be instructed to contact the site at any 
time from initiation of the run-in period through Visit 7/Week 20 if any fingerstick glucose 
values are ≤70 mg/dL (≤3.9 mmol/L).  
Witness Dosing
7.1.1.8.4
Administration of blinded study drug
and Met-IR will be witnessed by the investigator 
and/or trial staff at Visit 3/Week -2 (start of the placebo run-in) and at Visit 4/Day 1 (the first 
visit of the double-blind treatment period) after completion of all trial procedures including 
the collection of all fasting blood samples.
Dispense Single-Blind Placebo Run-in 
7.1.1.8.5
Subjects will be dispensed single-blind study drug (matching placebo for sitagliptin 100 mg) 
at Visit 3/Week -2 and instructed to take one tablet orally per day approximately the same 
time of day in the morning.  The last dose of placebo run-in should be taken on the day prior 
to Visit 4/Day 1.
Refer to Section 5.2.2 for further details.
Dispense Double-Blind Study Drug
7.1.1.8.6
Subjects will be dispensed double-blind study drug (sitagliptin or sitagliptin-matching 
placebo) at all trial visits from Visit 4/Randomization (Day 1) through Visit 6/Week 14 and 
instructed to take the double-blind study drug once a day, orally at approximately the same 
time every day.  
 
 
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Refer to Section 5.2.2 for further detail.
Medication Compliance Monitoring
7.1.1.8.7
All subjects will be directed to bring any used and unused bottles of blinded study drug and 
Met-IR to each visit.  The investigator must maintain a complete and current accountability 
record for the blinded study drug.
Compliance will be assessed by subject report (see Section 8.11).  Every effort will be made 
to maintain compliance as close to 100% as possible. 
Subjects who, based on self-report, are <80% compliant with single-blind placebo to 
sitagliptin and/or Met-IR during the 2-week, single-blind placebo run-in are ineligible for 
randomization.
The investigator or designee will counsel subjects who report taking <80% of the double-
blind study drug and/or Met-IR following randomization.  The investigator or designee will 
determine factors that resulted in <80% compliance and will take steps to improve 
compliance.  Subjects will be counseled on the importance of taking their medication as 
prescribed. Subject counseling will be documented in source documents.
Clinical Procedures/Assessments
7.1.2
Vital Signs (Sitting Blood Pressure and Pulse Rate)
7.1.2.1
Vital sign measurements include a duplicate measurement of sitting blood pressure and pulse 
rate.  Blood pressure and pulse rate will be measured using an automated, oscillometric
blood pressure measuring device at time points noted in the Trial Flow Chart – Section 6.0  
Site personnel should use the same blood pressure measuring device throughout the study for 
each subject. Refer to the Trial File Binder for additional details.
Height and Weight
7.1.2.2
Height and weight will be measured at each of the pre-defined nominal time points outlined 
in the Trial Flow Chart – Section 6.0.  Body weight will be measured using a standardized, 
digital scale (provided by the sponsor).  
Physical Examination
7.1.2.3
Full and brief physical examinations will be performed as outlined in the Trial Flow Chart –
Section 6.0.  Unless the study investigator feels there is a specific need, genitourinary, rectal 
and breast examination should be omitted from the full physical examination.  Brief physical 
examinations will include assessment of the heart, lungs, abdomen, and extremities.  Other 
body systems may be evaluated as per the judgment of the investigator or as needed to 
evaluate adverse events. Abnormalities considered clinically significant should be reported as 
adverse events.  
 
 
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12-Lead Electrocardiogram
7.1.2.4
A supine 12-lead ECG will be obtained at time point noted in the Trial Flow Chart – Section 
6.0.    
•
Subjects should avoid the ingestion of caffeine and nicotine-containing products for 
at least 30 minutes prior to the scheduled ECGs and blood pressure determinations.
•
12-lead ECGs should be performed after the subject has rested quietly for at least 10 
minutes in a supine position.
12-lead ECGs should be obtained prior to the nominal time assessment of blood pressure, 
and pulse rate as well as prior to blood collection.
The investigator is responsible for retaining all copies of the ECG reports.
Laboratory Procedures/Assessments
7.1.3
All laboratory tests outlined in the Trial Flow Chart - Section 6.0 will be performed by the 
central laboratory.  The optional site fingerstick A1C at Visit 1/Screening, the fasting 
fingerstick glucose measurement at Visit 4/Day 1, and all urine pregnancy tests will be 
performed at the investigational site.
Laboratory test results for chemistry, hematology, urinalysis, and lipids will not be masked.  
Glycemic measurements (e.g., glucose and  A1C) will be masked from Visit 4/Day 1.  
However, in order for the investigator to perform an evaluation for possible rescue or 
discontinuation from the blinded study drug, the central laboratory will report to the 
investigator in an unmasked manner if an FPG value meets criteria for glycemic rescue (see 
Section 5.6).
In addition, the central laboratory will flag the following safety measurements meeting 
specific criteria for discontinuation from blinded study drug:
•
eGFR <50 mL/min/1.73 m2;
•
elevations ≥3X the laboratory upper limit of normal (ULN) in liver transaminases (ALT 
and AST) (see Appendix 12.4 for guidance on retesting);
•
elevations in ALT and/or AST ≥3X the ULN with concurrent total bilirubin ≥2X the 
ULN and alkaline phosphatase <2X the ULN;
•
positive serum pregnancy test
Details regarding specific laboratory procedures/assessments to be performed in this trial are 
provided below.  
Refer to the Trial Flow Chart - Section 6.0 for specific laboratory tests performed at each 
trial visit.
 
 
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Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis)
7.1.3.1
Laboratory tests for hematology, chemistry and urinalysis are specified in Table 5.
Table 5  Laboratory Tests
Hematology
Chemistry
Others
Urinalysis

Hemoglobin

Hematocrit

RBC Count

Platelet Count

WBC Count

Neutrophils

Eosinophils

Monocytes

Basophils

Lymphocytes

BUN

Serum 
Creatinine 
(eGFR 
calculated using 
the MDRD
formula)

Glucose

Sodium

Potassium

Chloride

Total Carbon 
Dioxide 
(Bicarbonate)

AST (SGOT)

ALT (SGPT)

Alkaline 
Phosphatase

Total Bilirubin

Direct 
(conjugated) 
Bilirubina

Indirect 
(unconjugated)
Bilirubina


TSH

Fasting C-
peptide

A1C

FPG

Pregnancy Tests 
(where 
applicable)

Lipid Panel 
(i.e., Total 
Cholesterol, 
HDL-C, non-
HDL-C, LDL-
C, and 
Triglycerides)

Blood

Glucose

Protein

Leukocyte 
esterase

Nitrates

Specific Gravity

Microscopic 
exam, if 
abnormal results 
are noted
a Both direct and indirect bilirubin measured only when total bilirubin is greater than ULN.
Laboratory tests will be performed after at least a 10-hour fast (i.e., no food, double-blind 
study drug, metformin, or drink except water and non-AHA non-study drug as prescribed).  
Subjects who have not fasted prior to Visit 1/Screening should return to the clinic fasting 
prior to Visit 4/Randomization for fasting TG and FPG measurements.  After randomization, 
subjects who do not fast before a scheduled visit will be required to return fasting for the 
study visit within three days.
Future Biomedical Research Sample Collection
7.1.3.2
The following specimens are to be obtained as part of Future Biomedical Research:

DNA for future research 

Plasma for future research

Serum for future research
 
 
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Other Procedures
7.1.4
Withdrawal/Discontinuation
7.1.4.1
Subjects who discontinue/withdraw from treatment prior to completion of the treatment
regimen should be encouraged to continue to be followed for all remaining study visits.
When a subject discontinues/withdraws from participation in the trial, all applicable activities 
scheduled for the discontinuation visit should be performed at the time of discontinuation.  
Any adverse events which are present at the time of discontinuation/withdrawal should be 
followed in accordance with the safety requirements outlined in Section 7.2 - Assessing and 
Recording Adverse Events. All subjects discontinuing study medication should have a 14-
day post-last study drug dose telephone contact (see Section 6.0 for details).  .
Withdrawal From Future Biomedical Research
7.1.4.1.1
Subjects may withdraw their consent for Future Biomedical Research and have their 
specimens and all derivatives destroyed.   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 
, and a form will be provided by the Sponsor to 
obtain appropriate information to complete specimen withdrawal.  Subsequently, the 
subject's specimens will be removed from the biorepository and be destroyed.  A letter will 
be sent from the Sponsor to the investigator confirming the destruction. It is the 
responsibility of the investigator to inform the subject of completion of destruction.  Any 
analyses in progress at the time of request for 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 
specimen destruction cannot be processed.
Blinding/Unblinding
7.1.4.2
When the investigator or sub-investigator 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 sub-investigator the 
emergency unblinding call center will provide the information to him/her promptly and 
report unblinding to the sponsor.  The emergency unblinding call center will make a record 
promptly however, the investigator or sub-investigator must enter the intensity of the adverse 
experiences observed,   their relation to study drug, the reason thereof, etc., in the medical 
chart etc., before unblinding is performed.  
 
 
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Additionally, the investigator must go into the IVRS system and perform the unblind in the 
IVRS system to update drug disposition.  In the event that the emergency unblinding call 
center is not available for a given site in this trial, IVRS/IWRS should be used for emergency 
unblinding in the event that this is required for subject safety.
In the event that unblinding has occurred, the circumstances around the unblinding (e.g., date 
and reason) 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.
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:
Digital scale:  The study site is responsible for conducting accuracy checks (approximately 
monthly) to ensure the Sponsor-supplied scale to measure body weight is working correctly.  
Additional details are provided in the Trial File Binder.
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.
Refer to the Trial File Binder for details regarding study visit requirements including subject 
telephone contacts.
Assessing and Recording Adverse EventsAdverse Events and Patient/Device 
7.2
Events
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.
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.
 
 
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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 treatment 
allocation/randomization 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 treatment allocation/randomization through 14 days following 
cessation of treatment, all adverse events must be reported by the investigator. Such events 
will be recorded at each examination on the Adverse Event case report forms/worksheets.  
The reporting timeframe for adverse events meeting any serious criteria is described in 
section 7.2.3.1. The investigator will make every attempt to follow all subjects with non-
serious adverse events for outcome.
Electronic reporting procedures can be found in the Electronic Data Capture (EDC) data 
entry guidelines. Paper reporting procedures can be found in the Investigator Trial File 
Binder (or equivalent).
Definition of an Overdose for This Protocol and Reporting of Overdose to the 
7.2.1
Sponsor
An overdose must be reported if any of the following occurs during the conduct of this trial: 
(1) Dosing of >400 mg/day of sitagliptin or matching placebo, (2) Dosing >200 mg/day of 
sitagliptin or matching placebo for more than 28 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).
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.
 
 
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Pregnancies and lactations that occur after the consent form is signed but before treatment 
allocation/randomization 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 treatment 
allocation/randomization through 14 days following cessation of Sponsor’s product must be 
reported by the investigator.  All reported pregnancies
must be followed to the 
completion/termination of the pregnancy. Pregnancy outcomes of spontaneous abortion, 
missed abortion, benign hydatidiform mole, blighted ovum, fetal death, intrauterine death, 
miscarriage and stillbirth must be reported as serious events (Important Medical Events). If 
the pregnancy continues to term, the outcome (health of infant) must also be reported.
Such events must be reported within 24 hours to the Sponsor either by electronic media or 
paper. Electronic reporting procedures can be found in the EDC data entry guidelines. Paper 
reporting procedures can be found in the Investigator Trial File Binder (or equivalent).
Immediate Reporting of Adverse Events to the Sponsor
7.2.3
Serious Adverse Events
7.2.3.1
A serious adverse event is any adverse event occurring at any dose or during any use of 
Sponsor's product that:
●
Results in death;
●
Is life threatening;
●
Results in persistent or significant disability/incapacity;
●
Results in or prolongs an existing inpatient hospitalization;
●
Is a congenital anomaly/birth defect;
●
Is an other important medical event.
Note: In addition to the above criteria, adverse events meeting either of the below criteria, 
although not serious per ICH definition, are reportable to the Sponsor in the same timeframe 
as SAEs to meet certain local requirements. Therefore, these events are considered serious by 
the Sponsor for collection purposes.
●
Is a cancer;
●
Is associated with an overdose.
Refer to Table 6 for additional details regarding each of the above criteria.
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any serious adverse event, or follow up to a serious adverse event, 
including death due to any cause, that occurs to any subject must be reported within 24 hours 
to the Sponsor if it causes the subject to be excluded from the trial, or is the result of a 
protocol-specified intervention, including but not limited to washout or discontinuation of 
usual therapy, diet, placebo treatment or a procedure.
 
 
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For the time period beginning at treatment allocation/randomization through 14 days 
following cessation of treatment, any serious adverse event, or follow up to a serious adverse 
event, including death due to any cause, whether or not related to the Sponsor's product, must 
be reported within 24 hours to the Sponsor either by electronic media or paper. Electronic 
reporting procedures can be found in the EDC data entry guidelines. Paper reporting 
procedures can be found in the Investigator Trial File Binder (or equivalent).
Additionally, any serious adverse event, considered by an investigator who is a qualified 
physician to be related to the Sponsor's product that is brought to the attention of the 
investigator at any time outside of the time period specified in the previous paragraph also 
must be reported immediately to the Sponsor.
All subjects with serious adverse events must be followed up for outcome.
Events of Clinical Interest
7.2.3.2
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI) and must be reported to the Sponsor.
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, 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 treatment allocation/randomization through 14 days 
following cessation of treatment, any ECI, or follow up to an ECI, whether or not related to 
the Sponsor’s product, must be reported within 24 hours to the Sponsor, either by electronic 
media or paper.  Electronic reporting procedures can be found in the EDC data entry 
guidelines.  Paper reporting procedures can be found in the Investigator Trial File Binder (or 
equivalent).
Events of clinical interest for this trial include:
1. an overdose of Sponsor's product, as defined in Section 7.2.1 - Definition of an Overdose 
for This Protocol and Reporting of Overdose to the Sponsor, that is not associated with 
clinical symptoms or abnormal laboratory results. 
2. an elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of 
normal and an elevated total bilirubin lab value that is greater than or equal to 2X the 
upper limit of normal and, at the same time, an alkaline phosphatase lab value that is less 
than 2X the upper limit of normal, as determined by way of protocol-specified laboratory 
testing or unscheduled laboratory testing.*
*Note:  These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may require 
an additional evaluation for an underlying etiology. The trial site guidance for assessment 
and follow up of these criteria can be found in the Investigator Trial File Binder (or 
equivalent).
 
 
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Evaluating Adverse Events
7.2.4
An investigator who is a qualified physician will evaluate all adverse events with respect to 
the elements outlined in Table 6. The investigator’s assessment of causality is required for 
each adverse event.  Refer to Table 6 for instructions in evaluating adverse events.
 
 
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Table 6  Evaluating Adverse Events
Maximum
Mild
awareness of sign or symptom, but easily tolerated  (for pediatric trials, awareness of symptom, but easily tolerated)
Intensity
Moderate
discomfort enough to cause interference with usual activity (for pediatric trials, definitely acting like something is wrong)
Severe
incapacitating with inability to work or do usual activity (for pediatric trials, extremely distressed or unable to do usual activities)
Seriousness
A serious adverse event (AE) is any adverse event occurring at any dose or during any use of Sponsor's product that:
†Results in death; or
†Is life threatening; or places the subject, in the view of the investigator, at immediate risk of death from the event as it occurred [Note: This does not include an 
adverse event  that, had it occurred in a more severe form, might have caused death.]; or
†Results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to conduct normal life functions); or
†Results in or prolongs an existing inpatient hospitalization (hospitalization is defined as an inpatient admission, regardless of length of stay, even if the 
hospitalization is a precautionary measure for continued observation.   (Note: Hospitalization for an elective procedure to treat a pre-existing condition that has not 
worsened is not a serious adverse event.  A pre-existing condition is a clinical condition that is diagnosed prior to the use of a Merck product and is documented in the 
patient’s medical history.); or
†Is a congenital anomaly/birth defect  (in offspring of subject taking the product regardless of time to diagnosis); or
Is a cancer (although not serious per ICH definition, is reportable to the Sponsor within 24 hours to meet certain local requirements); or
Is associated with an overdose (whether accidental or intentional).  Any adverse event associated with an overdose is considered a serious adverse event for 
collection purposes. An overdose that is not associated with an adverse event is considered a non-serious event of clinical interest and must be reported within 24 
hours.
Other important medical events that may not result in death, not be life threatening, or not require hospitalization may be considered a serious adverse event when, 
based upon appropriate medical judgment, the event may jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes listed 
previously (designated above by a †).
Duration
Record the start and stop dates of the adverse event.  If less than 1 day, indicate the appropriate length of time and units
Action taken 
Did the adverse event cause the Sponsor's product to be discontinued?
Relationship to 
Sponsor's 
Product
Did the Sponsor's product cause the adverse event?   The determination of the likelihood that the Sponsor's product caused the adverse event will be provided by an 
investigator who is a qualified physician.  The investigator’s signed/dated initials on the source document or worksheet that supports the causality noted on the AE 
form, ensures that a medically qualified assessment of causality was done.  This initialed document must be retained for the required regulatory time frame.  The 
criteria below are intended as reference guidelines to assist the investigator in assessing the likelihood of a relationship between the test drug and the adverse event 
based upon the available information
The following components are to be used to assess the relationship between the Sponsor's product and the AE; the greater the correlation with the components 
and their respective elements (in number and/or intensity), the more likely the Sponsor's product caused the adverse event:
Exposure
Is there evidence that the subject was actually exposed to the Sponsor's product such as:  reliable history, acceptable compliance assessment (pill 
count, diary, etc.), expected pharmacologic effect, or measurement of drug/metabolite in bodily specimen?
Time Course
Did 
the 
AE 
follow 
in 
a 
reasonable 
temporal 
sequence 
from 
administration 
of 
the 
Sponsor's 
product? 
Is the time of onset of the AE compatible with a drug-induced effect (applies to trials with investigational medicinal product)?
Likely Cause
Is the AE not reasonably explained by another etiology such as underlying disease, other drug(s)/vaccine(s), or other host or environmental 
factors
 
 
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Relationship
The following components are to be used to assess the relationship between the Sponsor's product and the AE:  (continued)
to Sponsor's 
Product
(continued) 
Dechallenge
Was the Sponsor's product discontinued or dose/exposure/frequency reduced?
      If yes, did the AE resolve or improve?
           If yes, this is a positive dechallenge.    If no, this is a negative dechallenge.
(Note:  This criterion is not applicable if:  (1) the AE resulted in death or permanent disability; (2) the AE resolved/improved despite 
continuation of the Sponsor's product; (3) the trial is a single-dose drug trial); or (4) Sponsor's product(s) is/are only used one time.)
Rechallenge
Was the subject re-exposed to the Sponsor's product in this trial?
      If yes, did the AE recur or worsen?
          If yes, this is a positive rechallenge.    If no, this is a negative rechallenge.
(Note:  This criterion is not applicable if:  (1) the initial AE resulted in death or permanent disability, or (2) the trial is a single-dose drug trial); 
or (3) Sponsor's product(s) is/are used only one time.)
NOTE:  IF A RECHALLENGE IS PLANNED FOR AN ADVERSE EVENT WHICH WAS SERIOUS AND WHICH MAY HAVE BEEN 
CAUSED BY THE SPONSOR'S PRODUCT, OR IF RE-EXPOSURE TO THE SPONSOR'S PRODUCT POSES ADDITIONAL POTENTIAL 
SIGNIFICANT RISK TO THE SUBJECT THEN THE RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE SPONSOR
CLINICAL DIRECTOR AND THE INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE.
Consistency 
with Trial 
Treatment 
Profile
Is the clinical/pathological presentation of the AE consistent with previous knowledge regarding the Sponsor's product or drug class 
pharmacology or toxicology?
The assessment of relationship will be reported on the case report forms /worksheets by an investigator who is a qualified physician according to his/her best clinical judgment, including 
consideration of the above elements.
Record one of the following:
Use the following scale of criteria as guidance (not all criteria must be present to be indicative of a Sponsor's product relationship).
Yes, there is a reasonable 
possibility of Sponsor's product 
relationship.
There is evidence of exposure to the Sponsor's product.  The temporal sequence of the AE onset relative to the administration of the Sponsor's 
product is reasonable.  The AE is more likely explained by the Sponsor's product than by another cause. 
No, there is not a reasonable 
possibility of Sponsor's product 
relationship
Subject did not receive the Sponsor's product OR temporal sequence of the AE onset relative to administration of the Sponsor's product is not 
reasonable OR the AE is more likely explained by another cause than the Sponsor’s product.  (Also entered for a subject with overdose without 
an associated AE.)
 
 
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Sponsor Responsibility for Reporting Adverse Events
7.2.5
All Adverse Events will be reported to regulatory authorities, IRB/IECs and investigators in 
accordance with all applicable global laws and regulations, i.e., per ICH Topic E6 (R1) 
Guidelines for Good Clinical Practice.
8.0 STATISTICAL ANALYSIS PLAN
This section outlines the statistical analysis strategy and procedures for the study.  If, after 
the study has begun, but prior to any unblinding, changes are made to primary and/or key 
secondary hypotheses, 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 SAP (sSAP) and referenced in the Clinical 
Study Report (CSR) for the study.  
Statistical Analysis Plan Summary
8.1
Key elements of the statistical analysis plan are summarized below; the comprehensive plan 
is provided in Sections 8.2-8.12.  
Study Design Overview
Sitagliptin addition during metformin uptitration
Treatment Assignment
Subjects will be randomized in a 1:1 ratio to metformin (1000 mg 
b.i.d.) + sitagliptin group or metformin (1000 mg b.i.d.) group.
Stratification Factor: AHA status at screening (Not on AHA; On non-
metformin AHA; On metformin)
Analysis Populations
Efficacy: modified Full Analysis Set (mFAS)
Safety: All Subjects as Treated (ASaT)
Primary Endpoint(s)
A1C – change from baseline at Week 20
Key Secondary Endpoints
Proportion of subjects with A1C <7.0% at Week 20
Fasting Plasma Glucose (FPG) – change from baseline at Week 20
Statistical Methods for Key 
Efficacy/Immunogenicity/ 
Pharmacokinetic Analyses
The primary analysis will compare the efficacy of up-titration of 
metformin plus the addition of sitagliptin relative to up-titration of 
metformin alone in change from baseline in A1C at Week 20.  The 
mean change from baseline in A1C at Week 20 with up-titration of 
metformin plus the addition sitagliptin will be compared to that of up-
titration of metformin alone via a constrained longitudinal data 
analysis (cLDA) model.
For the analysis of the proportion of subjects with A1C <7.0% at 
Week 20, the Miettinen and Nurminen method will be used.  The 
cLDA model used for the analysis of A1C will be used to impute 
missing data.  
Change from baseline in FPG at Week 20 will be analyzed using a 
cLDA model. 
Statistical Methods for Key 
Safety Analyses
The study has no tier 1 safety endpoints.  For Tier 2 endpoints, 95% 
confidence intervals will be provided for between-group differences in 
the percentage of subjects with events; these analyses will be 
performed using the Miettinen and Nurminen method [15].
 
 
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Interim Analyses
No interim analyses are planned for this study.
Multiplicity
The study-wise type I error rate will be controlled at α = 0.05 (two-
sided) using an ordered testing procedure, beginning with change 
from baseline in A1C, followed by A1C goal <7.0% and then change 
from baseline in FPG. All tests will be conducted at α = 0.05 (two-
sided).
Sample Size and Power 
The planned sample size of 190 subjects per treatment arm will 
provide 93% power to detect a 0.4% between-group difference 
(metformin+sitagliptin vs. metformin) in change from baseline in 
A1C.
For A1C goal <7.0%, the planned sample size
will provide
approximately 90% power to detect a between-group difference of 14 
to 15 percentage points in the proportion of patients at goal, assuming 
that the proportion at goal is 14% to 18% in the metformin group.  
The planned sample size will provide approximately 90% power for
change from baseline in FPG, if the underlying treatment difference is 
-16 mg/dL.  
Responsibility for Analyses/In-House Blinding
8.2
The statistical analysis of the data obtained from this study will be the responsibility of the 
Clinical Biostatistics department of the SPONSOR.
This study will be conducted as a double-blind study under in-house blinding procedures.  
The official, database will not be unblinded until medical/scientific review has been 
performed, protocol deviations have been identified, and data have been declared final and 
complete.
The Clinical Biostatistics department will generate the randomized allocation schedule(s) for 
study treatment assignment.  Randomization will be implemented in an interactive voice 
response system (IVRS).
Hypotheses/Estimation
8.3
Objectives and hypotheses of this study are stated in Sections 3.1 and 3.2.  
Analysis Endpoints
8.4
Efficacy and safety endpoints that will be evaluated for within- and between-treatment 
differences are listed below.
The baseline value will be defined as the Visit 4/Week 0/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.
Efficacy Endpoints
8.4.1
The descriptions of the efficacy measurements and time points at which they are measured 
are described in Section 4.2.3.1 and Section 6.0 (Trial Flow Chart), respectively.  The 
efficacy endpoints to be analyzed are listed in Table 7.
 
 
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Table 7  Efficacy Endpoints
Primary Endpoint
Change from baseline in A1C at Week 20
Key Secondary Endpoints
Proportion of subjects with A1C < 7.0% at Week 20
Change from baseline in FPG at Week 20
Other Endpoints
Proportion of subjects with baseline A1C ≥ 8.5% with A1C  <7.0% at Week 20
Proportion of subjects receiving glycemic rescue therapy
Safety Endpoints
8.4.2
The descriptions of the safety measurements and time points at which they are measured are 
described in Section 4.2.3.2 and Section 6.0 (Trial Flow Chart), respectively.  The safety
endpoints to be analyzed are listed in Table 9 in Section 8.6.2.  These endpoints will be 
analyzed over 20 weeks.
Analysis Populations
8.5
Summaries of subject disposition will include all randomized subjects.  Summaries of 
baseline characteristics will be performed in the All Subjects Treated (AST) population, 
consisting of all randomized subjects who received at least one dose of study treatment.  
Subjects will be included in the treatment group to which they were randomized for both 
populations.
Efficacy Analysis Populations
8.5.1
The modified Full Analysis Set (mFAS) population will serve as the primary population for 
the analysis of efficacy data in this study.  The mFAS population consists of all randomized 
subjects who:

receive at least one dose of study treatment,

have at least one observation for the analysis endpoint (baseline or post-baseline).
Analyses in the mFAS population will exclude data after the initiation of rescue therapy 
[Section 5.6] or sustained use of prohibited antihyperglycemic agents (AHAs) [Section 5.5]
as well as data after the last dose of study medication plus an offset of 5 days.  Sustained use 
of additional AHAs is defined as >7 days (not necessarily consecutive).
The intention-to-treat (ITT) population will be a secondary population for efficacy analyses. 
The ITT population will consist of the same subjects as mFAS.  However, analyses in the 
ITT population will include all available data, including data obtained after the initiation of 
rescue or prohibited AHAs as well as after the last dose of study medication in subjects who 
remain in the study after discontinuing study medication.  
A secondary population for the analysis of A1C Goal < 7.0% (for the Missing = Failure 
supportive analysis approach) will be the All Subjects Treated (AST) population, consisting 
of all randomized subjects who received at least one dose of study treatment. This analysis 
will exclude data after the last dose of study medication plus an offset of 5 days.
 
 
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For all efficacy analyses, subjects will be included in the treatment group to which they are 
randomized, regardless of the treatment received during the course of the trial.  Details on the 
approach to handling missing data are provided in Section 8.6 Statistical Methods.
Safety Analysis Populations
8.5.2
Analyses of safety data will be performed in the All Subjects as Treated (ASaT) population 
consisting 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 except for any subjects 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 from baseline, a baseline measurement is also required.
Safety analysis will be based on observed data only.  No imputation will be performed for 
missing data.
Details on the approach to handling missing data for safety analyses are provided in Section 
8.6 Statistical Methods.
Statistical Methods
8.6
Statistical testing and inference for safety analyses are described in 8.6.2. Efficacy results 
that will be deemed to be statistically significant after consideration of the Type I error 
control strategy are described in Section 8.8, Multiplicity. All statistical tests will be 
conducted at α=0.05 (two-sided) level.
Statistical Methods for Efficacy Analyses
8.6.1
This section describes the statistical methods that address the primary and secondary 
objectives.
The primary estimands for the study consist of the following elements:

Target population: Patients with T2DM who have inadequate glycemic control on 
metformin

Endpoint: Mean change from baseline (in A1C, in FPG) at Week 20, proportion of 
patients with A1C <7.0% at Week 20

Measure of intervention effect: Difference in means or ratio of proportions (i.e., risk 
ratio) in the effect of randomized treatments on the endpoint if all subjects remained 
on treatment through Week 20
 
 
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For the primary analysis of change from baseline in A1C, a constrained longitudinal data 
analysis (cLDA) method proposed by Liang and Zeger [16] 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 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 also adjust for treatment, time, AHA status at screening, the 
interaction of time by AHA status at screening, and the interaction of time by treatment. An 
unstructured covariance matrix will be used to model the correlation among repeated 
measurements.  The treatment difference in terms of mean change from baseline at Week 20
will be estimated and tested from this model. 
Although the baseline measurement is included in the response vector, it is independent of 
treatment, and hence, the baseline means are constrained to be the same for different 
treatment groups. Of note, in the event that there are no missing data, the estimated 
treatment difference from the above cLDA model will be identical to that from a traditional 
longitudinal ANCOVA model which uses the baseline value as a covariate. However, unlike 
longitudinal ANCOVA, the cLDA model accounts for variability in the baseline values, thus 
providing more accurate standard errors and confidence intervals for individual treatment 
effects. Moreover, this model allows the inclusion of subjects who are missing either the 
baseline or post-baseline measurements, thereby increasing efficiency. Details of the model 
specification, assumptions, and SAS implementation code are given in the sSAP.
Analyses of the change from baseline in other continuous efficacy endpoints at Week 20 will 
be performed using the cLDA model as described above.
The present primary approach assumes data missing at random in compliance with the 
current ICH E9 guidance.  In the event that the ICH E9 guidance on missing data is updated 
and no longer regards the MAR assumption as valid for missing data handling, then the 
Jump-to-Reference (J2R) pattern mixture model will be used as the primary approach and the 
cLDA analyses will become a supportive approach for all three endpoints in the hypotheses.
 
 
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The cLDA method assumes that data are missing at random (MAR).  In this study, it is 
expected that Missing at Random and Missing Completely at Random (MAR/MCAR) 
mechanisms will underlie most of the missingness, and the proportion of data missing not at 
random (MNAR), driven solely by unobserved values of the study endpoints, will be small.  
However, because the MNAR mechanism can never be ruled out, sensitivity analyses will be 
performed to assess the robustness of the conclusions from the cLDA analyses to departures 
from MAR.  These analyses will be performed only if significance is achieved in the 
respective hypothesis test.

Pattern mixture model in conjunction with the tipping point approach in Ratitch et al 
[17]. With this method, missing values will be imputed 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 obtained the 
cLDA assuming MAR. For each imputed value, a positive adjustment Δ1 will be 
added to the metformin+sitagliptin group (to the detriment of metformin+sitagliptin).  
For each value of Δ1, a negative adjustment Δ2 will be added to the metformin group 
(to the improvement of metformin).  The inference will be carried out for a range of 
values of Δ1 and Δ2, a two-dimensional adjustment.  A contour plot will be 
constructed of values of Δ1 and Δ2 that render the significant result into non-
significant, which provides a measure of robustness of the primary result. 

J2R imputation, which falls under the category of pattern mixture models known as 
reference-based imputation (RBI, Carpenter et al 2013) [18], and is described below.
In J2R, missing data in the control group are imputed under the MAR assumption, 
while missing data in the treatment groups are imputed under a MNAR assumption 
using the control group profile for time points after withdrawal.
Standard multiple imputation techniques are overly conservative as they tend to 
overestimate parameter variances. Therefore, a more appropriate variance for the J2R 
based on pattern mixture model approximation (Liu and Pang, 2015) [19] will be used 
for the J2R sensitivity analysis of change from baseline in A1C and change from 
baseline in FPG.  Details describing this methodology with relevant equations, model 
specifications, assumptions, and the SAS implementation code will be provided in the 
sSAP.
A detailed accounting of missing data will be provided, including a tabulation of the reasons 
for missingness (where known), distribution of missing and non-missing data by visit, and 
plots of the profile of mean A1C responses among subjects with different missingness 
patterns. 
 
 
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For the analysis of percentages of individuals at the A1C goal of <7.0% (53 mmol/mol) at 
Week 20 or the analysis of percentages of individuals with baseline A1Cs ≥8.5% at the A1C 
goal of <7.0% (53 mmol/mol) at Week 20, the cLDA model that is used for the analysis of 
A1C assuming MAR will also be used to impute the missing data on A1C.  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.  Observed data will not be imputed.  Subjects will be 
categorized as ‘at goal’ or ‘not at goal’ based on Week 20 A1C value after imputations.
To estimate the between-group rate difference, each of the 10 imputed data sets will be 
summarized to obtain the proportion of subjects at the goals within each group.  The 
estimated proportions of subjects at the goals from the 10 imputed data sets will be combined 
using standard multiple imputations (MI) techniques proposed by Rubin [20] to yield an 
overall estimate of the response rate and associated variance for each group. The estimated 
response rates and adjusted effective sample sizes will then be used to obtain the confidence 
interval for between-group difference in proportion and relative risk via M&N [15] method.  
The p-value will be provided for the relative risk based on the M&N method stratified by the 
AHA status at screening.  
Sensitivity analyses will be performed to assess the robustness of the conclusions from the 
M&N A1C goal < 7.0% analyses to departures from MAR. One sensitivity analysis for the 
proportion of subjects at the A1C goal of <7.0% will also be performed, with imputation of 
“Missing=Not at Goal”. The percentages of subjects at target A1C control at Week 20 will 
be analyzed assuming that all missing Week 20 A1C values were not at target.  This analysis 
will be performed in the AST population.
A second sensitivity analysis for the proportion of subjects at the A1C goal of <7.0% will be 
performed in the mFAS population.  In this approach, 1000 bootstrap samples (with 
replacement and stratified by treatment and AHA status at screening) of individual patients
will be created.  Within each bootstrap sample, 10 sets of complete data will be generated 
with missing A1C data imputed under the J2R assumption.  The bootstrap distribution of the 
between-group difference in proportion of subjects at goal and risk ratio will be constructed 
based on the mean of the estimates across the 10 imputed data sets from each of the 1000 
bootstrap samples. The 95% CI for the between-group difference in proportion at A1C goal 
and risk ratio will be computed using the estimated bootstrap mean and standard deviation.  
The p-value will be provided for the relative risk.  Details describing this methodology will 
be provided in the sSAP.
The proportion of patients rescued in each treatment group will be summarized.  A time-to-
rescue analysis will be performed using the Kaplan-Meier estimator and the log-rank test. 
For this analysis, subjects will be censored at the time of discontinuation from the study 
medication, discontinuation/completion from the study, or initiation of a sustained use of 
AHAs other than study medication or rescue therapy, if one of these occurred prior to the 
initiation of rescue therapy. 
 
 
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Analyses of A1C and FPG will also be performed to address the intention-to-treat (ITT) 
estimand.  The target population and endpoints for ITT will be the same as for the primary 
estimand.  However, the measure of intervention effect for ITT will be the difference in 
means (or ratio of proportions) at Week 20 comparing randomized treatments plus other 
AHAs (as needed) regardless of whether treatment continued to Week 20.  Statistical 
methods for ITT will be the same primary methods used for the primary estimand.
Table 8 summarizes the key efficacy analyses.
Table 8  Analysis Strategy for Key Efficacy Variables
Endpoint
Primary vs. 
Supportive 
Approach†
Statistical Method
Analysis Population
Missing Data Approach
Primary Endpoint/Primary Hypothesis
Change from baseline in 
A1C at Week 20
P
S
S
S
cLDA
cLDA
cLDA
cLDA
mFAS
mFAS
mFAS
ITT
Model-based
PMM (tipping point)
PMM (J2R)
Model-based
Key Secondary Endpoints/Secondary Hypotheses
Proportion of subjects 
with A1C < 7.0% at 
Week 20
P
S
S
S
M&N
M&N
Bootstrap
M&N
mFAS
AST
mFAS
ITT
MI
Missing=Not at Goal
PMM (J2R)
MI
Change from baseline in 
FPG at Week 20
P
S
S
S
cLDA
cLDA
cLDA
cLDA
mFAS
mFAS
mFAS
ITT
Model-based
PMM (tipping point)
PMM (J2R)
Model-based
Other Endpoints
Proportion of subjects 
with baseline A1C ≥
8.5% with A1C < 7.0% 
at Week 20
P
M&N
mFAS
MI
Proportion of subjects 
receiving glycemic 
rescue therapy
P
Kaplan-Meier
All randomized 
subjects
N/A
†P=Primary approach; S=Supportive approach.
  A1C=Glycosylated hemoglobin; AST=All Subjects Treated; cLDA=Constrained longitudinal data analysis; 
mFAS=modified Full analysis set; FPG=Fasting Plasma Glucose; J2R = Jump to Reference; N/A=Not 
applicable; M&N= Miettinen and Nurminen; MI=Multiple Imputation; PMM = Pattern Mixture Model
The strategy to address multiplicity issues with regard to multiple hypotheses is described in 
Section 8.8 Multiplicity.
 
 
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Statistical Methods for Safety Analyses
8.6.2
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
adverse experiences (AEs), laboratory tests, and vital signs.
The following analysis approaches will be used:

To avoid the confounding effect of rescue therapy, the primary approach for all safety 
analyses will exclude those safety-related data points that occurred following the 
sustained use of additional antihyperglycemic agents (AHAs).  This analysis 
approach will consider all on-treatment data up to Week 20 and data up to and 
including the 14-day post-treatment follow-up.  

A secondary approach will include those safety-related data points that occurred 
following the sustained use of additional antihyperglycemic agents (AHAs).  The 
analysis will include all on-treatment data up to Week 20 and data up to and including 
the 14-day post-treatment follow-up.  

A third approach to safety analyses that applies only to AE summary measures, 
specific AEs, and serious AEs will include data after the first dose of double-blind 
study medication regardless of whether the subject has discontinued from study 
medication and will consider all data up to Week 20 and data up to and including the 
14-day post-treatment follow-up.  
The analysis of safety results will follow a tiered approach (Table 9).  The tiers differ with 
respect to the analyses that will be performed.  Tier 2 parameters will be assessed via point 
estimates with 95% confidence intervals provided for between-group comparisons; only 
point estimates by treatment group are provided for Tier 3 safety parameters.  There are no
“Tier 1” safety endpoints. Therefore all safety endpoints will be considered Tier 2 or Tier 3.  
Adverse experiences (specific terms as well as system organ class terms) and predefined 
limits of change in laboratory and vital signs parameters 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; all other adverse experiences 
and predefined limits of change will belong to Tier 3.
The threshold of at least 4 events was chosen because the 95% confidence interval for the 
between-group difference in percent incidence will always include zero when treatment 
groups of equal size each have less than 4 events and thus would add little to the 
interpretation of potentially meaningful differences.  Because many 95% confidence intervals 
may be provided without adjustment for multiplicity, the confidence intervals should be 
regarded as a helpful descriptive measure to be used in review, not a formal method for 
assessing the statistical significance of the between-group differences in adverse experiences 
and predefined limits of change.
 
 
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Continuous measures such as changes from baseline in laboratory and vital signs will be 
considered Tier 3 safety parameters.  Summary statistics for baseline, on-treatment, and 
change from baseline values will be provided by treatment group in table format.  Mean 
change from baseline over time will be plotted with the corresponding standard errors.  
The broad clinical and laboratory AE categories consisting of the percentage of subjects with 
any AE, a drug-related AE, a serious AE, an AE which is both drug-related and serious, and 
who discontinued due to an AE, documented hypoglycemia episodes will also be considered 
Tier 2 endpoints.  The 95% confidence intervals will be provided for between-treatment 
differences in the percentage of subjects with events; these analyses will be performed using 
the Miettinen and Nurminen method [15], an unconditional, asymptotic method.
Table 9  Analysis Strategy for Safety Parameters
Safety Tier
Safety Endpoint†
95% CI for 
Treatment 
Comparison
Descriptive 
Statistics
Tier 1
Not applicable
Tier 2
Any AE†
X
X
Any Serious AE
X
X
Any Drug-Related AE
X
X
Any Serious and Drug-Related AE
X
X
Discontinuation due to AE
X
X
Selected hypoglycemia endpoints (see below)
X
X
Specific AEs†, SOCs, or PDLCs (incidence ≥4 
subjects in one of the treatment groups)
X
X
Tier 3
Specific AEs, SOCs or PDLCs‡ (incidence <4 of 
subjects in all of the treatment groups)
X
Change from Baseline Results (Laboratory 
measurements, Vital Signs)
X
† Adverse Experience references refer to both Clinical and Laboratory AEs.
‡ Includes only those endpoints not already pre-specified as Tier-2 endpoints.
SOC=System Organ Class; PDLC=Pre-Defined Limit of Change; X  = results will be 
provided.
Analysis of Hypoglycemia
The Tier 2 analysis for hypoglycemia will include the numbers and percentages of subjects 
experiencing one or more of the following:

Documented symptomatic hypoglycemia with a concurrent glucose measurement of 70 
mg/dL (3.9 mmol/L).
A listing of all hypoglycemia episodes with a concurrent glucose measurement of 70 mg/dL 
(3.9 mmol/L) will be provided.  For each event, the listing will include glucose level, 
symptoms, precipitating factors, and severity.  Severe hypoglycemia will be defined as 
episodes of hypoglycemia that required assistance, either medical or non-medical, regardless 
of whether such assistance was obtained.  Severe episodes will be included regardless of 
biochemical documentation.
 
 
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Demographic and Baseline Characteristics
8.6.3
The comparability of the treatment groups for each relevant characteristic will be assessed by 
the use of tables and/or graphs.  No statistical hypothesis tests will be performed on these 
characteristics.  The number and percentage of subjects screened, randomized, the primary 
reasons for screening failure, and the primary reason for discontinuation will be displayed.  
Demographic variables, baseline characteristics, primary and secondary diagnoses, and prior 
and concomitant therapies will be summarized by treatment either by descriptive statistics or 
categorical tables.  The following demographic/anthropometric, diabetes-related, and 
baseline efficacy variables will be summarized by treatment either by descriptive statistics or 
categorical tables.  Depending on the variable of interest, statistics such as sample size, mean, 
SD, median, range and proportion will be provided.

Continuous baseline demographic variables: age (years), weight (kg), height (cm), and 
body mass index (BMI; kg/m2).

Categorical baseline demographic variables: age (< median, ≥ median), gender (male, 
female), and race (White, Black, Asian, American Indian or Alaska Native, Native 
Hawaiian or Other Pacific Islander, or Multi-Racial), ethnicity (Hispanic/Latino or not).

Baseline A1C, and distribution of A1C at baseline (A1C levels <8%, ≥8% and <9%, ≥9% 
and <10%, ≥10%)

Baseline FPG

AHA Status at Screening (Not on AHA, On non-metformin AHA, On Metformin)

Time since diagnosis of diabetes mellitus (years)

Geographic region (Americas, Europe, Asia, Other)
The above summaries will be provided for all subjects who received at least one dose of 
study therapy.
Interim Analyses
8.7
No interim analyses are planned for this study.
Multiplicity
8.8
The study-wise type I error rate will be controlled at α = 0.05 (2-sided) using an ordered 
testing procedure.
The study will first test for change from baseline in A1C.  If the success criterion for A1C is 
met, the secondary hypothesis for A1C goal of <7% at Week 20 will be tested.  If the success 
criterion for A1C goal of <7% at Week 20 is met then the secondary hypothesis for FPG will 
be tested.  All three tests will be conducted at α = 0.05 (2-sided).
 
 
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Sample Size and Power Calculations
8.9
Sample Size and Power for Efficacy Analyses
8.9.1
This study will randomize approximately 380 subjects (in a 1:1 ratio) into the 
metformin+sitagliptin group and metformin group.
The study will have 93% power to establish that up-titration of metformin plus the addition 
of sitagliptin is superior to up-titration of metformin alone in lowering A1C, at α=0.05 (2-
sided), if the underlying treatment difference is -0.4 %.  
The power and sample size are based on the following assumptions at Weeks 6, 14, and 20:
1) Cumulative attrition rate (due to dropout and/or censoring caused by initiation of 
a sustained use of additional antihyperglycemic agents (AHAs) at Week 6, Week 
14, and Week 20 are 1%, 3% and 18% in the metformin+sitagliptin group and 
2%, 5% and 27% in the metformin group.
The attrition rates were estimated 
through simulation studies based on data from the sitagliptin+metformin factorial 
study (Study 036) and metformin add-on studies (Studies 053 and 403).
2) Conditional correlation matrix (correlation matrix of the post-randomization 
measurements conditional on the baseline value) is
1.00 0.85 0.77
0.85 1.00 0.92
0.77 0.92 1.00
3) Conditional standard deviation of 1.1%
4) An underlying true between-group difference in A1C change of -0.40% based on 
the expected effect of the combination therapy in the study population with an 
effective sample size of 174 within the metformin only group and 180 in the 
metformin+sitagliptin group.
A sample size of 190 patients per group will provide approximately 90% power for A1C 
goal <7.0% at Week 20 to detect a between-group difference of 14 to 15 percentage points
in the proportion of patients at goal, assuming that the proportion at goal is 14% to 18% in 
the metformin group.  The assumed proportions at goal with metformin and between-group 
difference in proportions were based on simulations assuming different baseline A1C 
distributions.
Table 10 shows the power for A1C goal <7.0% under various assumptions. 
 
 
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Table 10  Power (%) for the Analysis of A1C Goal < 7.0% at Week 20
A1C < 7.0% at Week 20
for Metformin (%)
True Difference (%)
(Met+sita vs. Met)
Power (%)
95% CI
Half Width (%)
14
14
89
8.7
15
14
88
8.8
15
15
92
8.9
17
15
90
9.1
18
15
89
9.2
The calculation for the A1C goal analysis using the M&N method is based on effective 
sample sizes of 170 and 163 in the metformin+sitagliptin group and metformin group, 
respectively.  The effective sample sizes were estimated from simulation studies that took 
into account data attrition and missing data imputation.
Table 11 below shows the power for change from baseline in FPG based on the cLDA model 
at α=0.05 (2-sided).  The study will provide ≥90% power if the true difference in FPG 
reduction is -16 mg/dL or greater, assuming a SD of 45 mg/dL, and an effective sample size 
of 164 in the metformin group and 173 in the metformin+sitagliptin group.
Table 11  Power (%) Under Various FPG Assumptions
Sample Size Per Arm
Randomized 
True Difference (mg/dL)
Conditional Standard 
Deviation (mg/dL)
Power (%)
95% CI 
Half-Width 
(mg/dL)
190
-18
40
99
8.6
-18
45
96
9.6
-16
40
96
8.6
-16
45
90
9.6
Subgroup Analyses and Effect of Baseline Factors
8.10
To determine whether the treatment effect at Week 20 is consistent across various subgroups 
listed below, the estimate of the between-group treatment effect (with a nominal 95% CI) for 
the primary endpoint will be estimated and plotted within each category of each subgroup.

Baseline A1C (A1C levels <8.5%, and ≥8.5%)

Age categories: ≤ or > median age

Gender (female, male)

AHA Status at Screening (Not on AHA, On non-metformin AHA, On Metformin)
In addition, a forest plot will be produced, which provides the estimated point estimates and 
confidence intervals for the treatment effect across the categories of subgroups listed above.
 
 
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The consistency of the treatment effect will be assessed in the context of a repeated measures 
ANCOVA (RMANCOVA) method, which is a generalization of the standard ANCOVA to 
accommodate repeated measurements. Subgroup analyses will not use the cLDA method that 
is used for the primary analysis because the assumption of equal baseline means that is made 
by the cLDA method will not apply within subgroups. The RMANCOVA model will adjust 
for treatment, subgroup, and treatment-by-subgroup interaction. Time is treated as a 
categorical variable and time-specific versions of each term listed above at each week will be 
used to acknowledge the repeated nature of the measurements. An unstructured covariance 
matrix will be used to model the correlation among repeated measurements. Treatment 
effects and nominal 95% CIs by category for the classification variables listed above will be 
reported as well as presented graphically. Formal statistical testing of treatment-by-subgroup 
interactions will not be performed. 
The treatment effect across study centers will be summarized for A1C at Week 20 with 
descriptive statistics.
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.
Compliance (Medication Adherence)
8.11
The computation of compliance in the All Subjects Treated (AST) set will be based on the 
study medication case report form. Both the assigned treatment and any matching placebo 
pills will be included in the compliance calculation.
For each subject, percent compliance will be calculated using the following formula:
Compliance =
Number of Compliant Days
× 100%.
Number of Days in the Double-blind Treatment Period
A day within the Double-blind Treatment Period will be considered a compliant day if the 
subject takes 1 tablet of sitagliptin 100 mg or matching placebo, as well as the appropriate 
dose of Met-IR background medication.  The dose of Met-IR is intended to be 1500 mg (3 x 
500 mg tablets) per day from Visit 4/Day1 to Day 7 and 2000 mg (4 x 500 mg tablets) per 
day after Day 7.  If the subject is unable to tolerate the study-prescribed dose of Met-IR and, 
at the discretion of the study investigator, continues participation at a lower dose of Met-IR, 
they will be considered compliant if they take the dose of Met-IR prescribed by the study 
investigator.
If
the 
study 
medication 
eCRF 
indicates 
general 
compliance 
problems 
with 
sitagliptin/matching placebo or Met-IR, the subject will be considered non-compliant for that 
day regardless of the number of tablets reported.
The "Number of Days in Double-blind Treatment Period" for the compliance calculation is 
defined for each subject as the total number of days from the first dose of double-blind study 
medication (sitagliptin/sitagliptin-matching placebo) to the last day of double-blind study 
medication.  
Summary statistics will be provided on percent compliance by treatment group.
 
 
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Extent of Exposure
8.12
The extent of exposure to double-blinded study treatment will be evaluated by summary 
statistics (N, mean, median, standard deviation and range) and frequencies for the "Number 
of Days on Therapy" by treatment group, based on daily dosing records on the study 
medication eCRF.
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 12.
Clinical supplies will be packaged to support enrollment and replacement subjects as 
required.  When a replacement subject is required, the Sponsor or designee needs to be 
contacted prior to dosing the replacement supplies.
Table 12  Product Descriptions
Product Name & 
Potency
Dosage Form
Source/Additional 
Information
Sitagliptin Phosphate 
100 mg
Tablet
Provided by the sponsor
Sitagliptin Phosphate 
100 mg Placebo
Tablet
Provided by the sponsor
All placebos were created by the Sponsor to match the active product.
Packaging and Labeling Information
9.2
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements.
Subjects will receive blinded Sitagliptin Phosphate 100 mg or Placebo Finished Good 
Bottles. Each bottle at Visit 3 will contain 21 tablets.  Each bottle in the treatment phase from 
Visit 4 through Visit 6 will contain 63 tablets.
Clinical Supplies Disclosure
9.3
The emergency unblinding call center will use the treatment/randomization schedule for the 
trial to unblind subjects and to unmask treatment identity.  In the event that the emergency 
unblinding call center is not available for a given site in this trial, the central electronic 
treatment allocation/randomization system (IVRS/IWRS) should be used in order to unblind 
subjects and to unmask treatment/vaccine identity. The Sponsor will not provide random 
code/disclosure envelopes or lists with the clinical supplies.
 
 
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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 
and reason) 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.
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.
Standard Policies
9.6
Trial 
site 
personnel 
will 
have 
access 
to 
a 
central 
electronic 
treatment 
allocation/randomization system (IVRS/IWRS system) to allocate subjects, to assign 
treatment to subjects and to manage the distribution of clinical supplies. Each person 
accessing the IVRS system must be assigned an individual unique PIN.  They must use only 
their assigned PIN to access the system, and they must not share their assigned PIN with 
anyone.
 
 
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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 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.clinicaltrialregister.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 trials 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.
 
 
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Authorship credit should be based on 1) substantial contributions to conception and design, 
or acquisition of data, or analysis and interpretation of data; 2) drafting the article or revising 
it critically for important intellectual content; and 3) final approval of the version to be 
published. Authors must meet conditions 1, 2 and 3.  Significant contributions to trial 
execution may also be taken into account to determine authorship, provided that 
contributions have also been made to all three of the preceding authorship criteria.  Although 
publication planning may begin before conducting the trial, final decisions on authorship and 
the order of authors’ names will be made based on participation and actual contributions to 
the trial and writing, as discussed above. The first author is responsible for defending the 
integrity of the data, method(s) of data analysis and the scientific content of the manuscript.
The Sponsor must have the opportunity to review all proposed abstracts, manuscripts or 
presentations regarding this trial 45 days prior to submission for publication/presentation. 
Any information identified by the Sponsor as confidential must be deleted prior to 
submission; this confidentiality does not include efficacy and safety results. Sponsor review 
can be expedited to meet publication timelines.
11.0 LIST OF REFERENCES
1. American Diabetes Association. Standards of medical care in diabetes–2014. Diabetes 
Care. 2014;37(Suppl 1):S14–80.
2. Danaei G, Finucane MM, Lu Y, et. al. National, regional, and global trends in fasting 
plasma glucose and diabetes prevalence since 1980: systematic analysis of health 
examination surveys and epidemiological studies with 370 country-years and 2.7 million 
participants. Lancet 2011; 378(9785):31-40.
3. American Diabetes Association.  Economic costs of diabetes in the U.S. in 2012. 
Diabetes Care 2013: 1-14.
4. Centers for Disease Control and Prevention. National diabetes fact sheet: national 
estimates and general information on diabetes and prediabetes in the United States, 
2011. Atlanta, GA: U.S. Department of Health and Human Services, Centers for Disease 
Control and Prevention, 2011.
5. Cade, WT. Diabetes-Related Microvascular and Macrovascular Diseases in the Physical 
Therapy Setting. Phys Ther. 2008 Nov; 88(11): 1322–1335.
6. American Diabetes Association. Standards of medical care in diabetes–2015.  Diabetes 
Care. 2015;38 (Suppl 1): S33-40.
7. Folazof C, Schwartz S, Foley J.  Effect of vildagliptin as add-on therapy to a low-dose 
metformin.  World J Diabetes 2010; 1(1): 19-26.
8. Hermans M, Delibasi T, Farmer I et al.   Effects of saxagliptin added to sub-maximal 
doses of metformin compared with uptitration of metformin in type 2 diabetes: the 
PROMPT study.  Current Medical Research and Opinion 2012; 28(10): 1635-1645.   
9. Effects of rosiglitazone added to sub-maximal doses of metformin compared with dose 
escalation of metformin in type 2 diabetes: the EMPIRE Study.  Current Medical 
Research and Opinion 2005; 21(12): 2029-2035   
 
 
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10. Goldstein B, Feinglos M, Lunceford J et al.  Effects of initial combination therapy with 
sitagliptin, a dipeptidyl peptidase-4 inhibitor, and metformin on glycemic control in 
patients with type 2 diabetes.  Diabetes Care 2007; 30 (8): 1979-1987.  
11. Januvia US Product Circular.  2015.
12. The Rules for Governing Medicinal Products in the European Union Volume 10-
Guidance Documents Applying to Clinical Trials Guidance on Investigational Medicinal 
Protducts (IMPS) and Non Investigational Medicinal Products (NIMPS)(Rev. 1, March 
2011)
13. Nathan, David M., Long-Term Complications of Diabetes Mellitus. The New England 
Journal of Medicine. (June 10, 1993).
14. National Research Council. The prevention and treatment of missing data in clinical 
trials. 
Washington, 
DC: 
National 
Academies 
Press, 
2010 
(http://www.nap.edu/catalog.php?record_ id-12955).
15. Miettinen OS, Nurminen M. Comparative analysis of two rates. Statistics in Medicine 
1985;4:213-226
16. Liang, K. Y. and Zeger, S. (2000). Longitudinal data analysis of continuous and discrete
responses for pre-post designs. Sankhyā: The Indian Journal of Statistics, Series B 62, 
134–148.
17. Ratitch B, O’Kelly M, Tosiello R.  Missing data in clinical trials: from clinical 
assumptions to statistical analysis using pattern mixture models.  Pharmaceutical 
Statistics.  2013, 12:337 – 347.
18. Carpenter, James R., Roger, James H., and Kenward, Michael G (2013). Analysis of 
Longitudinal Trials with Protocol Deviation: A Framework for Relevant, Accessible 
Assumptions, and Inference via Multiple Imputation.  Journal of Biopharmaceutical 
Statistics, 23: 1352 – 1371.
19. Liu, G. Frank and Pang, Lei (2015). On Analysis of Longitudinal Clinical Trials with 
Missing Data Using Reference-Based Imputation. Journal of Biopharmaceutical 
Statistics. 2015: DOI: 10.1080/10543406.2015.1094810.
20. Rubin DB. Multiple Imputation for Nonresponse in Surveys. 1987; Wiley, New York.
 
 
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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 collected in this trial as outlined in Section 7.1.3.2 – Future Biomedical 
Research Sample Collection will be used to study various causes for how subjects may 
respond to a drug/vaccine.  Future biomedical research specimen(s) will be stored to 
provide a resource for future trials conducted by the Sponsor focused on the study of 
biomarkers responsible for how a drug/vaccine enters and is removed by the body, how a 
drug/vaccine works, other pathways a drug/vaccine may interact with, or other aspects 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 Visit 1.  If delayed, 
present consent at next possible Subject Visit. Informed consent must be obtained 
prior to collection of all Future Biomedical Research specimens.  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. Each consent will be assessed for appropriate 
specimen permissions.  
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 Collections
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 for transfer to the storage facility.  This first 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 first 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 Merck Biorepository 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.
 
 
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6. Withdrawal From Future Biomedical Research 
Subjects may withdraw their consent for Future Biomedical Research and have their 
specimens and all derivatives destroyed.   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 
 and a form will be provided to 
obtain appropriate information to complete specimen withdrawal. Subsequently, the 
subject's specimens will be removed from the biorepository and be destroyed. 
Documentation will be sent to the investigator confirming the destruction. It is the 
responsibility of the investigator to inform the subject of completion of destruction.  Any 
analyses in progress at the time of request for 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 specimen destruction can not 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 (e.g., ISO17799) to protect against unauthorized access.
 
 
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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 any exploratory results are definitively associated with clinical significance for subjects
while the clinical trial is still ongoing, investigators will be contacted with information. 
After the clinical trial has completed, if any exploratory results are definitively associated 
with clinical significance, the Sponsor will endeavor to make such results available 
through appropriate mechanisms (e.g., scientific publications and/or presentations). 
Subjects will not be identified by 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 future biomedical research, 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 
.
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
 
 
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Understanding the Intent, Scope and Public Health Benefits of Exploratory Biomarker Research: A Guide for 
12.3
IRBs/IECs and Investigational Site Staff
 
 
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Management of Subjects with Elevated Liver Enzymes (ALT or AST ≥3X ULN)
12.4
Every increase in ALT, and/or AST, above the limits described in the protocol is defined as 
clinically significant (i.e., ALT or AST ≥3-times the upper limit of normal [ULN]).  Under 
these circumstances, the Central Laboratories will alert the Investigators/ Coordinators.
In addition, when ALT and/or AST levels are elevated beyond the clinical significant margin 
above, the Investigators/Coordinators must recall the patient, attempt to identify the cause of 
the elevation, and repeat the blood test(s).  Detailed instructions are provided below.
For patients who have ALT or AST increases (either ALT or AST ≥3-times the ULN) 
with a total bilirubin lab value ≥2-times ULN and, at the same time, the alkaline 
phosphatase lab value is <2-times ULN, please follow the guidance document entitled 
"Event of Clinical Interest (ECI) Guidance for Potential DILI (Drug-Induced Liver Injury) in 
Clinical Trials" located in the Investigator Trial File Binder and refer to the ECI guidance in 
the protocol (Section 7.2.3.2).
For patients with ALT or AST increases (either ALT or AST ≥3-times the ULN) but 
who do not also meet the above criteria for both total bilirubin and alkaline phosphatase, the 
process below should be followed.  These events do not qualify as ECIs per protocol.  
A. Patients 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; 
nitrofurantoin; 
oxyphenisatin; 
perhexiline 
maleate; 
phenytoin; 
propylthiouracil; rifampin; sulfonamides; tetracyclines) or other new medications.
4. Search for alternative medical causes such as cholelithiasis, recent alcohol 
consumption, history of intercurrent illness (e.g., viral syndrome), hepatitis, or 
potential exposure to viral hepatitis (transfusion).
5. Repeat determination of ALT, AST, total bilirubin, and alkaline phosphatase (within 
3 days of initial report of abnormal level).
6. Perform serologic tests including: (a) Hepatitis A (IgM); (b) Hepatitis B (surface 
antigen and core IgM); (c) Hepatitis C (antibody).
 
 
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B. Actions
ALT and/or AST elevations ≥3-times ULN at any visits will result in a mandatory re-test 
within 3 days of initial report.  Based upon initial abnormal ALT/AST level:
1. If ALT or AST levels are ≥3-times ULN, but ≤5-times ULN, consideration can be 
given to keeping patient on randomized therapy until repeat determination (performed 
within 3 days of initial abnormal level).
2. If ALT or AST levels are >5-times ULN, patients should have their randomized 
therapy interrupted immediately.
Once interrupted, reinstatement of therapy must occur only after consultation with a 
Clinical Monitor (SPONSOR or its delegate).
Based upon repeat determination (performed within 3 days of initially reported 
abnormal ALT or AST level):
1. If ALT and/or AST levels are confirmed as being elevated but <3-times ULN, 
consultation with a Clinical Monitor (SPONSOR or its delegate) is required prior to 
continuing the patient in the study.
2. If ALT and/or AST levels are confirmed as being elevated ≥3-times ULN, patients 
will be discontinued from the study.
Note:  If the repeat determination is still ≥3-times elevated, but has substantially 
decreased (>30% decline) from the initial abnormal value, a second repeat should be 
performed within 3 days of the initial repeat.  If ALT and/or AST levels return below the 
3-times margin consideration can be given to continue the patient in the study after a 
discussion with, and approval by, the Clinical Monitor (SPONSOR or its delegate).
All persistent elevations in ALT or AST ≥3-times ULN at the completion/ discontinuation of 
the study will warrant follow-up including a repeat blood test within 1 week and until 
complete resolution of the abnormality.
 
 
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Product:  MK-0431 
97
Protocol/Amendment No.: 848-00 
MK-0431-848-00 Final Protocol
8-Mar-2016
Confidential
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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