A Phase III, Multicenter, Double-Blind, Randomized, Placebo-Controlled Clinical Trial to Evaluate the Safety and Efficacy of Sitagliptin in Pediatric Patients With Type 2 Diabetes Mellitus With Inadequate Glycemic Control
Phase: PHASE3
Conditions: Diabetes Mellitus, Type 2 Diabetes
Sponsor: Merck Sharp & Dohme LLC

Official Protocol Title: 
NCT number: 
NCT01485614 
Document Date: 
12-Jun-2018
A Phase III, Multicenter, Double-Blind, Randomized, Placebo-
Controlled Clinical Trial to Evaluate the Safety and Efficacy of 
Sitagliptin in Pediatric Patients with Type 2 Diabetes Mellitus with 
Inadequate Glycemic Control

Product:  MK-0431
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THIS PROTOCOL AMENDMENT 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, NJ, 08889-0100, U.S.A.
Protocol-specific Sponsor Contact information can be found in the Administrative Binder.
TITLE:
A Phase III, Multicenter, Double-Blind, Randomized, Placebo-Controlled Clinical Trial to 
Evaluate the Safety and Efficacy of Sitagliptin in Pediatric Patients with Type 2 Diabetes 
Mellitus with Inadequate Glycemic Control
INVESTIGATOR:
PRIMARY:
CLINICAL PHASE: III
US IND NUMBER:
65,495
SITE:
INSTITUTIONAL REVIEW BOARD/ETHICS REVIEW COMMITTEE:
 
 
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TABLE OF CONTENTS
SUMMARY OF CHANGES...............................................................................................7
PRIMARY REASONS FOR THIS AMENDMENT .......................................................7
ADDITIONAL CHANGES FOR THIS AMENDMENT................................................8
1. SUMMARY.................................................................................................................14
TITLE ....................................................................................................................14
1.1
INDICATION........................................................................................................14
1.2
SUMMARY OF RATIONALE.............................................................................14
1.3
SUMMARY OF STUDY DESIGN ......................................................................14
1.4
SAMPLE ...............................................................................................................15
1.5
DOSAGE/DOSAGE FORM, ROUTE, AND DOSE REGIMEN.........................15
1.6
STUDY FLOW CHART .......................................................................................18
1.7
2. CORE PROTOCOL.....................................................................................................22
OBJECTIVES AND HYPOTHESES ...................................................................22
2.1
2.1.1
Primary ...........................................................................................................22
2.1.2
Secondary .......................................................................................................22
PATIENT INCLUSION CRITERIA.....................................................................23
2.2
PATIENT EXCLUSION CRITERIA....................................................................26
2.3
STUDY DESIGN AND DURATION...................................................................31
2.4
2.4.1
Summary of Study Design..............................................................................31
2.4.2
Treatment Plan................................................................................................31
2.4.2.1
Study Visits General Information ...........................................................32
2.4.2.2
Visit 1/Screening Visit............................................................................33
2.4.2.3
Visit 2 Single-Blind Placebo Run-in.......................................................34
2.4.2.4
Visit 3/Randomization Visit....................................................................34
2.4.2.5
Visit 3/Day 1 through Visit 11/Week 54: Double-Blind Treatment 
Period ......................................................................................................35
2.4.2.6
Glycemic Rescue.....................................................................................36
2.4.2.6.1
Rescue Step 1 (Blinded)..................................................................38
2.4.2.6.2
Rescue Step 2 (Open-Label)............................................................39
2.4.2.6.3
Treat-to-Goal Phase B.....................................................................40
2.4.2.7
Discontinuation .......................................................................................41
2.4.2.8
Post-Study Telephone Follow-up............................................................43
2.4.3
Beginning and End of Study Definition .........................................................43
LIST OF EFFICACY / PHARMACOKINETIC / IMMUNOGENICITY, 
2.5
ETC., MEASUREMENTS ....................................................................................43
LIST OF SAFETY MEASUREMENTS...............................................................43
2.6
STATISTICAL ANALYSIS PLAN SUMMARY ................................................44
2.7
2.7.1
Efficacy Analyses...........................................................................................44
2.7.2
Safety Analyses ..............................................................................................44
2.7.3
Power and Sample Size ..................................................................................44
3. PROTOCOL DETAILS...............................................................................................46
RATIONALE ........................................................................................................46
3.1
 
 
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3.1.1
Background and Rationale for this Study.......................................................46
3.1.2
Rationale for Efficacy Endpoints ...................................................................47
3.1.3
Rationale for Selection of Patient Population ................................................47
3.1.4
Rationale for Dose Regimen ..........................................................................47
3.1.5
Rationale for Placebo Use ..............................................................................48
3.1.6
Future Biomedical Research...........................................................................49
3.1.7
Supplemental Dental Data Sub-Study............................................................49
STUDY PROCEDURES.......................................................................................50
3.2
3.2.1
Concomitant Medication(s)/Treatment(s) ......................................................50
3.2.2
Diet/Activity/Other.........................................................................................51
3.2.3
Procedures ......................................................................................................52
3.2.3.1
Monitoring of Glycemic Control ............................................................52
3.2.3.2
Monitoring for Ketonuria/Ketonemia .....................................................52
3.2.3.3
Assessment and Management of Hypoglycemia ....................................52
3.2.3.4
Pregnancy Testing and Contraception ....................................................54
3.2.3.5
Anthropometric Measurements...............................................................55
3.2.3.6
Laboratory Monitoring............................................................................55
3.2.3.7
ECG Procedures......................................................................................56
3.2.3.8
Meal Tolerance Test (MTT) ...................................................................56
3.2.3.9
Pediatric Quality of Life Inventory.........................................................56
3.2.3.10 Tanner Staging Procedures .....................................................................57
3.2.3.11 Visual Oral Examination Procedures......................................................57
3.2.3.12 Bone Age Assessment Procedures..........................................................57
3.2.3.13 Informed Consent....................................................................................58
3.2.3.13.1 General Informed Consent ..............................................................58
3.2.3.13.2 Consent and Collection of Specimens for Future Biomedical 
Research ..........................................................................................59
3.2.3.13.3 Collection of Specimens for Future Biomedical Research from 
Minors .............................................................................................59
3.2.3.13.4 Consent for the Supplemental Dental Data Sub-Study ...................59
3.2.3.14 Future Biomedical Research Collection of Specimens...........................59
3.2.3.15 Assignment of Screening Number ..........................................................59
3.2.3.16 Patient Identification Cards.....................................................................59
3.2.3.17 Stratification............................................................................................59
3.2.3.18 Randomization/Allocation ......................................................................59
3.2.3.19 Post-Study Follow-Up.............................................................................60
3.2.3.20 Blinding/Unblinding ...............................................................................61
3.2.3.21 Interruption/Discontinuation/Withdrawal from Study Medication.........62
3.2.3.21.1 Withdrawal from Future Biomedical Research...............................62
3.2.3.22 Discontinuation Visit Procedures............................................................63
3.2.3.23 Collect Substance Use Information.........................................................63
3.2.3.24 Supplemental Dental Data Sub-Study.....................................................63
EFFICACY MEASUREMENTS ..........................................................................63
3.3
3.3.1
Clinical and Laboratory Measurements for Efficacy .....................................63
3.3.2
Medication Compliance..................................................................................64
SAFETY MEASUREMENTS ..............................................................................64
3.4
 
 
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3.4.1
Clinical and Laboratory Measurements for Safety.........................................64
3.4.2
Data Monitoring .............................................................................................64
3.4.2.1
Executive Oversight Committee .............................................................64
3.4.2.2
Data Monitoring Committee ...................................................................64
3.4.3
Recording Adverse Events .............................................................................65
3.4.4
Definition of an Overdose for This Protocol..................................................66
3.4.4.1
Reporting of Overdose to SPONSOR.....................................................66
3.4.5
Reporting of Pregnancy to Sponsor................................................................67
3.4.6
Immediate Reporting of Adverse Events to the SPONSOR ..........................67
3.4.6.1
Serious Adverse Events ..........................................................................67
3.4.6.2
Selected Non-serious Adverse Events ....................................................68
3.4.7
Guidance on Adverse Events Related to Glycemia........................................69
3.4.7.1
Hyperglycemia........................................................................................69
3.4.7.2
Hypoglycemia .........................................................................................69
3.4.7.2.1
Documentation ................................................................................69
3.4.7.2.2
Guidance..........................................................................................69
3.4.8
Evaluating Adverse Events.............................................................................69
3.4.9
SPONSOR Responsibility for Reporting Adverse Events .............................72
STATISTICAL ANALYSIS PLAN (SAP)...........................................................72
3.5
3.5.1
Responsibility for Analyses/In-House Blinding.............................................72
3.5.2
Hypotheses/Estimation...................................................................................72
3.5.3
Analysis Endpoints.........................................................................................72
3.5.3.1
Efficacy Endpoints..................................................................................73
3.5.3.2
Safety Endpoints .....................................................................................74
3.5.3.3
Derivation of Efficacy Endpoints ...........................................................74
3.5.3.4
Derivation of Safety Endpoints...............................................................75
3.5.4
Analysis Populations ......................................................................................75
3.5.4.1
Efficacy Analysis Populations ................................................................75
3.5.4.2
Safety Analysis Populations....................................................................76
3.5.5
Statistical Methods .........................................................................................76
3.5.5.1
Statistical Methods for Efficacy Analyses ..............................................77
3.5.5.2
Statistical Methods for Safety Analyses .................................................84
3.5.5.3
Summaries of Baseline Characteristics, Demographics, and Other 
Analyses..................................................................................................88
3.5.6
Multiplicity.....................................................................................................88
3.5.7
Sample Size and Power Calculations .............................................................89
3.5.8
Subgroup Analyses.........................................................................................90
3.5.9
Interim Analyses.............................................................................................90
3.5.10 Medication Adherence....................................................................................91
3.5.11 Extent of Exposure .........................................................................................92
LABELING, PACKAGING, STORAGE, DISPENSING, AND RETURN OF 
3.6
CLINICAL SUPPLIES..........................................................................................92
3.6.1
Product Descriptions ......................................................................................92
3.6.2
Packaging Information ...................................................................................93
3.6.3
Clinical Supplies Disclosure...........................................................................93
3.6.4
Storage and Handling Requirements..............................................................93
 
 
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3.6.5
Returns and Reconciliation.............................................................................93
3.6.6
Comparator Statement....................................................................................93
3.6.7
Distributing to Sites and Dispensing to Patients ............................................94
DATA MANAGEMENT ......................................................................................94
3.7
BIOLOGICAL SPECIMENS................................................................................94
3.8
4. ADMINISTRATIVE AND REGULATORY DETAILS ............................................95
CONFIDENTIALITY ...........................................................................................95
4.1
4.1.1
Confidentiality of Data...................................................................................95
4.1.2
Confidentiality of Patient Records .................................................................95
4.1.3
Confidentiality of Investigator Information ...................................................96
COMPLIANCE WITH LAW, AUDIT, AND DEBARMENT.............................96
4.2
COMPLIANCE WITH FINANCIAL DISCLOSURE REQUIREMENTS..........98
4.3
QUALITY CONTROL AND QUALITY ASSURANCE ....................................98
4.4
COMPLIANCE WITH INFORMATION PROGRAM ON CLINICAL 
4.5
TRIALS FOR SERIOUS OR LIFE THREATENING CONDITIONS ................98
PUBLICATIONS ..................................................................................................98
4.6
5. LIST OF REFERENCES...........................................................................................100
6. APPENDICES ...........................................................................................................106
BLOOD PRESSURE AND ANTHROPOMETRIC MEASUREMENTS .........106
6.1
BLOOD PRESSURE TABLE FOR GENDER/AGE/HEIGHT FOR BOYS 
6.2
AGE 10 TO17......................................................................................................109
BLOOD PRESSURE TABLE BY GENDER/AGE/HEIGHT FOR GIRLS 
6.3
AGE 10 TO 17.....................................................................................................110
LABORATORY EVALUATIONS.....................................................................111
6.4
STANDARD OPERATING PROCEDURES FOR LIVER ENZYME 
6.5
ELEVATIONS ....................................................................................................114
PREDEFINED LIMITS OF CHANGE (PDLC).................................................116
6.6
MEAL TOLERANCE TEST (MTT) BLOOD SAMPLES, COLLECTION 
6.7
TIMES AND PROCEDURE...............................................................................117
TANNER STAGING...........................................................................................119
6.8
BMI-FOR-AGE CHARTS ..................................................................................121
6.9
VISUAL ORAL EXAMINATION PROCEDURES ..........................................123
6.10
MAPPING OF RELATIVE DAY RANGES TO WEEKS.................................124
6.11
PATIENT RANDOMIZED TWICE...................................................................125
6.12
COLLECTION AND MANAGEMENT OF SPECIMENS FOR FUTURE 
6.13
BIOMEDICAL RESEARCH ..............................................................................126
6.13.1 Scope of Future Biomedical Research .........................................................126
6.13.2 Definitions ....................................................................................................126
6.13.3 Summary of Procedures for Future Biomedical Research ...........................126
6.13.4 Confidential Patient Information for Future Biomedical Research..............128
6.13.5 Biorepository Specimen Usage ....................................................................129
6.13.6 Withdrawal From Future Biomedical Research ...........................................129
6.13.7 Retention of Specimens................................................................................129
6.13.8 Data Security ................................................................................................130
 
 
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6.13.9 Reporting of Future Biomedical Research Data to Patients.........................130
6.13.9.1 Gender, Ethnicity, and Minorities.........................................................131
6.13.10
Risks Versus Benefits of Future Biomedical Research ........................131
6.13.11
Self-Reported Ethnicity.........................................................................131
SUPPLEMENTAL DENTAL DATA SUB-STUDY..........................................132
6.14
6.14.1 Sub-Study Objective.....................................................................................132
6.14.2 Sub-Study Design and Procedures ...............................................................132
6.14.3 Sub-Study Sample Size ................................................................................133
6.14.4 Sub-Study Inclusion Criteria ........................................................................133
6.14.5 Sub-Study Patient Definition........................................................................133
6.14.6 Sub-Study Flow Charts.................................................................................134
LIST OF PRIOR AMENDMENTS.....................................................................136
6.15
7. ATTACHMENTS......................................................................................................137
8. SIGNATURES...........................................................................................................149
SPONSOR’S REPRESENTATIVE ....................................................................149
8.1
INVESTIGATOR................................................................................................149
8.2
 
 
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SUMMARY OF CHANGES
Note: Protocol amendment P083-15 was not implemented. The changes listed in the Summary of Changes Section of amendment 
P083-16 are the same as those included in amendment P083-15.
PRIMARY REASONS FOR THIS AMENDMENT
Section 
Number
Section Title
Description of Change
Rationale
1.5
Sample
The sample size was updated. 
Sample size is being increased to allow an 
additional contribution of patients to support 
the safety and efficacy summary.
2.4.3
Beginning and End of Study 
Definition
Section was added.
To reflect protocol template updates and to 
indicate when the study will be completed and 
when post-study reporting activities have been 
initiated. 
3.5.1
Responsibility for Analyses/ 
In-House Blinding
Updated to include 2 database locks.
Database will be locked in stages to 
accommodate submission to regulatory 
agencies.
3.5.5.1
Statistical Methods for 
Efficacy Analyses
Provided clarification on analysis using the 
treatment effect estimand.
Added analyses using the treatment policy 
estimand, including the ‘retrieved dropout’ 
(RD) and ‘return-to-baseline’ approaches for 
handling missing data.
Added 2 sensitivity analyses
To define estimands as recommended by 
ICH E9 (R1).
To comply with regulatory request. 
To comply with regulatory request.
 
 
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ADDITIONAL CHANGES FOR THIS AMENDMENT
Section 
Number
Section Title
Description of Change
Rationale
1.5
Sample
Clarified the definition for stable dose of 
background insulin.
To provide additional details for different 
types of insulin (basal and bolus) 
administration. This change was part of a 
protocol clarification letter (PCL).
1.6
Dosage/Dosage Form, Route, 
and Dose Regimen
Clarified the definition for stable dose of 
background insulin.
Down-titration of metformin was updated in 
the content of the blister pack and dose 
regimen during Phase B table.
To provide additional details for different 
types of insulin (basal and bolus) 
administration. This change was part of a 
PCL.
To provide additional details on down-
titration of metformin. 
1.7 
Study Flow Chart
Dispensation of the patient identification 
card was moved from Visit 1 to Visit 2.
Clarified that dental sub-study procedures do 
not apply to Brazil and Serbia.
Consistency with Section 3.2.3.16 - Patient 
Identification Cards. This change was part of 
a PCL.
Brazil and Serbia are not participating in the 
dental sub-study. The text in the protocol will 
allow us to proceed without creating country 
specific amendments for Brazil and Serbia. 
2.2
Patient Inclusion Criteria
Clarified the definition for stable dose of 
background insulin.
Clarified that the screening laboratory 
assessments must be repeated if the duration 
between the Screening Visit and Visit 3 is 
>28 days.
To provide additional details for different 
types of insulin (basal and bolus) 
administration. This change was part of a 
PCL.
To ensure patient laboratory results for 
eligibility assessment are recent. 
 
 
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Section 
Number
Section Title
Description of Change
Rationale
2.3
Patient Exclusion Criteria
Clarified that the screening laboratory 
assessments must be repeated if the duration 
between the Screening Visit and Visit 3 is 
>28 days.
Clarified that the results of the antibody 
screen for anti-GAD or ICA-512 must be 
available and evaluated before the patient 
can be randomized at Visit 3.
To ensure patient laboratory results for 
eligibility assessment are recent. 
To align the protocol requirements with 
laboratory turn-around times.
2.4.1
Summary of Study Design
The number of patients per group was 
removed from the Study Design figure. 
Simplify figure. 
2.4.2.1
Study Visits General 
Information
Clarified that patients should fast ≥10 hours 
prior to Rescue and Discontinuation Visits. 
Window between Visit 2 and Visit 3 was
added
To clarify instructions outlined in Section 1.7 
Study Flow Chart. This change was part of a 
PCL.
To clarify the duration of the placebo run-in 
period and to harmonize with the current 
guidance to investigators. 
2.4.2.3
Visit 2 Single-Blind Placebo 
Run-in
Emphasized completion of procedures before 
dosing.
Clarified that the results of the antibody 
screen for anti-GAD or ICA-512 must be 
available and evaluated before the patient 
can be randomized at Visit 3.
To ensure that results from procedures are 
not affected by administration of study 
medication. This change was part of a PCL.
To align the protocol requirements with 
laboratory turn-around times.
2.4.2.4
Visit 3/Randomization Visit
Emphasized completion of procedures before 
dosing.
To ensure that results from procedures are not 
affected by administration of study 
medication. This change was part of a PCL. 
 
 
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Section 
Number
Section Title
Description of Change
Rationale
2.4.2.5
Visit 3/Day 1 through Visit 
11/Week 54
Emphasized completion of procedures 
before dosing.
At visit 8, patients participating in the Meal 
Tolerance Test (MTT) will have the 
witnessed dose administered 30 minutes 
prior to ingesting the standard meal.
To ensure that results from procedures are 
not affected by administration of study 
medication. This change was part of a PCL. 
For consistency with Appendix 6.7.
2.4.2.6.1
Rescue Step 1 (Blinded)
Glycemic Rescue Criteria Table was 
updated.
Down-titration of metformin was updated
For consistency with the Study Design 
figure. 
To provide additional details on down-
titration of metformin.
2.7
Statistical Analysis Plan
Clarified that details of the statistical analysis 
plan for the supplemental dental data sub-
study will be provided in a separate document
For consistency with the SAP description in 
Section 3.5.
2.7.3
Power and Sample Size
Power and sample size were updated.
To reflect revised sample size. 
3.1.7
Supplemental Dental Data 
Sub-Study
Reviewer information was updated.
Clarified that dental sub-study procedures do 
not apply to Brazil and Serbia.
Dental data will be assessed by an 
independent pediatric dentist reviewer.
Brazil and Serbia are not participating in the 
dental sub-study. The text in the protocol will 
allow us to proceed without creating country 
specific amendments for Brazil and Serbia.
3.2.3.6
Laboratory Monitoring
Clarified fasting labs should be collected 
during Visits 1, 3, 8, 11, Rescue, and 
Discontinuation.
Clarified that CD26 values will remain 
masked to both patient and investigator
throughout the study.
To clarify instructions outlined in Section 1.7 
Study Flow Chart. This change was part of a 
PCL.
Clarification 
 
 
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Section 
Number
Section Title
Description of Change
Rationale
3.2.3.12
Bone Age Assessment 
Procedures
Reference of Independent review charter was 
added.
For additional detailed description of bone age 
assessments. 
3.2.3.19
Post-Study Follow-Up
Clarified that dental photos will be taken only
for patients who consent to the dental 
substudy.
Clarification.
3.2.3.20
Blinding/Unblinding
Text on unblinding of patients was updated.
To reflect protocol template updates. 
3.5
Statistical Analysis Plan
Data analysis plan for the dental substudy was 
removed.
Analyses of data from the dental substudy will 
be described in a separate document.
3.5.3.1
Efficacy Endpoints
Added hemoglobin A1C at Week 14.
Endpoints involving proinsulin will not be 
analyzed as AUC. 
Regulatory agency requirement. 
Proinsulin is collected at a single time point 
and therefore AUC cannot be derived. 
3.5.3.3
Derivation of Efficacy 
Endpoints
Clarified definition of composite index of 
insulin sensitivity.
Clarification.
3.5.3.4
Derivation of Safety 
Endpoints
Section was added.
To clarify how endpoints will be derived 
during analyses. 
3.5.4.1
Efficacy Analysis 
Populations
Completers population was removed.
Handling of patients randomized twice and 
patients with incorrect assignment was 
added.
The population is not related to the study’s
estimands. 
To document handling of data.
3.5.5.1
Statistical Methods for 
Efficacy Analyses
Included Treatment Effect estimand and 
Treatment Policy estimand and their 
corresponding analyses.
Removal of analysis of covariance 
(ANCOVA)/last observation carried forward 
(LOCF).
Summary statistics will be provided using 
observed data for change from baseline in 2-
hour PMG, AUC endpoints, and endpoints 
derived from 9-point MTT at Week 20.
To comply with regulatory request. 
ANCOVA/LOCF is not consistent with the 
study’s estimands.
There will be insufficient participants with 
MTT data for model-based statistical 
analyses.
 
 
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Section 
Number
Section Title
Description of Change
Rationale
3.5.5.2
Statistical Method for Safety 
Analyses
Changed safety analyses approach – primary 
approach will include data after rescue except 
for hypoglycemia endpoints.
Simplification of analysis approach.
3.5.5.3
Summaries of Baseline 
Characteristics, 
Demographics, and Other 
Analyses
Description of variables was updated. 
Removal of demographic baseline 
characteristics summary for patients who 
continue to Phase B.
Simplification.
No separate analysis for this group is 
planned.
3.5.7
Sample Size and Power 
Calculations
Updated sample size information.
To reflect revised sample size. 
3.5.8
Subgroup Analyses
Description of subgroups was updated.
Simplification.
3.5.9
Interim Analyses
Emphasized that the first database lock for the 
primary efficacy analysis is not an interim 
analysis.
Clarification.
3.5.10
Medication Adherence
Adherence definition was added.
To reflect compliance based on time in study.
3.6.1
Product Descriptions
Corrected product description.
Blister card table was added.
Correction.
5
List of references
List of references was updated.
Deleted references that are no longer 
applicable.
6.11
Mapping of Relative Day 
Ranges to Weeks
Information was updated.
To clarify how results will be mapped to 
individual time points during analysis. 
6.12 (new)
Patient Randomized Twice
Appendix added to define handling of patient
randomized twice. 
To document handling of data. 
6.14
Supplemental Dental Data 
Sub-study
Clarified that dental sub-study procedures do 
not apply to Brazil and Serbia. 
Brazil and Serbia are not participating in the 
dental sub-study. The text in the protocol will 
allow us to proceed without creating country 
specific amendments for Brazil and Serbia. 
6.14.2
Sub-Study Design and 
Procedures
Dental data will be assessed by an independent 
pediatric dentist reviewer. 
Reviewer information was updated. 
 
 
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12-Jun-2018
Section 
Number
Section Title
Description of Change
Rationale
6.14.7
Sub Study Statistical 
Analysis Plan
Section was deleted.
The statistical plan for the dental substudy will 
be presented in a separate document.
6.15
List of Prior Amendments
List was updated.
Update.
Throughout the document
The word ‘subject’ was replaced with 
‘patient’.
Editorial and formatting changes.
Consistency throughout the document.
 
 
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1. SUMMARY
TITLE
1.1
A Phase III, Multicenter, Double-Blind, Randomized, Placebo- Controlled Clinical Trial to 
Evaluate the Safety and Efficacy of Sitagliptin in Pediatric Patients with Type 2 Diabetes 
Mellitus with Inadequate Glycemic Control.
INDICATION
1.2
For the treatment of pediatric patients (10 to 17 years of age, inclusive) with type 2 diabetes 
mellitus (T2DM) with inadequate glycemic control.
SUMMARY OF RATIONALE
1.3
This study (MK-0431 P083) is designed to assess the safety and efficacy of sitagliptin, 
relative to placebo, as initial oral therapy for the treatment of T2DM in pediatric patients 
(10 to 17 years of age, inclusive) with inadequate glycemic control.
SUMMARY OF STUDY DESIGN
1.4
P083 is a multinational, two Phase, double-blind, parallel-group study of approximately 
56 weeks duration, including a screening period of up to 1 week [Visits 1 to 2], a 1-week 
single-blind placebo run-in period [Visits 2 to 3], a 20-week placebo-controlled, double-
blind treatment period [Visits 3 to 8; Phase A] and a 34-week double-blind active-controlled 
treatment period [Visits 8 to 11; Phase B] during which patients randomized to the placebo 
arm who have not initiated glycemic rescue therapy with metformin during Phase A will 
receive metformin (in a blinded manner) as shown in Table 1-1, Table 1-2 and Figure 2-1.  A 
telephone contact will be performed 14 days after the last dose of study medication (whether 
due to study completion or premature discontinuation from the study) to assess for any 
serious adverse events (SAEs).
At Visit 2, eligible patients will undergo diet and exercise counseling and initiate sitagliptin-
placebo and metformin-placebo.  Eligible patients will be randomized (1:1) at Visit 3/Day 1
to either sitagliptin or placebo. Patients meeting progressively stricter glycemic thresholds 
will be eligible to initiate glycemic rescue therapy (Step 1 and Step 2, Section 2.4.2.6) in both 
Phase A and Phase B.  Except for Step 2 rescue and Step 2 treat-to goal, study medication 
will be managed through the Interactive Voice Response System (IVRS) using blister packs.
The content of the blister pack and the dose regimen for study medication, including Step 1 
and Step 2 rescue, are described in Table 1-1 (for the placebo run-in and Phase A) and 
Table 1-2 (for Phase B).
A supplemental dental data sub-study has been added to the protocol via amendment; the 
rationale for the sub-study is provided in Section 3.1.7. Procedures specific to the 
supplemental dental data sub-study amendment are outlined in Appendix 6.14 and apply to 
all randomized patients who took at least one dose of study medication, i.e., those who are 
new to P083, those ongoing (on or off study medication) in P083, and those who have 
completed P083 (on or off study medication).  Patients who have withdrawn consent from 
 
 
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P083 are not eligible.  Appendix 6.14 outlines the definition of new, ongoing, and completed 
patients.  
Note: Patients currently enrolled in MK-0431 P351 (a non-interventional follow-up study to 
MK-0431 P083) are also eligible to be contacted to participate in this sub-study. 
Consent will be required to participate in this sub-study (see Section 3.2.3.13.4).
SAMPLE
1.5
At least 190, but no more than 220 patients 10 to 17 years of age (inclusive) with T2DM who 
have inadequate glycemic control are eligible to participate if they meet ONE of the 
following enrollment criteria:

not on treatment with an antihyperglycemic agent (AHA) for ≥12 weeks prior to Visit 
1 and have inadequate glycemic control (hemoglobin A1c [A1C] of ≥6.5% and 
≤10.0% at Visit 1)
OR

on a stable dose (variance in dose to be ≤15 % of total daily dose) of insulin (without 
any other antihyperglycemic agents) for at least 12 weeks prior to Screening 
Visit/Visit 1 and have inadequate glycemic control (A1C of ≥7% and ≤10.0% at 
Visit 1). This stable regimen can include (1) a stable dose of basal insulin (±15%) 
AND/OR (2) stable prescribed doses of bolus insulin (±15%) (a) for each fingerstick 
glucose range for patients on sliding scale AND, if applicable, (b) for corrective doses 
and carbohydrate coverage.
At least 30% of randomized patients will be 10 to 14 years of age and at least 20% of patients 
will be recruited from European Union (EU) member states or countries with ethnicity and 
life-style similar to those in EU countries. Further, at least 1/3 and not more than 2/3 of the 
patients in each age subset (10 to 14, 15 to 17 years) will be female.
DOSAGE/DOSAGE FORM, ROUTE, AND DOSE REGIMEN
1.6
Sitagliptin (100 mg), metformin (500 mg) and their matching placebos will be supplied as 
oral tablets in blister packs. The dose regimen for the study is shown in Table 1-1 and
Table 1-2.
Background insulin and open-label insulin for Step 2 rescue and Treat-to-Goal Step 2 will be 
sourced locally and administered subcutaneously based on instructions provided by the 
investigator (based on accepted local, national or international guidelines for the indication 
and use of insulin).
Doses of background insulin should remain stable (variance in dose to be ≤15% of total 
daily dose) for the duration of the trial (See Section 2.4.2.6, Section 2.4.2.6.1 for up-
titration, Section 3.2.3.3 for down-titration, and Section 1.5 for stable regimen).
 
 
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Any open-label alternate glycemic rescue medication (other than metformin, or a DPP-
4 inhibitor, or a GLP 1 receptor agonist) used for Step 2 rescue for patients ≥18 years of 
age will be sourced locally by subsidiary or designee, investigator site, or by 
prescription.
Note: Not all specific insulin types that are approved in adults are approved for use in 
pediatric patients with T2DM, although the use of insulin therapy in pediatric patients is 
supported by practice guidelines.
Table 1-1
Content of the Blister Pack and Dose Regimen in Phase A
Treatment Phase
Treatment Arm
Sitagliptin
Placebo
Placebo Run-In
1 tablet of sitagliptin-placebo prior to the morning meal and 2 
tablets of metformin-placebo prior to both the morning and evening 
meals.
Phase A (From Visit 3 
through Visit 8)
1 tablet of sitagliptin prior to 
the morning meal and 2 tablets 
of metformin-placebo prior to 
both the morning and evening 
meals1,2
1 tablet of sitagliptin-placebo prior 
to the morning meal and 2 tablets 
of metformin-placebo prior to 
both the morning and evening 
meals1,2
1 Step 1 Rescue for patients in both treatment arms: All patients who require glycemic rescue therapy 
(including patients on background insulin) will be rescued with metformin.  The patients’ study 
medication kit (with the blister packs) will be replaced with a new one in which the metformin-placebo 
has been replaced by active metformin in a blinded fashion (starting at 500 mg/day and up-titrated by 
500 mg every week to a final dose of 1000 mg bid.).
2 Step 2 Rescue for patients in both treatment arms: Patients who continue to require glycemic rescue 
therapy after Step 1 Rescue will initiate open-label insulin. Patients on background insulin therapy 
should have the dose of their background insulin up-titrated for Step 2 rescue. Refer to Section 2.4.2.6 
for further details.
 
 
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Table 1-2
Content of the Blister Pack and Dose Regimen during Phase B
Treatment Phase
Treatment Arm
Sitagliptin
Placebo
Phase B (From Visit 8 
through Visit 11)
Patients who have not initiated 
glycemic rescue therapy in Phase 
A will continue to receive 1 tablet 
of sitagliptin prior to the morning 
meal and 2 tablets of metformin-
placebo prior to both the morning 
and evening meals. 1,3
Patients who have not initiated 
glycemic rescue therapy in Phase A 
will receive 1 tablet of sitagliptin-
placebo prior to the morning meal, 
and metformin-placebo in the blister 
pack will be replaced by active 
metformin in a blinded fashion 
(starting at 500 mg/day and uptitrated 
by 500 mg every week to a final dose 
of 1000 mg bid.). Patients who are 
not able to tolerate a higher dose of 
metformin (or matching placebo) will 
have their dose reduced at an 
unscheduled visit and should continue 
on the maximal tolerated dose for the 
duration of the study. 2,3
1 Step 1 Rescue for patients in the sitagliptin arm: All patients who require glycemic rescue therapy 
(including patients on background insulin) will be rescued with metformin.  The patients’ study 
medication kit (with the blister packs) will be replaced with a new one – the new blister pack will contain 
active sitagliptin, and the metformin-placebo will have been replaced by active metformin in a blinded 
fashion (starting at 500 mg/day and uptitrated by 500 mg every week to a final dose of 1000 mg bid.).
Patients who are not able to tolerate a higher dose of metformin (or matching placebo) will have their 
dose reduced at an unscheduled visit and should continue on the maximal tolerated dose for the duration 
of the study.
2 Step 1 Rescue for patients in the placebo arm who have switched to metformin: All patients who require 
glycemic rescue therapy (including patients on background insulin) will be rescued with sitagliptin.  The 
patients’ study medication kit (with the blister packs) will be replaced with a new one – the new blister 
pack will contain active metformin, and the sitagliptin-placebo will have been replaced by active 
sitagliptin in a blinded fashion.
3 Step 2 Rescue for patients in both treatment arms: Patients who continue to require glycemic rescue 
therapy after Step 1 Rescue will initiate open-label insulin. Patients on background insulin therapy should 
have the dose of their background insulin up-titrated for Step 2 rescue. Refer to Section 2.4.2.6 for further 
details.
 
 
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STUDY FLOW CHART
1.7
Screen
ing
Single-
Blind 
Placebo 
Run-In
Randomi
zation
Double-Blind Treatment
Phase A
Double-Blind Treatment
Phase B
Rescue Step 
1/ or Treat to 
Goal Step 1 or
Discontinua-
tion1
Rescue
Step 2
Or Treat to 
Goal Step 
21
2-Week 
Post-Study 
Phone 
Contact
Visit
1
Visit
2
Visit
3
Visit
4
Visit
5
Visit
6
Visit
7
Visit
8
Visit
9
Visit
10
Visit
11
Rescue1/
D/C2 Visit
Week
-1
Week 0/  
Day 1
Week
2
TC
Week
4
Week 
8
Week 
14
Week
20
Week
30
Week
42
Week
54
Week 56 
OR 14 days 
post D/C
Study Procedures
Obtain informed consent and assent3,4
X
Dispense patient identification card
X
Obtain informed consent and assent for Future Biomedical 
Research5
X
Evaluate Inclusion/Exclusion criteria4
X
X
X
Monitor for Adverse Events6
X
X
X
X
X
X
X
X
X
X
X
X
X7
Collect medical history8
X
Review prior/concomitant medication
X
X
X
X
X
X
X
X
X
X
X
X
X
Perform physical exam
X
X
X
X
Perform Tanner staging
X
X
X
X
Visual oral examination (including inspection of teeth)4
X
X
X
X
Measure vital signs (HR, BP measured twice)
X
X
X
X
X
X
X
X
X
X
X
X
Measure weight (measured twice)
X
X
X
X
X
Measure height (measured 3 times)
X
X
X
X
Determine BMI Percentile
X
Measure waist circumference (measured twice)
X
X
X
X
Perform 12-lead ECG (locally read)
X9
X
X
X
X-ray of Left Hand and Wrist (for bone age / central vendor)
X10
X11
X
X
Pediatric Quality of Life Questionnaire (PedsQL)
X12
Diet/exercise counseling13
X
Diet/exercise monitoring
X
X
X
X
X
X
X
X
X
X
X
Dispense Hypoglycemia Assessment Tool(s)14
X
X
X
X
X
Instruct on hypoglycemia symptoms and  management
X
X
X
X
X
X
X
X
X
Review  the Hypoglycemia Assessment Tool (s) 
X
X
X
X
X
X
X
X
X
X
X
Dispense 2 glucose meters and provide instructions for Self 
Monitoring of Blood Glucose (SMBG) and screening kit for 
ketones 
X
Review rescue criteria15
X
X
X
X
X
X
X
X
Witnessed Dose
X
X
X16
Dispense single-blind placebo medication
X
 
 
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Screen
ing
Single-
Blind 
Placebo 
Run-In
Randomi
zation
Double-Blind Treatment
Phase A
Double-Blind Treatment
Phase B
Rescue Step 
1/ or Treat to 
Goal Step 1 or
Discontinua-
tion1
Rescue
Step 2
Or Treat to 
Goal Step 
21
2-Week 
Post-Study 
Phone 
Contact
Visit
1
Visit
2
Visit
3
Visit
4
Visit
5
Visit
6
Visit
7
Visit
8
Visit
9
Visit
10
Visit
11
Rescue1/
D/C2 Visit
Week
-1
Week 0/  
Day 1
Week
2
TC
Week
4
Week 
8
Week 
14
Week
20
Week
30
Week
42
Week
54
Week 56 
OR 14 days 
post D/C
Assess for single-blind medication compliance
X
Dispense double-blind study medication
X
X
X
X
X
X
X
X2
Assess for double-blind medication compliance
X
X
X
X
X
X
X
X
X
X
Review SMBG measurements
X
X
X
X
X
X
X
X
X
X
X
Monitoring and Central Laboratory Procedures
Site finger stick A1C17
X
Fasting plasma glucose (FPG)18
X
X
X
X
X
X
A1C
X
X
X
X
X
X
X
X
X19
Site finger stick glucose
X
Fasting C-peptide18
X
Diabetes Autoantibody Panel
X
Complete Blood Count (CBC)/Differential
X
X
X
X
X
X
Fasting insulin and proinsulin20
X
X
X
X
Chemistry panel
X
X
X
X
X
X
X
X
Lipid panel18
X
X
X
X
X
TSH
X
Meal Tolerance Test (MTT) 9 point: -10, 0, 10, 20, 30, 60, 
90,120, 18021
X
X
X
X
Dipstick Urinalysis22
X
X
X
X
X
X
Urine microalbumin/creatinine ratio23
X
X
X
X
Urine Pregnancy test (for all females) 24
X
X
X
X
X
X
X
X
X
X1
X1
CD26 assay25
X
X
X
X25
IGF-1 and IGF-BP3
X
X
X
X
Biochemical Markers of Bone Turnover and calcitonin26
X
X
X
X
Blood sample (serum) for Future Biomedical Research27
X
X
X
X
Blood sample (plasma) for Future Biomedical Research27
X
X
X
X
Blood for Future Biomedical Research (for DNA)28
X
 
 
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CD= cluster of differentiation; D/C= discontinuation visit; DNA= deoxyribonucleic acid; EC= ethics committee; ECG= electrocardiogram; IGF= Insulin-like growth factor; IRB= institutional review 
board; TC= Telephone call; WBC= White blood cells.
NOTE: Visits (with the exception of  Visits 1, 3, 8, 11, Step-1 rescue, Treat-to-target Step-1, or Discontinuation visits) may be performed, if approved by the country and local IRB/EC, by a qualified 
health professional at the patient’s home or location other than the site.
1
All rescue procedures should be performed prior to the initiation of rescue therapy Step 1 or Step 2 or treat-to-goal Step 1/Step 2. If the rescue visit (Step 1 or Step 2 or  treat-to-goal  Step 1/Step 2) occurs 
on a regular scheduled visit, all procedures for that visit should be performed.  If  the rescue Step 1 or treat-to-goal Step 1or Discontinuation  visit is performed as an unscheduled visit within 4 weeks of 
Visit 3 or Visit 8, do not perform: physical examination,  X-ray procedure, Tanner staging, visual oral examination, height measurement, waist circumference measurement, ECG, complete blood 
count/differential, chemistry panel, lipid panel, MTT, dipstick urinalysis, urine microalbumin/creatinine ratio, biochemical samples of bone turnover and calcitonin, CD 26, FBR sampling, and IGF-1 and 
IGF-BP3.  For the Rescue or Discontinuation visits, the urine pregnancy test is needed only if the prior visit is more than 4 weeks apart. Note: the Discontinuation Visit is conducted for all patients who 
stop or discontinue study medication but is only a study discontinuation visit for patients who are stopping study medication due to withdrawal of consent, All patients who discontinue study medication 
will be counseled and encouraged to remain in the study, and to return to the site for the Week 20 and Week 54 visits, as applicable (described in Section 3.2.3.19). 
2
After the 14 day post- study medication discontinuation telephone contact is made, patients who do not withdraw consent (1) should return to the clinic for key visits (Week 20 and/or Week 54 as 
applicable) to have the following procedures performed: physical examination (including Tanner Staging), laboratory assessment of glycemic endpoints (A1C and FPG), and safety parameters (CBC, 
chemistry panel, urine microalbumin to creatinine ratio, and dipstick urinalysis), and collection of adverse events. Patients who are unable or unwilling to return to the clinic at key visits will be contacted 
by phone to obtain adverse events, concomitant medications and weight.  For patients unable or unwilling to return to the clinic for key visits and who receive their diabetes care from the study doctor,
A1C and FPG values will be obtained from their records, if available; such patients who receive their diabetes care from someone other than the study doctor should have their diabetes doctor provide 
A1C and FPG values, if available. (2) At visits that are not key visits (i.e., not at week 20 and week 54) patients will continue to be contacted by phone in a timeframe similar to their original study visit 
schedule up until the patient has reached 54 weeks from randomization (Visit 3/Day 1). Refer to Section 3.2.3.19 for further details.  
3
Consent form must be signed prior to any study specific procedures; informed consent will be obtained from parent/legal guardian and assent will be obtained from the patient.
4
See Appendix 6.14 for the supplemental dental data sub-study flow charts and other details. Note: Procedures for the Supplemental Dental Data Substudy do not apply to Brazil and Serbia.
5
Future Biomedical Research consent from the parent/legal guardian and assent should be obtained prior to collecting the blood (DNA), plasma and serum samples.
6
Collect information about intercurrent illnesses.
7
Collect serious adverse events only.
8
For male and female patients 10 to ≤14 years, collect up to 5 years of relevant medical history. For male and female patients 15 to 17 years, collect up to 7 years of relevant medical history.
9
The ECG may be done at Visit 2 or Visit 3 but must be read and evaluated for study eligibility before the patient receives double-blind study medication at Visit 3.
10
The baseline X-ray must be performed after Visit 2 and prior to dispensation of study medication at Visit 3.  The baseline X-ray will be read upon receipt at the Central Vendor; if there is a status of 
“skeletal maturity,” then no further X-rays are required during the study. For additional details on X-ray procedure timing refer to Section 3.2.3.12.
11
The Visit 8 X-ray will be read upon receipt at the Central Vendor; if there is a status of “skeletal maturity,” then no further X-rays are required during the study.
12
The Peds QLwill be administered to patients and their parents in countries where local validated translations of the questionnaire are available.  Note: The Peds QL will not be administered to illiterate 
parents and their children.
13
Patients will be seen by a dietitian or qualified health professional for diet/exercise counseling at Visit 2.
14
The Hypoglycemia Assessment Tool(s) will be provided in paper or as an electronic device, per site approval.   The Tool(s) will be reviewed at each visit, and re-dispensed as required per the modality in 
use. The electronic device (if used) should be dispensed at Visit 2.  The Low Blood Sugar Calendar and Notepad in paper will be collected and reviewed at each visit.  A new Low Blood Sugar Calendar 
will be dispensed at Visit 2, Visit 6, Visit 8, Visit 9, and Visit 10.  The Low Blood Sugar Calendar from the previous visit will be re-dispensed at Visit 3, Visit 5, and Visit 7. 
15
The patient and parent/guardian will be informed of the finger stick glucose rescue threshold that is applicable until the next visit and will be instructed to call the site if the fasting finger stick glucose 
value is greater than this threshold on 3 consecutive days. Patients and parents should be counseled that if one fasting finger stick glucose value is above the threshold for rescue, the fasting finger stick 
glucose value has to be checked the following morning. If the fasting finger stick glucose value is above the threshold for rescue on two consecutive days, the fasting finger stick glucose has to be checked 
on the third day as well, and the site called if all three values are above the threshold for rescue). After the patient calls the site with fasting finger stick glucose values that exceed the thresholds for 3 
consecutive days, and after assessing for compliance with study medication (refer to Section 2.4.2.6) an FPG will be performed, and the patient will be rescued if the FPG is greater than the threshold 
specified in Table 2-2.  For reference, site personnel will record the threshold for rescue in the finger stick glucose log book.
16
Patients who participate in the MTT at Visit 8/Week 20 will be contacted by the site the day after the visit to collect the date and time that study medication was taken. 
17
Site finger stick A1C may be used, if available, at the discretion of the investigator, for screening purposes only; laboratory A1C must be used to meet inclusion criteria for eligibility.
18
If the patient is not fasting at Visit 1/Screening Visit, a fasting lipid profile, fasting C-peptide and FPG should be obtained at or prior to Visit 2 rather than at Visit 1.
19
Blood sample for A1C should not be collected if the Discontinuation or Rescue Visit occurs prior to Week 8.
20
If a patient is undergoing the MTT, then do not obtain separate samples for fasting insulin and proinsulin as these samples are obtained as part of the MTT. Do not perform fasting insulin and proinsulin 
on patients with background insulin therapy.
 
 
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21
MTT will be performed only in patients who agree to undergo this procedure. Do not perform MTT on patients with background insulin therapy.
22
If dipstick (midstream urine specimen) is positive for blood, WBC (e.g., leukocyte esterase or nitrites), or protein, then a sample for a complete urinalysis (including microscopy) should be sent to the 
central laboratory.  Dipstick should not be performed if patient is menstruating.
23
The urine sample for microalbumin/creatinine ratio should not be collected if the patient is menstruating, has vigorously exercised within 24 hours, or has had fever or an active infection within two days 
of the visit.
24
Females will have a urine pregnancy test (and serum pregnancy test if required by the site’s Institutional Review Board [IRB] / Ethics Committee [EC]).  Patients with a positive urine pregnancy test 
during the double-blind treatment period will have a serum pregnancy test.
25
The parent/legal guardian should not schedule the patient for an immunization 2-4 weeks prior to Visits 3, 8 and 11.  If the Rescue Visit occurs prior to Visit 8, a sample for the CD26 assay  should be 
obtained at that time instead of at Visit 8/Week 20. For patients who have not received rescue therapy in Phase B, if a sample for CD26 was not obtained or analyzed at Visit 8, it can still be obtained at 
or prior to Visit 9.
26
Biochemical markers of bone turnover include urine (second AM void) N-terminal cross-linking telopeptide of bone collagen (NTX) and creatinine; and serum bone-specific alkaline phosphatase (Ostase 
assay).
27
Future Biomedical Research (FBR) informed consent must be obtained before FBR samples for plasma and serum are collected.  The plasma and serum samples for FBR should be collected at Visit 3
(pre-dose), Visit 8, Visit 11, Rescue (if applicable) and/or Discontinuation. If FBR consent is obtained at a later time in the study, then FBR plasma and serum samples should be obtained only at the 
remaining scheduled time points.
28
Future Biomedical Research (FBR) informed consent must be obtained before FBR samples for DNA are collected.  The FBR sample for DNA should be obtained pre-dose, at Visit 5, at the same time as 
other blood collections, and as the last sample drawn.  If FBR consent is obtained at a later date, then the FBR sample for DNA can be obtained at the same time as a remaining scheduled blood collection.  
 
 
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2. CORE PROTOCOL
OBJECTIVES AND HYPOTHESES
2.1
2.1.1
Primary
In pediatric patients (ages 10 to 17 years) with T2DM with inadequate glycemic control:
1. Objective:  After 20 weeks, to assess the effect of treatment with sitagliptin compared 
with placebo on A1C.
Hypothesis:  Sitagliptin reduces A1C more than placebo after 20 weeks of treatment.
2. Objective:  To assess the safety and tolerability of sitagliptin.
2.1.2
Secondary
In pediatric patients (ages 10 to 17 years) with T2DM with inadequate glycemic control, 
after 20 weeks:
1. Objective: To assess the effect of treatment with sitagliptin compared with placebo on 
fasting plasma glucose (FPG).
2. Objective: To assess the effect of treatment with sitagliptin compared with placebo on 
the proportion of patients requiring glycemic rescue therapy.
3. Objective: To assess the effect of treatment with sitagliptin compared with placebo on 
the proportion of patients at goal (A1C <7.0%).
4. Objective: To assess the effect of treatment with sitagliptin compared with placebo on 
body mass index (BMI).
5. Objective: To assess the effect of treatment with sitagliptin compared with placebo on 
fasting measures of beta cell function by assessing change from baseline in HOMA-and 
proinsulin/insulin ratio as well as on 2-hour post-meal glucose (PMG) and indices of 
insulin secretion derived from C-peptide, insulin, and glucose profiles with a standard 
meal challenge.
6. Objective:  To summarize data on the following:

Growth velocity

Change from baseline in Tanner staging

Skeletal maturation (∆ Bone age/∆ Chronologic age)

Percentage change from baseline in IGF-1 and IGF-BP3 

Change from baseline in markers of bone turnover and calcitonin

Percentage change from baseline in CD26 expression 

Change from baseline in measures of dentition 
 
 
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In pediatric patients (ages 10 to 17 years) with type 2 diabetes mellitus (T2DM) with 
inadequate glycemic control, after 54 weeks:
1. Objective:  To assess the effect of treatment with sitagliptin (change from baseline) on 
A1C, FPG, the proportion of patients requiring glycemic rescue therapy, BMI, fasting 
measures of beta cell function by assessing change from baseline in HOMA-and 
proinsulin/insulin ratio as well as on 2-hour PMG and indices of insulin secretion derived 
from C-peptide, insulin, and glucose profiles with a standard meal challenge. 
2. Objective: To assess change from baseline in the placebo group (for patients in the 
placebo group who switched to metformin at the end of Phase A) in A1C, FPG, 
proportion of patients requiring glycemic rescue therapy, BMI, fasting measures of beta 
cell function by assessing change from baseline in HOMA-and proinsulin/insulin ratio 
as well as on 2-hour PMG and indices of insulin secretion derived from C-peptide, 
insulin, and glucose profiles with a standard meal challenge. 
3. Objective: To assess the effect of treatment with sitagliptin on the proportion of patients 
at goal (A1C <7.0%).
4. Objective:  To summarize data on the following:

Growth velocity

Change from baseline in Tanner staging

Skeletal maturation (∆ Bone age/∆ Chronologic age)

Percentage change from baseline in IGF-1 and IGF-BP3 

Change from baseline in markers of bone turnover and calcitonin

Percentage change from baseline in CD26 expression

Change from baseline in measures of dentition 
PATIENT INCLUSION CRITERIA
2.2
All laboratory measurements (to determine eligibility) are to be performed after an overnight 
fast ≥10 hours in duration.  Patients with screening values outside the ranges described in the 
protocol may, at the discretion of the investigator, have one repeat determination performed 
by the central laboratory.  If the repeat value satisfies the criterion they may continue the 
screening process.  Only the specific out-of-range value/finding should be repeated (not the 
entire panel).
If the period of time between the date when the screening laboratory measurements were 
obtained and the Visit 3 date exceeds 28 days, patients must have all screening laboratory 
measurements repeated.
For the supplemental dental data sub-study, inclusion criteria for participation in the sub-
study are found in Appendix 6.14.
 
 
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Patients must meet all of the following criteria to participate in the study.
At Visit 1
1. Patient has T2DM as indicated by “yes" answers to all of the following:
a) Patient has diabetes by American Diabetes Association (ADA) criteria (e.g. 
laboratory determinations of FPG ≥126 mg/dL [7.0 mmol/L], or random plasma 
glucose ≥200 mg/dL [11.1 mmol/L], or two-hour oral glucose tolerance test [OGTT]
plasma glucose ≥200 mg/dL [11.1 mmol/L], or A1C ≥6.5% [test performed using a 
method that is NGSP certified and standardized to the DCCT assay], and confirmed 
per ADA guidelines).
b) Patient is assessed as having a clinical profile consistent with T2DM (e.g., based upon 
body weight, family history, presentation).
c) Patient has Body Mass Index (BMI) percentile ≥85th percentile at screening (or 
patient has a history of being overweight or obese at time of diagnosis of T2DM).  
The body mass index-for-age charts from the WHO can be found in Appendix 6.9.
Note: If patient does not have a BMI ≥85th percentile at the time of screening, the 
documentation of overweight or obesity at the time of diagnosis of T2DM must be 
included in the source documents at the site.
d) Patient has a fasting C-peptide value >0.6 ng/mL at Screening Visit/Visit 1.
2. Patient either: 
a) Has not received treatment with any AHA during the 12 weeks prior to the Screening 
Visit/Visit 1. However, patients who have had no more than a total of 10 days of 
treatment with an oral AHA (i.e., metformin, sulfonylureas, meglitinides or alpha-
glucosidase inhibitors) during the 12 weeks prior to the Screening Visit/Visit 1 are 
eligible. 
Note: For patients who have received treatment with an oral AHA for more than a total 
of 10 days within the 12 weeks prior to the Screening Visit/Visit 1, therapy should not 
be stopped (washed-off) to make them eligible for the study.
OR
b) Is on a stable dose (variance in dose to be ≤15 % of total daily dose) of insulin 
(without any other AHA) for at least 12 weeks prior to Screening Visit/Visit 1. This 
stable regimen can include (1) a stable dose of basal insulin (±15%) AND/OR (2) stable 
prescribed doses of bolus insulin (±15%) (a) for each fingerstick glucose range for 
patients on sliding scale AND, if applicable, (b) for corrective doses and carbohydrate 
coverage.
Note: At screening, patients on insulin doses that are not stable can have their insulin doses
adjusted and be eligible to participate after their dose remains stable for ≥12 weeks, if they 
meet all other eligibility criteria. In India, only patients on stable doses of insulin will be 
eligible.
 
 
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3. Patient has an A1C of ≥6.5% and ≤10.0%.
Note: Patients on insulin have an A1C ≥7.0% and ≤10.0%.
4. Patient is between 10 and 17 years of age (inclusive) on the day of signing informed 
consent with randomization to occur prior to the patient’s 18th birthday.
5. Patient is either a male, or patient is a female who is unlikely to conceive, as indicated by 
at least one “yes” response to the following which will remain consistent for the projected 
duration of the study and for 14 days after the last dose of study medication:
a) Patient is a non-sterilized female who is currently not sexually active and agrees to 
follow statement "c" if heterosexual activity is initiated
OR
b) Patient agrees to abstain from heterosexual activity
Note: If abstinence is not a locally acceptable method of contraception, then one other 
adequate birth control method must be used.
OR
c) Patient agrees to use an adequate method of contraception.
Note: Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception. Acceptable 
methods of birth control are: hormonal contraceptive, intrauterine device (IUD), 
diaphragm with spermicide, contraceptive sponge, or use of condom by the partner.  
Patients initiating hormonal contraception during the study should use one additional 
method during the first two months.
6. Parent/guardian understands the study procedures, alternative treatments available and 
risks involved with the study, and voluntarily agrees to the patient's participation by 
giving informed written consent, and the patient has an age-appropriate understanding of 
the same to give informed written assent.  If the parent/guardian is illiterate, please see 
Section 3.2.3.13.1 for details.  In addition, the parent/guardian may also consent to have 
the child participate in Future Biomedical Research (FBR) by signing a separate consent.  
Note:  otherwise eligible patients will be able to participate in the main study even if they 
opt to not participate in FBR.
7. Patient and a family member or adult closely involved in the patient’s daily activities (in 
the opinion of the investigator) will participate in the patient's treatment and study 
protocol (i.e., available for telephone calls, study visits and administration of study 
medication as needed).
 
 
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At Visit 3/Day 1/Randomization
8. Patient has ≥80% compliance with placebo treatment during the single-blind run-in as 
measured by site-performed tablet count.
PATIENT EXCLUSION CRITERIA
2.3
All laboratory measurements (to determine eligibility) must be performed after an overnight 
fast ≥10 hours in duration.  Patients with screening values outside the ranges described in the 
protocol may, at the discretion of the investigator, have one repeat determination performed 
by the central laboratory.  If the repeat value satisfies the criterion, the patient may continue 
the screening process.  Only the specific out-of-range value/finding should be repeated (not 
the entire panel).
If the period of time between the date when the screening laboratory measurements were 
obtained and the Visit 3 date exceeds 28 days, patients must have all screening laboratory 
measurements repeated.
Individuals are excluded from participation in the study if they meet any of the following 
criteria.
At Visit 1
Glucose Metabolism and Therapy Criteria
1. Patient has a history of type 1 diabetes mellitus, autoimmune diabetes mellitus or has a 
positive antibody screen for anti-GAD or ICA-512.
Note: The results of the antibody screen for anti-GAD or ICA-512 must be available and 
evaluated before the patient can be randomized at Visit 3.
2. Patient has known monogenic diabetes, secondary diabetes, or a genetic syndrome or 
disorder known to affect glucose tolerance other than diabetes.
3. Patient has symptomatic hyperglycemia and/or moderate to large ketonuria and/or
positive test for ketonemia, requiring immediate initiation of antihyperglycemic therapy.
Specific Treatments
4. Patient has previously taken a DPP-4 inhibitor (such as sitagliptin, vildagliptin, alogliptin, 
or saxagliptin) or GLP-1 receptor agonist (such as exenatide or liraglutide).
Note:  Patients who have participated in single-dose studies with these agents at least 
12 weeks prior to screening are eligible to participate.
5. Based on past experience, patient has hypersensitivity or contraindication (according to 
the product circular in the country of the investigational site) to metformin.
 
 
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6. Patient has initiated chronic treatment with a medication known to cause:
-weight gain within 30 days of Visit 1; OR
-weight loss (such as orlistat) or increase blood glucose within 8 weeks of Visit 1.
Note: Patients on a weight loss program and not in the maintenance phase, or who have 
undergone bariatric surgery within 12 months prior to signing the informed consent will 
be excluded. 
Note: Patients who have been treated with an anti-psychotic agent within the past 12 
weeks will also be excluded.
7. Patient is currently participating in or has participated in another study with an 
investigational compound or device within the prior 12 weeks of signing the informed 
consent (including patients who have participated in single-dose studies with these 
agents) and does not agree to refrain from participating in any other study while 
participating in this study.
8. Patient is on or likely to require treatment with ≥14 consecutive days or repeated courses 
of pharmacologic doses of corticosteroids.
Note: Inhaled, nasal, and topical corticosteroids are permitted.
9. Patient has undergone a surgical procedure within the prior 4 weeks or has major surgery 
planned during the study.
Note: Patients who have undergone minor surgery within the prior 4 weeks and are fully 
recovered or patients who have planned minor surgery may participate. Minor surgery is 
defined as a surgical procedure involving local anesthesia.
Concomitant Conditions or Diseases of Organs and Systems
10. Patient has a history of congenital heart disease or cardiovascular disease other than 
hypertension.
11. Patient has a Visit 1 systolic or diastolic blood pressure of ≥95th percentile for age, 
height percentile and gender (see Appendix 6.2 and 6.3) and is not considered likely to 
have values <95th percentile for age, height percentile and gender by Visit 3/Day 1 with 
appropriate antihypertensive therapy.
Note: Investigators are encouraged to maximize blood pressure control according to 
current guidelines.  Patient may have blood pressure medications adjusted and be 
enrolled if repeat blood pressure measurement no longer meets exclusion criteria.
 
 
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12. Patient has a medical history of active liver disease (other than non-alcoholic hepatic 
steatosis), including chronic active hepatitis B or C, primary biliary cirrhosis, or 
symptomatic gallbladder disease.
13. Patient has active nephropathy (i.e., nephrotic syndrome or glomerulonephritis).
Exception:  Patients with diabetic nephropathy will be eligible if they meet all other 
eligibility criteria.
14. Patient has chronic myopathy, mitochondrial disorder, or a progressive neurological or 
neuromuscular disorder (e.g., polymyositis, or multiple sclerosis).
15. Patient has human immunodeficiency virus (HIV) as assessed by medical history.
16. Patient has a clinically significant hematological disorder (such as aplastic anemia, 
thrombocytopenia, myeloproliferative or myelodysplastic syndrome).
17. Patient is under treatment for hyperthyroidism.
Note: Patients under treatment for hypothyroidism with a normal TSH value may 
participate.
18. Patient exhibits abnormal growth patterns or is being treated with growth hormone.
19. Patient has a history of malignancy or clinically important hematologic disorder.
Exception:  (1) patients with adequately treated non-melanomatous skin carcinoma or 
carcinoma in situ of the cervix may participate; and (2) patients with other malignancies 
which have been successfully treated >5 years prior to screening, where in the judgment 
of both the investigator and treating physician, appropriate follow-up has revealed no 
evidence of recurrence from the time of treatment through the time of screening. 
However, patients with a history of leukemia, lymphoma, malignant melanoma, or 
renal cell carcinoma are ineligible for the study regardless of the time since 
treatment, and in such cases, no exceptions will apply.
20. Patient has a history of idiopathic acute pancreatitis or chronic pancreatitis.
Other Criteria
21. Patient has a known history of recreational or illicit drug use, or of alcohol abuse or 
dependence (within the past year).
22. Patient has donated blood products or has had phlebotomy of >10% of estimated total 
blood volume within 8 weeks of signing informed consent, or intends to donate blood 
products or receive blood products within the projected duration of the study.
23. Patient is pregnant, has a positive urine pregnancy test at Screening Visit/Visit 1, is 
expecting to conceive within the projected duration of the study, or is breast-feeding.
 
 
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24. Patient is unlikely to adhere to the study procedures and appointment schedule, is 
planning to relocate outside of the geographic area (including attending school at a 
remote location) during the study, has poor mental function or parent/guardian is, in the 
opinion of the investigator, mentally or legally incapacitated preventing informed consent 
from being obtained.
25. Patient has a history or current evidence of any condition, therapy, lab abnormality or 
other circumstance which, in the opinion of the investigator, might pose a risk to the 
patient, make participation not in the patient’s best interest, might confound the results of 
the study, or interfere with the patient’s participation for the full duration of the study.
Exclusion Criteria Based on Lab Abnormalities
26. Patient has exclusionary laboratory values as listed in Table 2-1 below.
Table 2-1
Laboratory Exclusion Criteria
Parameter1
Study Limit for Exclusion
eGFR2
<55 mL/min/1.73m2
ALT
>2.5 times ULN
AST
>2.5 times ULN
TSH3
Outside Normal Range
TG4
>500 mg/dL (5.65 mmol/L)
Hemoglobin
Below Normal Range 
ALT= alanine amino transferase; AST= aspartate aminotransferase; eGFR= estimated 
glomerular filtration rate; TSH= thyroid stimulating hormone; TG= triglycerides; ULN= 
upper limit of normal. 
1 If screening laboratory values are repeated, the last laboratory draw/result should be used for 
inclusion.
2 As assessed by modified MDRD.
3 Patients with abnormal TSH must be excluded and may be re-screened with the permission of 
the Merck Clinical Monitor if they have a normal TSH after they have been on a stable 
thyroid replacement regimen for at least 6 weeks prior to Visit 1 with no further dose 
changes during the pre-randomization period.
4 Patients with elevated TG may be re-screened with the permission of the Merck Clinical 
Monitor if they have a normal TG after they have been on a stable lipid-lowering medication 
regimen for at least 4 weeks prior to Visit 1 with no further dose changes during the pre-
randomization period.  Refer to Section 3.2.1 for details.
 
 
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At Visit 2
27. Patient has symptomatic hyperglycemia or moderate to large ketonuria or positive test for 
ketonemia.
28. Patient has a clinically significant ECG abnormality which, in the opinion of the 
investigator, exposes the patient to risk by enrolling in the study or which indicates that 
the patient meets Visit 1 exclusion criterion “10”, or patient has a prolonged QTc interval 
for age.
At Visit 3/Randomization
29. Patient has symptomatic hyperglycemia, and/or ketonuria or positive test for ketonemia
requiring immediate initiation of AHA and in the opinion of the investigator is not 
considered likely to respond to diet and exercise intervention.
30. Patient 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 run-in which meets any previously described study 
exclusion criterion.
Note:  If a patient requires initiation of a new medication (other than single-blind study 
medication) at Visit 3, the current visit should be changed to an "Unscheduled Visit" and 
the patient should be rescheduled for a Visit 3 to occur 1 to 2 weeks later, except if 
patient needs initiation or adjustment of medications discussed in Section 3.2.1.  
Additional single-blind placebo run-in medication should be dispensed at this 
Unscheduled Visit.
31. Patient has a positive urine pregnancy test.
32. Patient has a site fasting fingerstick glucose (FFSG) >240mg/dL (13.3 mmol/L).  Note: If 
the investigator believes that the value does not reflect the patient’s recent glycemic 
control, then the patient should not be excluded at this time.  The current visit should be 
changed to an unscheduled visit and the patient should be rescheduled for Visit 3/ Day 1.  
If at the rescheduled visit, the patient meets this exclusion criterion, the patient MUST be 
excluded.
 
 
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STUDY DESIGN AND DURATION
2.4
2.4.1
Summary of Study Design
Figure 2-1
Study Design
Refer to Appendix 6.14 for the supplemental dental data sub-study details.  
2.4.2
Treatment Plan
Refer to the Study Flow Chart (Section 1.7) for the procedures to be performed at each visit
(Note: Refer to the Flow charts in Section 6.14.5 for the procedures to be performed at each 
visit for the Supplemental Dental Data Sub-Study). 
Following initial screening and 
evaluation at Visit 1 eligible patients will proceed to Visit 2/Week -1.  At Visit 2, patients 
will undergo diet and exercise counseling and initiate sitagliptin- and metformin-placebos
provided in blister packs ( Table 1-1 ). Patients who enter the study on background insulin 
will continue on the same dose (variance of ≤15% of total daily dose) and formulation of 
insulin throughout the study unless they meet criteria for Rescue Step 2 or Treat to Goal Step 
2 or downtitrate their dose due to hypoglycemia.
 
 
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At Visit 3/Day 1, patients will be randomized (1:1) to either sitagliptin OR placebo (Phase A 
period).
At Visit 8/Week 20 (start of Phase B), patients in the sitagliptin group who have not initiated 
glycemic rescue therapy in Phase A will continue to receive sitagliptin and placebo to 
metformin. Patients in the placebo group who have not initiated glycemic rescue therapy in 
Phase A will receive sitagliptin-placebo and initiate metformin (refer to Table 1-2).
Throughout the study, glycemic endpoints, including A1C and FPG will remain masked to 
the patient and investigator.  However, in order for the investigator to perform an evaluation 
for possible glycemic rescue and/or discontinuation, the central laboratory will report to the 
investigator in an unmasked manner any FPG laboratory value (and/or A1C value in Phase B) 
meeting rescue and/or discontinuation criteria (refer to Sections 2.4.2.6 and 2.4.2.7). During 
Phase B, it is recommended that the investigator "treat-to-goal" if the patient's A1C is ≥7.0% 
as described in Section 2.4.2.6.3.
Patients meeting progressively stricter glycemic rescue criteria will be eligible to initiate 
glycemic rescue therapy (Step 1 and Step 2). Please refer to Table 1-1 and Section 2.4.2.6 for 
details.
Note: The patient and family will be instructed to monitor for ketonuria/ketonemia and check 
fingerstick blood sugars frequently and to contact the site if the patient experiences an acute 
intercurrent illness (e.g., fever >101F [38.3C] and/or gastrointestinal symptoms including 
vomiting and abdominal pain) at any time during the study.  For patients not on baseline 
insulin therapy, insulin therapy may be initiated during a brief, intercurrent illness, based on 
the investigator's clinical judgment. For those patients on background insulin therapy, insulin 
can be uptitrated based on the investigator's clinical judgment. Additionally, if the patient has 
symptoms of dehydration, investigators may consider interrupting blinded study medication 
until these symptoms resolve.  Patients requiring transient (i.e., <14 days) initiation of insulin 
or an increase in their insulin dose (>15% of the dose at screening for patients on background 
insulin therapy) due to an intercurrent illness will not be considered as having initiated 
rescue.  Standard rescue criteria outlined in Section 2.4.2.6 will not apply during an acute 
intercurrent illness.
2.4.2.1
Study Visits General Information
Fasting Prior to Scheduled Visits
Patients should be counseled to fast (i.e., no food, double-blind study medication, or drink 
except water and non-antihyperglycemic non-study medications as prescribed) for at least 
10 hours prior to Visits 1, 3, 8, 11, Rescue, and Discontinuation. The investigator should 
manage insulin doses appropriately for patients on background insulin to prevent/minimize 
the risk of hypoglycemia while fasting.
 
 
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Scheduling Visits, Visit Windows, and Study Duration
At the end of each study visit, the next study visit should be scheduled.  Every effort should 
be made to adhere to the visit schedule (refer to Study Flow Chart – Section 1.7), and 
generally, visits should be scheduled ±7 days of the designated time-point.  If unavoidable, a 
visit may be scheduled at a time outside of this recommended range, but the schedule for 
subsequent visits must be adjusted so that the total duration of the double-blind study period 
is as close as possible to 54 weeks.  The interval between Visit 2 and Visit 3 should be a 
minimum of 6 days (with 100% compliance with single-blind placebo medication) and a 
maximum of 14 days (with ≥80% compliance with single-blind placebo medication if the 
interval between Visit 2 and Visit 3 is 7-14 days).  If a visit is scheduled at a time other than 
the protocol designated time, careful consideration must be given to the amount of study 
medication the patient has available. Visits (with the exception of Visits 1, 3, 8, 11, Step-1 
rescue, Treat-to-target Step-1, or Discontinuation visits) may be performed, if approved 
by the country and local IRB/EC, by a qualified health professional at the patient’s home or 
location other than the site. These visits should be performed according to the guidelines that 
may exist at the participating institution, and should be consistent with the investigator’s 
usual clinical practice.
Visit Reminders – Telephone Contacts
Prior to each visit, patients should be contacted and reminded of:

The date and time of appointment.

The requirement to fast for at least 10 hours prior to the clinic Visits 1, 3, 8, 11,  Rescue,
and Discontinuation.

The requirement not to take any blinded study medication the morning of the clinic visit 
for Visits 8 and 11. 
Note:  Non-study medications that are not antihyperglycemic medications should be 
taken as directed by the prescribing physician.

The requirement to bring all study medication, blood glucose meter, hypoglycemia 
assessment tool(s), and any collected self-monitored blood glucose (SMBG) information 
to the clinic visit.

Parent/legal guardian should not schedule the patient for an immunization 2-4 weeks 
prior to Visits 3, 8, and 11.
2.4.2.2
Visit 1/Screening Visit
At Visit 1, written informed consent from the parent/legal guardian and written assent from 
the patient will be obtained.  Patients will be screened according to the Visit 1
Inclusion/Exclusion criteria and will receive a screening number.  Vital signs, body 
weight/BMI/BMI percentile, height and fasting blood samples (as indicated in the Study 
 
 
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Flow Chart Section 1.7) will be obtained in patients assessed as eligible to participate in the 
study.
At the site, the investigator may choose to screen patients with fingerstick A1C 
measurements, if available, (prior to drawing blood samples for central laboratory screening 
measurements) to evaluate the likelihood of the patients subsequently meeting study 
glycemic inclusion criteria.  If, based upon this fingerstick A1C value, the investigator 
believes the patient is an unlikely candidate for the study the patient may be excluded prior to 
undergoing any additional study procedures.
Note:  Investigators should be aware that although fingerstick A1C is generally predictive of 
values measured in the central laboratory, modest differences can occur in individual 
patients.  Therefore, a fingerstick A1C cannot substitute for a central laboratory 
measured A1C to determine if a patient meets study A1C inclusion criteria.
2.4.2.3
Visit 2 Single-Blind Placebo Run-in
Patients who are:
1) not on an AHA (for ≥12 weeks prior to Visit 1) and have a Visit 1 A1C of ≥6.5% and 
≤10.0%, OR
2) on a stable dose of insulin (see inclusion criterion #2), and have a Visit 1 A1C of ≥7.0% 
and ≤10.0%,
and meet all other enrollment criteria will be eligible to enter the single-blind placebo run-in 
period. Note: The results of the antibody screen for anti-GAD or ICA-512 must be available 
and evaluated before the patient can be randomized at Visit 3.
The first dose of single-blind placebo should be taken as a witnessed dose in the clinic 
after completion of all Visit 2 study procedures.  Patients will then take single-blind 
placebo as directed for one week prior to randomization (Table 1-1). It is essential that all 
procedures be performed before the patient takes the witnessed dose for this visit. 
The hypoglycemia assessment tool(s) will be dispensed at Visit 2. Eligible patients will have 
1) diet/exercise counseling; 2) training in performing SMBG and checking urine or blood for 
ketones; 3) instruction on hypoglycemia symptoms, hypoglycemia management, and 
completion of the hypoglycemia assessment tool(s).
For assessment and management of hypoglycemia, refer to Section 3.2.3.3.
2.4.2.4
Visit 3/Randomization Visit
At Visit 3, patients who meet all study enrollment criteria will have all baseline laboratory 
tests and study procedures performed (refer to Study Flow Chart – Section 1.7).
Assignment of a randomization number occurs only at Visit 3/Day 1.
 
 
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At Visit 3/Day 1, patients will be randomized to receive treatment with sitagliptin or placebo.
The first dose of double-blind study medications should be taken as a witnessed dose in 
the clinic after completion of all procedures for the study visit ( Table 1-1 ). It is essential 
that all procedures be performed before the patient takes the witnessed dose for this visit.
2.4.2.5
Visit 3/Day 1 through Visit 11/Week 54: Double-Blind Treatment Period
Phase A: Double-Blind Study Medication: From Day 1 to Week 20 (Table 1-1)
Patients in the sitagliptin group will receive 1 tablet of sitagliptin prior to the morning meal 
and 2 tablets of metformin-placebo prior to both the morning and evening meals.
Patients in the placebo group will receive 1 tablet of sitagliptin-placebo prior to the morning 
meal and 2 tablets of metformin-placebo prior to both the morning and evening meals.
At Visit 8, it is essential that all procedures be performed before the patient takes the 
witnessed dose for this visit (except for patients undergoing MTT, see Appendix 6.7).
Refer to Table 1-1 in Section 1.6 for treatment administration details and to Section 2.4.2.6 
for glycemic rescue.
Note: Patients will always take 5 tablets per day (3 tablets prior to the morning meal and 
2 tablets prior to the evening meal) from one single blister card.
Note: Visit 4 (Week 2) is a telephone call visit. The site should call the patient/parent to:

monitor for AEs, 

review concomitant medications, 

review hypoglycemia assessment tool(s),

review SMBG measurements, and rescue criteria,

assess for compliance with diet and exercise and study medication, 

instruct on hypoglycemia symptoms and management. 
Note: AEs and changes in concomitant medication should be documented in the 
appropriate electronic case report form (eCRF). Hypoglycemia should be 
documented in the hypoglycemia assessment (HA) eCRF (refer to Section 3.2.3.3).
Phase B: Double-Blind Medication: From Week 20 through Week 54 (Table 1-2)
Patients randomized to the sitagliptin group who have not initiated glycemic rescue therapy 
during Phase A will continue to receive sitagliptin and metformin-placebo.
 
 
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Patients randomized to the placebo arm who have not initiated glycemic rescue therapy
during Phase A, will continue to receive sitagliptin placebo and will initiate metformin (refer 
to Table 1-2).
At the start of Phase B, investigators should evaluate the patient’s most recent renal function 
tests (including eGFR and creatinine values) and determine if the patient can safely initiate
metformin in a blinded manner based on the local label for metformin.
At the start of Phase B, patients who are not undergoing a MTT must have the first dose of 
Phase B study medication dispensed at this visit as a witnessed dose in the clinic after
completion of all procedures for the study visit. Patients who are undergoing a MTT will take 
the dose of double-blind study medication from the previous visit’s blister-pack (Phase A) as 
a witnessed dose exactly 30 minutes prior to the start of the standard meal for the MTT
(T= -30 minutes).  For these patients, the first Phase B dose will be taken AFTER the study 
visit, as the evening dose (Tablets D and E). Please refer to Section 6.7 for dosing 
instructions. Refer to Table 1-2 for treatment administration details and to Section 2.4.2.6 for 
glycemic rescue.
2.4.2.6
Glycemic Rescue
Mandatory glycemic rescue will be initiated in both Phase A and Phase B for patients 
meeting defined glycemic criteria (Table 2-2).  The patient and parent/guardian will be (1) 
informed of the fasting fingerstick glucose values that meet the threshold corresponding to 
the patient’s duration in the study (e.g., a patient has 3 consecutive fasting fingerstick values 
>225 mg/dL [12.5 mmol/L] between Visits 5 and 6) and (2) instructed to call the site if the 
patient has 3 consecutive days of fasting fingerstick glucose values that exceed the specified 
thresholds. Patients and parents should be counseled that if one fasting fingerstick glucose 
value is above the threshold for rescue, the fasting fingerstick glucose value has to be 
checked the following morning. If the fasting fingerstick glucose value is above the threshold 
for rescue on two consecutive days, the fasting fingerstick glucose has to be checked on the 
third day as well, and the site called if all three values are above the threshold for rescue. 
Since the glucose thresholds become lower as the study progresses, study site personnel will 
inform the patient and parent/guardian of the glucose threshold (Table 2-2) at each visit.  For 
reference, site personnel will record the threshold level in the fingerstick glucose log book 
provided to the patient as well.
When the patient calls the site with fasting fingerstick glucose values that exceed the 
thresholds for 3 consecutive days, the site should call the patient for an unscheduled visit if in 
the investigator’s judgment the patient has been compliant with study medication. At the 
unscheduled visit, an FPG will be performed at the local and central laboratory. The FPG 
value obtained at the local laboratory can be used to assess rescue criteria. The patient will be 
rescued if the FPG is greater than the threshold specified in Table 2-2. Rescue Step 1 
involves blinded rescue treatment (implemented through IVRS) and if that fails, the second 
step (Rescue Step 2) will involve open-label insulin.  
 
 
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Patients who, in the investigator’s judgment, are not compliant with blinded study medication 
should be retrained by site personnel on compliance with treatment and diet/exercise.  The 
patient should be contacted a week later to assess if fasting fingerstick glucose values still 
meet rescue criteria and follow rescue procedures.
At the rescue Step 1, or Treat to Goal Step 1 Visit, patients should return their current study
medication kit to the clinic and stop taking study medication from that kit at that time.  At 
this rescue Step 1/Treat to Goal Step 1 visit, a new kit will be dispensed.  Each blister pack in 
the new kit will contain both the patient’s study medication before rescue and the rescue 
medication.  The patient will only take a total of 5 tablets from one blister pack per day. 
For rescue Step 2 or Treat to Goal Step 2, there will be no changes to the blister packs, and 
the patient will continue to take the 5 tablets per day (study medication and rescue 
medication). Open-label insulin will be initiated at this point for patients who are not on 
insulin. Patients who are already on insulin therapy from the Screening Visit will have their 
insulin dose uptitrated.
Note: Investigators should evaluate the patient’s most recent renal function tests (including 
eGFR and creatinine values) and determine if the patient can safely initiate Step 1 glycemic 
rescue therapy in a blinded manner based on the local label for metformin.
Note: If at any time a patient has
•
fingerstick glucose value >400 mg/dL (22.2 mmol/L) with or without 
ketonuria/ketonemia, OR
•
moderate to large ketonuria or positive test for ketonemia regardless of blood 
glucose levels
the investigator should consider initiating insulin for patients not on insulin treatment at 
screening, or should consider up-titrating insulin therapy for those patients on insulin 
treatment at screening.
The initiation of insulin for patients not on insulin at screening, or an increase in insulin dose 
of >15% from baseline for patients on background insulin, will be considered Rescue Step 2, 
even if they have not undergone Rescue Step 1 and a rescue visit should occur. Procedures 
performed for this Rescue Visit (refer to Section 1.7) will depend on whether the patient 
has previously undergone Rescue Step 1 procedures or not:
•
If the patient has previously undergone Rescue Step 1, then all Rescue Step 2 
Visit procedures must be performed prior to initiation or uptitration of insulin.
•
If the patient has not previously undergone Rescue Step 1, then all Rescue Step 1 
Visit procedures must be performed prior to initiation or uptitration of insulin. 
 
 
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Note:  For Step 2 open-label rescue (Section 2.4.2.6.2) and for Step 2 treat-to-goal (Section 
2.4.2.6.3), if initiating insulin is unacceptable or considered inappropriate, an alternate 
antihyperglycemic (oral) medication may be used for patients ≥18 years of age at the 
discretion of the investigator (in either Phase A or Phase B).  The use of DPP-4 inhibitors 
(sitagliptin, vildagliptin, saxagliptin, alogliptin, etc.), metformin, or GLP-1 receptor agonists 
is prohibited for purposes of alternate rescue medication.
Note:  Patients <18 years of age for whom initiating insulin or uptitration of insulin for Step 
2 open-label rescue (Section 2.4.2.6.2) or for Step 2 Treat-to-Goal (Section 2.4.2.6.3) is 
considered clinically inappropriate will need to be discontinued from study medication.
Note: For patients who are undergoing a MTT see Appendix 6.7. 
2.4.2.6.1
Rescue Step 1 (Blinded)
After randomization, all patients (including patients on insulin as background therapy) 
meeting protocol-specified glycemic criteria (Table 2-2) must initiate blinded glycemic 
rescue therapy (sitagliptin or metformin) as specified in Table 2-3, Table 1-1 and Table 1-2.  
For patients on background insulin therapy, the insulin dose should not be up-titrated for Step 
1 rescue.
A patient must be rescued if:
- fasting fingerstick glucose measurements at home meet the rescue thresholds for three 
consecutive days and is confirmed by a FPG value obtained at an unscheduled visit from a 
local laboratory that meets rescue criteria (a split sample should be sent to the central lab);
OR
- a single FPG value from the central laboratory at any visit meets rescue criteria even if the 
patient does not report fasting fingerstick glucose values above the threshold.
In Rescue Step 1, study medication and rescue medication (both included in the same blister 
card) will be administered in a double-blind, double-dummy manner. 
Table 2-2
Glycemic Rescue Criteria
FFSG Thresholds 1
FPG Thresholds 2
After Week 2 through Week 4
>240 mg/dL (13.33 mmol/L)
>240 mg/dL (13.33 mmol/L)
After Week 4 through Week 8
>225 mg/dL (12.50 mmol/L)
>225 mg/dL (12.50 mmol/L)
After Week 8 through Week 14
>200 mg/dL (11.11 mmol/L)
>200 mg/dL (11.11 mmol/L) 
After Week 14 through Week 54
>180 mg/dL (10.00 mmol/L)
>180 mg/dL (10.00 mmol/L)
FFSG= fasting fingerstick glucose; FPG= fasting plasma glucose. 
1 The initial FFSG values that would trigger repeat FFSG measurements.  An FPG measurement will be triggered if 3 
consecutive FFSG values meet this criterion, and rescue will be initiated if the FPG is above threshold.
2- After assessing for patient compliance with study medication, perform confirmatory FPG if first a.m. fasting 
fingerstick glucose value is greater than the defined threshold on 3 consecutive days.
 
 
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Table 2-3
Protocol-Specified Glycemic Rescue Medication
Treatment Group
Rescue Step 1 (Blinded)
Rescue Step 2 (Open-label)1
Phase A
Sitagliptin
Metformin2
Insulin
Placebo
Metformin2
Insulin
Phase B
Sitagliptin
Metformin2
Insulin
Metformin3
Sitagliptin
Insulin
AHA= antihyperglycemic agent; DPP-4=dipeptidyl peptidase IV; GLP-1= glucagon-like peptide 1.
1If initiation of insulin is considered unacceptable for a given patient who is ≥18 years of age, an alternative oral 
AHA may be used at the discretion of the investigator. The use of open-label DPP-4 inhibitors, metformin, or 
GLP-1 receptor agonists, is prohibited for rescue. For patients on background insulin therapy if up-titration of 
insulin is unacceptable, no alternate oral AHA may be used and the patient will need to be discontinued from 
study medication (refer to Section 2.4.2.7). Patients <18 years of age for whom initiating insulin or uptitration of 
insulin for is considered clinically inappropriate will need to be discontinued from study medication.
2 Patients who are not able to tolerate a higher dose of metformin will have their dose reduced at an unscheduled 
visit and should continue on the maximal tolerated dose for the duration of the study.
3 Patients in the placebo/metformin arm who initiate metformin treatment in Phase B. 
Note: Even if rescued, patients will always take 5 tablets per day from one single blister card.
Note: For patients who are undergoing a MTT see Appendix 6.7.
Patients who initiated Step 1 blinded glycemic rescue therapy during Phase A will continue 
on their blinded study medication and blinded rescue therapy (contained in the same blister 
pack) for the remainder of the trial and initiate or uptitrate their dose of open-label insulin 
(Step 2 rescue) if they become eligible.
2.4.2.6.2
Rescue Step 2 (Open-Label)
Six weeks after initiating Rescue Step 1, and after considering patient compliance with 
blinded study medication as stated in Section 2.4.2.6, if the patient's glucose levels continue 
to meet glycemic thresholds presented in Table 2-2 the patient will continue taking the 
combination of blinded study therapy and blinded rescue medication from Rescue Step 1 and, 
in addition, will initiate or uptitrate their dose of open-label insulin therapy (Table 2-3).  The 
insulin regimen and dosing will be at the discretion of the investigator (based on accepted 
local, national or international guidelines for the indication and use of insulin).
For patients on background insulin therapy, insulin doses can be up-titrated for Rescue 
Step 2; the change in insulin dose would be at the discretion of the investigator.  Any change 
in insulin dose >15% of the screening dose for this purpose will be considered as “Rescue 
Step 2”. Six weeks after initiating Rescue Step 2 or Treat to Goal Step 2, for patients who are 
receiving basal insulin, the investigator can choose to add prandial insulin if deemed 
appropriate.
Note: Patients requiring transient (i.e., <14 days) initiation of insulin or an increase in their 
insulin dose (>15% of dose at baseline, for patients on background insulin therapy) due to an 
intercurrent illness will not be considered as having initiated Rescue Step 2.
 
 
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If initiation of insulin use is considered unacceptable for a given patient ≥18 years of age, an 
alternative oral AHA may be used at the discretion of the investigator (refer to 
Section 2.4.2.6).
Note: For patients who are undergoing an MTT see Appendix 6.7.
2.4.2.6.3
Treat-to-Goal Phase B
During Phase B (i.e., from Visit 8) A1C values will be unmasked to the investigator by the 
central laboratory if ≥7.0%.  Patients with fasting fingerstick glucose <180 mg/dL during 
Phase B, may at the discretion of the investigator, be treated to achieve a glycemic goal of 
A1C <7.0% (or as close to normal without significant hypoglycemia) if, in the investigator’s 
judgment, the patient has been compliant with study medication.  The procedures outlined in 
Sections 2.4.2.6.1 and 2.4.2.6.2 for initiating Step 1 rescue and Step 2 rescue respectively 
should also be used to implement Step 1 treat-to-goal (Table 2-4) and Step 2 treat-to-goal for 
an A1C ≥7.0%.
Treat-to-Goal Step 1
In order to achieve the glycemic goal of <7.0% (or as close to normal without significant 
hypoglycemia) during Phase B, those patients who did not initiate blinded glycemic rescue 
Step 1 during Phase A will be eligible to initiate blinded treatment to achieve an A1C of 
<7.0% (Treat-to-Goal- Step 1).
Note: For patients who are undergoing an MTT see Appendix 6.7.
Table 2-4
Blinded Treat-to-Goal- Step 1
Blinded Rescue Agent
Blinded Treatment Assignment
Sitagliptin 
Metformin 
Metformin
Sitagliptin
Treat-to-Goal Step 2 (Open-Label)
At least six weeks after initiating Rescue Step 1 or Treat-to-Goal Step 1, if the patient's A1C 
is ≥7.0%, the patient will continue taking the combination of blinded study therapy and 
medication from Step 1 and, in addition, may initiate or uptitrate their dose of open-label 
insulin therapy.
The insulin regimen and dosing will be at the discretion of the investigator.  The dose of 
insulin can be titrated to achieve the glycemic goal of A1C of <7.0%.  Patients for whom 
such up-titration cannot be safely achieved will be discontinued from study medication.
 
 
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Patients meeting glycemic rescue criteria for whom the addition or up-titration of open-label 
insulin (Treat-to-Goal Step 2) or alternate glycemic rescue medication is deemed clinically 
inappropriate by the investigator will be discontinued from study medication.
For patients on background insulin therapy, insulin doses can be up-titrated for Treat-to-Goal 
Step 2; the change in insulin dose would be at the discretion of the investigator.  Any change 
in insulin dose >15% of the screening dose for this purpose will be considered as “Treat-to-
Goal Step 2”. 
Note: Six weeks after initiating Rescue Step 2 or Treat to Goal Step 2, for patients who are 
receiving basal insulin, the investigator can choose to add prandial insulin if deemed 
appropriate.
If initiation of insulin use is considered unacceptable for a given patient ≥18 years of age, an 
alternative oral AHA may be used at the discretion of the investigator (refer to Section 
2.4.2.6).
2.4.2.7
Discontinuation
The SPONSOR should be immediately contacted when a patient is discontinued or study 
medication is interrupted because of an adverse event (AE) or a laboratory safety test 
abnormality. All patients will be followed until resolution (i.e., return to normal or patient’s 
baseline, or diagnosis determined, or course of abnormalities established) for any laboratory 
safety test abnormality resulting in discontinuation.
The reason for protocol-specified discontinuation from the study is listed below.
a) Informed consent withdrawn or patient requests discontinuation from study.
Reasons for protocol-specified discontinuation from study medication are listed below:
Note: Patients who discontinue study medication without withdrawing consent will have 
their diabetes managed as considered clinically appropriate by their primary doctor. Please 
see Section 3.2.3.19 for follow-up of these patients. Initiation of open-label AHA will not be 
considered as prohibited medication in these patients.
b) Hyperglycemia: Patients ≥18 years of age meeting glycemic rescue criteria >6 weeks 
after initiating Rescue Step 1 or Step 1 Treat-to-Goal, for whom:
1- the addition of open-label insulin or the addition of an alternate glycemic rescue 
medication (Rescue Step 2 or Treat-to-goal Step 2) is deemed clinically inappropriate 
by the investigator,
OR
2- up-titration of open-label insulin (Rescue Step 2 or Treat-to-goal Step 2) for 
patients on background insulin or for those who have initiated insulin at rescue or up-
titration of an alternate glycemic rescue medication is deemed clinically inappropriate 
by the investigator.
 
 
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Patients <18 years of age for whom initiating insulin or up-titration of insulin for 
Step 2 open-label rescue (Section 2.4.2.6.2) or for Step 2 Treat-to-Goal 
(Section 2.4.2.6.3) is considered clinically inappropriate will need to be discontinued 
from study medication.
c) Hypoglycemia: repeated (2 or more episodes since the prior study visit) FPG or 
fingerstick glucose <50 mg/dL (2.78 mmol/L) with or without symptoms of 
hypoglycemia or ≤70 mg/dL (3.89 mmol/L) with symptoms of hypoglycemia, and
without a reasonable explanation (such as increased physical activity and/or skipped 
meal).
Patients who are on open-label insulin (background or rescue therapy) or an alternate 
titratable oral agent for Rescue Step 2 or Treat to Goal Step 2 and meet these criteria 
can have their insulin/alternate agent dose reduced or interrupted at the investigator’s 
discretion and may continue in the study.
Note: The investigator should make sure the patient’s glucose meter and test strips 
are functioning accurately and that the test procedure is being correctly performed by 
the patient prior to discontinuation.
d) Elevation in alanine aminotransferase (ALT)/ aspartate aminotransferase (AST) 
ALT/AST 3-times the ULN as specified in Appendix 6.5.
OR
Elevations in ALT and/or AST ≥3-times the upper limit of normal with concurrent 
total bilirubin ≥2-times the upper limit of normal and alkaline phosphatase <2-times 
the upper limit of normal (see the guidance document entitled Event of Clinical 
Interest (ECI) Guidance for Potential DILI (Drug-Induced Liver Injury) in Clinical 
Trials in the Investigator Trial File Binder and refer to the ECI guidance in 
Section 3.4.6.2.).
e) eGFR that is consistently <50 mL/min/1.73m2.
Note:  A consistent value is defined as a repeat measurement performed as soon as 
possible (must be within 3 to 7 days of notification from the central laboratory).
f)
Requirement for one of the excluded medications listed in Section 3.2.1.
g) Pregnancy
Note: A positive urine pregnancy test requires immediate interruption of study 
medication until serum -hCG can be performed and found to be negative.  Patient 
must be permanently discontinued and followed per Sections 3.2.3.4 and 3.4.5, if 
pregnancy is confirmed by a positive serum pregnancy test.
h) Phase A: Patient develops any condition for which sitagliptin is contraindicated 
according to the approved labels in the country in which the study site is located.
 
 
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Phase B: Patient develops any condition for which metformin or sitagliptin is 
contraindicated according to the approved labels in the country in which the study site 
is located.
Note: Patients who have undergone Step-1 rescue in Phase A and all patients in Phase 
B should be discontinued if their serum creatinine or eGFR values contraindicate the 
use of metformin based on the local label.
i)
Any medical condition or personal circumstance which, in the opinion of the 
investigator, exposes the patient to risk by continuing in the study or does not allow 
the patient to adhere to the requirements of the protocol.
If a patient discontinues study medication, he/she should complete all discontinuation visit 
procedures as described in Section 3.2.3.22. Please refer to Section 3.2.3.19 on how to 
manage patients who discontinue study medication but who do not withdraw consent.
Note: For patients who are undergoing an MTT see Appendix 6.7.
2.4.2.8
Post-Study Telephone Follow-up
For all patients (except for those who withdraw consent), a post-study telephone follow-up 
call will be performed 14 days after the last dose of study medication (whether due to study 
completion or premature discontinuation from the study) to query for serious adverse events. 
If any serious adverse event requires a supplemental procedure, this should be performed as 
medically necessary (Refer to section 3.2.3.19).
2.4.3
Beginning and End of Study Definition
The study begins when the first patient signs the ICF. End of Study will be declared when the 
last patient completes the last study related phone call (ie, 2-week post-study phone call) or 
Visit, withdraws from the trial, or is determined to be lost to follow up. Note: 56 weeks after 
the last patient is randomized, any patient with an outstanding status will be declared as ‘lost 
to follow up’.
LIST OF EFFICACY / PHARMACOKINETIC / IMMUNOGENICITY, ETC., 
2.5
MEASUREMENTS
Efficacy measurements include laboratory assessment of: A1C, FPG, lipid panel, and
measures of beta cell function (change from baseline in HOMA-, proinsulin/insulin ratio, 
and, in a subset of patients who agree to undergo a standard meal challenge, 2-hour PMG and
indices of insulin secretion derived from C-peptide, insulin, and glucose profiles).
LIST OF SAFETY MEASUREMENTS
2.6
Safety assessments will include collection of adverse events, clinical evaluation (physical 
examination, vital signs, body weight), laboratory safety studies (blood chemistry, 
hematology, urine microalbumin/creatinine ratio, and urinalysis), visual oral examination, 
supplemental dental data, radiologic assessments (bone age), and growth assessments 
(measurement of height and calculation of BMI, growth velocity).  In addition, biochemical 
markers of bone turnover, calcitonin, CD26, IGF-1 and IGF-BP3 levels will be assessed.
 
 
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STATISTICAL ANALYSIS PLAN SUMMARY
2.7
Key elements of the statistical analysis plan are summarized below; the comprehensive plan 
is provided in Section 3.5 of the protocol details.
Details of the statistical analysis plan for the supplemental dental data sub-study will be 
provided in a separate document.
2.7.1
Efficacy Analyses
The primary endpoint, primary analysis population, and statistical method that will be 
employed for the efficacy analysis are presented in Table 2-5 below.
The primary efficacy hypothesis will be evaluated by comparing sitagliptin vs. placebo on 
change from baseline in A1C at Week 20.  No multiplicity adjustment is planned as there is a 
single comparison of 2 treatments using 1 endpoint in the primary hypothesis. Other efficacy 
analyses will be considered supportive and/or explanatory.  
Table 2-5
Summary of Analysis Strategy for Key Efficacy Endpoint
Endpoint/Variable
Statistical Method
Analysis 
Population
Missing Data 
Approach
Primary
A1C – Change from baseline at Week 20
cLDA
FAS
Model-based
A1C= hemoglobin A1c; cLDA= constrained longitudinal data analysis; FAS= full analysis set.
2.7.2
Safety Analyses
The All-Patients-as-Treated (APaT) population will be employed for safety analyses.  
Adverse events of symptomatic hypoglycemia and selected Gastrointestinal adverse events 
(diarrhea, nausea, abdominal pain [including discomfort], and vomiting) are pre-specified 
Tier 1 safety parameters for which p-values and 95% confidence intervals for between-
treatment differences in the percentage of patients with the adverse event of symptomatic 
hypoglycemia will be calculated using the Miettinen and Nurminen (M&N) method.
2.7.3
Power and Sample Size
This study will randomize at least 190 patients, but no more than 220 patients, including 
approximately 10 to 11 patients randomized to the metformin arm prior to its removal from 
the study design in amendment 5 to this protocol (P083-05).  Power calculations are based on 
90 patients in each of the sitagliptin and placebo treatment groups.  
A sample size of 90 patients per arm will be equivalent to an effective sample size of 82 
patients per arm at Week 20 in the power calculation for the primary hypothesis test using the 
cLDA model in the FAS population. 
 
 
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An effective sample size of 82 patients per arm will provide 82% power to detect a treatment 
difference of 0.5% at Week 24 (α=0.05, two-sided test) assuming the conditional standard 
deviation is 1.1 %. The half-width of the 95% CI is expected to be 0.34%.
Table 2-6 shows the power based on two true differences using α=0.05 (two-sided).
Table 2-6
Power for Superiority in Change from Baseline in A1C 
82 Effective Patients per Group and α = 0.05 (two-sided)
True Difference (%)
Standard Deviation (%)
Power (%)
0.6
1.1
93%
0.5
1.1
82%
 
 
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3. PROTOCOL DETAILS
RATIONALE
3.1
3.1.1
Background and Rationale for this Study
The incidence and prevalence of T2DM in the pediatric population is increasing worldwide 
[1-21].  While prevalence may vary by region, there appear to be common risk factors, 
including familial predisposition and sedentary lifestyle [22; 23].  Other known risk factors 
include race/ethnicity [5; 9-11], puberty [24-25], polycystic ovarian syndrome [26], and a 
history of abnormal intrauterine growth [5; 27; 28].  As in adults [29], T2DM in children is 
characterized by insulin resistance [30-32], beta-cell dysfunction (with a progressive decline 
in beta-cell function over time) [33-34], and overproduction of hepatic glucose [32] 
accompanied by elevated glucagon levels (especially following meals) [35].
T2DM is associated with the development of microvascular complications, particularly 
nephropathy [36-39], as well as the presence of several cardiovascular risk factors that 
increase the likelihood of early macrovascular complications in this population [3; 39-42].  
As in adults, blood glucose levels influence the development and progression of both the 
microvascular and likely macrovascular complications of T2DM [36; 43].  Therefore, given 
the substantial lifelong cumulative exposure to hyperglycemia for this population, the 
availability of effective therapies is necessary.
While lifestyle modification is effective [44], it is difficult to implement and maintain, and 
tends to benefit a relative minority of youths with T2DM [25; 44].  Metformin is the only 
broadly approved oral agent for first-line therapy when lifestyle modifications fail in youths 
with T2DM [45-47].  Although initially effective in lowering A1C, studies suggest that 35-
50% of pediatric patients need an additional agent within a year of diagnosis [48].  Since the 
development and progression of T2DM in youths is characterized by a rapid and progressive 
increase in insulin resistance and decrease in insulin production, along with overproduction 
of hepatic glucose and excessive levels of glucagon [30-31; 33; 49-50], the development of 
safe and effective agents that target various aspects of these key defects is important [51].
Sitagliptin, an orally active, well-tolerated, potent and selective inhibitor of dipeptidyl 
peptidase IV (DPP-4), provides glycemic improvement by increasing the concentration of 
incretin hormones, including the key glucoregulatory hormones, glucagon-like peptide 1 
(GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), which act to lower glucose 
through enhancement of insulin biosynthesis and release and suppression of glucagon 
secretion [52].  Based upon its mechanisms of action and the similar pathophysiology 
underlying T2DM in youths and adults, the favorable safety and efficacy profiles of 
sitagliptin are predicted to be similar for youths relative to adults.
 
 
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3.1.2
Rationale for Efficacy Endpoints
To assess longer-term glucose-lowering efficacy (weeks to months), A1C will be measured.  
Since A1C reflects 24-hour glucose concentrations—hence both fasting and post-meal 
glucose—this measure provides a more useful index of the glycemic efficacy of sitagliptin 
than FPG alone.  Moreover, A1C is the key glycemic parameter which correlates with 
reduction of risk of diabetic complications; hence, demonstration that sitagliptin lowers A1C 
is important in establishing the value of this medication in the management of patients with 
T2DM.  Fasting plasma glucose will also be followed at each visit to characterize the time 
course of glucose control.
In this study, a 9-point meal tolerance test (MTT) will be obtained to assess treatment effects
on fasting glucose, post-meal glucose and insulin secretion.  Samples for glucose, insulin, 
and C-peptide will be taken at each time point, and proinsulin at time 0. This test will use a 
standardized, predominantly solid meal. The response to a solid meal should better model the 
patient’s usual day-to-day food intake, and hence better predict the post-meal glucose control 
that sitagliptin can provide.
3.1.3
Rationale for Selection of Patient Population
This is a study designed to assess the safety and efficacy of sitagliptin in the pediatric 
population; because the safety of a new agent is best assessed in a drug naïve patient 
population, this study will enroll patients with T2DM who have not been on an AHA for 
≥12 weeks prior to Visit 1 and have inadequate glycemic control (A1C 6.5%-10%).  Since 
T2DM is not prevalent in children less than 10 years of age, this study will only include 
patients 10 to 17 years of age (inclusive) with T2DM.
A drug naïve population of pediatric patients 10 to 17 years of age with T2DM is an 
important population in which to assess the safety and efficacy profile of a new agent. 
However, a significant proportion of pediatric patients 10 to 17 years of age with T2DM are 
being treated with insulin alone, and despite being on insulin, have inadequate glycemic 
control [53-57].  Thus, the addition of sitagliptin to ongoing insulin therapy is a potential, and 
likely, treatment regimen in pediatric patients.  The safety and efficacy of the addition of 
sitagliptin to patients with inadequate glycemic control on insulin has already been 
established in adults, and a similar profile is expected in pediatric patients 10 to 17 years of 
age. Therefore, including insulin-using patients in this clinical trial will broaden the 
representativeness of the clinical trial population, and will allow the results to be more 
generalizable to a wider range of patients who could benefit from therapy with sitagliptin.
3.1.4
Rationale for Dose Regimen
Sitagliptin
The sitagliptin dose for this study was based on data from Protocol 081(A single-dose study 
to assess the pharmacokinetics, safety, and tolerability of sitagliptin in adolescents). This 
study evaluated single oral 50-, 100-, and 200-mg doses in adolescents with type 2 diabetes, 
and compared the pharmacokinetics of sitagliptin in this population with that in adult patients 
with diabetes (Protocol 005).  All doses were generally well-tolerated, with the 100-mg dose 
 
 
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meeting the prespecified primary hypothesis for similarity of sitagliptin AUC(0-) between 
adults and adolescents.  Furthermore, an exploratory PK/PD analysis indicated that the 
relationship between plasma sitagliptin concentration and DPP-4 inhibition is similar in 
adolescents and adults.
Metformin
The titration and dosing of metformin follows the guidelines in the label as well as clinical 
practice guidelines.  Metformin/metformin placebo will be started at 500 mg/day. The dose 
will be increased in 500 mg weekly increments up to a total daily dose of 1000 mg bid, if 
tolerated, by 3 weeks.
3.1.5
Rationale for Placebo Use
The placebo-control group is an essential arm in this trial, as it supports the evaluation of 
safety and efficacy of sitagliptin in youths 10 to 17 years of age (inclusive) with T2DM and 
inadequate glycemic control.  Glucose concentrations can change over time related to 
changes in diet, activity, and other factors, and hence a comparison to pretreatment baseline 
glucose concentrations, rather than to placebo treatment group glucose levels, would not 
accurately characterize the glucose-lowering efficacy of sitagliptin in this population.  Non-
placebo controlled, active-comparator studies provide important information, but the efficacy 
profile of an agent is best characterized by comparison to placebo, especially in the first such 
trial of the agent in the pediatric population.  Furthermore, in this first study of sitagliptin in 
this population, the safety profile of sitagliptin is best compared to placebo.  
Despite the importance of this placebo-controlled study in characterizing the safety and 
efficacy of sitagliptin in this population, the medical risk of inadequate glycemic control has 
been considered and efforts to limit this risk have been implemented in this protocol.  
Although long-term—that is, over years—inadequate glycemic control has been shown to 
increase the risk of diabetic complications, the risk of short-term inadequate control is likely 
to be much smaller.  To ensure that patients will not be exposed to poorer control for an 
undue period of time, strict glycemic rescue and discontinuation criteria have been included 
in the study design.  Progressively stricter glycemic rescue/discontinuation criteria will be 
implemented, so that patients with poorer glycemic control will be rescued early in the 
double-blind treatment period.  In addition, the placebo-controlled phase of this study (Phase 
A) will only last for 20 weeks, at the end of which all patients in the placebo group who have 
not met rescue criteria will be switched to active therapy (with metformin) in a blinded 
fashion.  Furthermore, all patients will receive initial counseling for diet and exercise and 
ongoing monitoring of diet and exercise and will be counseled to monitor fingerstick glucose 
concentrations so that they can be 'rescued' promptly, should they meet rescue thresholds; all 
of these measures are expected to reduce the duration of exposure to prolonged 
hyperglycemia.
 
 
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3.1.6
Future Biomedical Research
Merck will conduct Future Biomedical Research specimens collected 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 patients. 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, and/or to ensure that patients receive 
the correct dose of the correct drug at the correct time.  The details of this Future Biomedical 
Research sub-trial are presented in Appendix 6.13:  Collection and Management of 
Specimens for Future Biomedical Research.
3.1.7
Supplemental Dental Data Sub-Study
Note: Procedures for the Supplemental Dental Data Substudy do not apply to Brazil and 
Serbia.
The visual oral examination (VOE) is an agency-mandated binding element in MK-0431 
P083 based on pre-clinical findings observed in rats summarized below.   

In the 14-week oral range-finding study in rats, sitagliptin doses of 500 mg/kg/day, 
1000 mg/kg/day, 1500 mg/kg/day, and 2000 mg/kg/day provided exposures margins 
of approximately 58-, 132-, 181-, and 271 fold, respectively, over the therapeutic 
AUC in patients receiving 100 mg/day of 8.5 µM•hr.  Thickened upper incisors were 
seen in males and females at 1500 mg/kg/day and 2000 mg/kg/day beginning in Drug 
Week 10.  This change was also associated with degeneration of the incisor 
ameloblasts and odontoblasts and gingivitis noted histologically.  There were no 
changes noted in the molar or other, non-incisor, teeth.  Missing and broken upper 
incisors were also noted in males at 1500 mg/kg/day and males and females at 2000 
mg/kg/day beginning in Drug Week 11.  The broken teeth were considered secondary 
to the histologic findings in the teeth and gums.  The NOEL for this change in the 
continuously growing incisor teeth was 500 mg/kg/day (approximately 58 fold 
margin over the AUC at the clinical dose of 100 mg/day).

In the 2-year carcinogenicity study in rats, sitagliptin doses of 50 mg/kg/day, 
150 mg/kg/day, and 500 mg/kg/day providing exposure margins of approximately 6-, 
19-, and 58-fold, respectively, over the therapeutic AUC in patients receiving 
100 mg/day of 8.5 µM•hr.  There was a dose-dependent increase in treatment-related 
horizontal striped discoloration and lightened upper and/or lower incisors in both 
males and females at all doses.  The discoloration was first noted in Drug Week 31 
(discoloration) and Drug Week 53 (lightening) at 500 mg/kg/day with nearly all 
animals exhibiting both teeth signs by study termination.  At 150 mg/kg/day the 
discoloration was first noted in Drug Week 33 (males) or Drug Week 41 (females).  
At 50 mg/kg/day, only a few animals were observed with horizontal striped 
discoloration and/or lightened incisors by study termination.
 
 
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
These dental findings were limited to the continuously growing incisors of the rat.  
There were no changes observed in teeth of the mice in the 14-week range-finding 
study (doses up to 1000 mg/kg/day providing exposure of up to 2340 µM•hr) or in the 
2-year carcinogenicity study (doses up to 500 mg/kg/day providing exposure of 
597 µM•hr).  There was no evidence of developmental changes involving the teeth in 
the rabbit developmental toxicity studies.  The mouse and rabbit also have 
continuously growing incisors.  Further, these changes were not observed in the 
chronic dog or 3 month monkey studies conducted.  Based on these findings it is 
concluded that the findings related to the rat incisors noted in the 14-week oral range-
finding and carcinogenicity studies were species-specific findings.
The purpose of this sub-study is to augment the VOE data currently being collected in the 
main study P083. In addition, it will allow the dental data to be assessed by an independent
reviewer who is a trained pediatric dentist.
Patients participating in the main study, P083 (new, and ongoing patients on/off study 
medication), will be asked to participate in a Supplemental Dental Data Sub-Study.  Patients 
who completed 54 weeks of the main study (on/off study medication), including patients 
participating in MK-0431 P351 (a non-interventional follow-up study to MK-0431 P083), are 
also eligible to participate.  Patients who have withdrawn consent from P083 are not eligible.  
Note: Patients currently enrolled in MK-0431 P351 are also eligible to be contacted to 
participate in this sub-study.
Details of this sub-study are presented in Appendix 6.14: Supplemental Dental Data Sub-
Study.
STUDY PROCEDURES
3.2
Timing of laboratory specimens or specific procedures can be found in the Study Flow Chart 
(Section 1.7).
3.2.1
Concomitant Medication(s)/Treatment(s)
Patients with concomitant medical conditions (such as hypothyroidism, hypertension, and 
dyslipidemia) should be treated according to local guidelines.  Note:  It is the responsibility 
of the investigator to ensure that patients with concomitant medical conditions are: 1) treated 
according to local guidelines and 2) on a stable dose of thyroid medication regimen for at 
least 6 weeks prior to Visit 1 and/or a stable dose of lipid-lowering and antihypertensive 
medications for at least 4 weeks prior to Visit 1.
Note:  Thyroid medications to treat hyperthyroidism are prohibited.
Antihyperglycemic Medications
Double-blind study medication, and open-label insulin (background or rescue therapy), and 
alternate agents (other than metformin, or a DPP-4 inhibitor, or a GLP 1 receptor agonist) are 
 
 
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the only AHAs permitted in the study. Patients who discontinue study medication may be 
treated with antihyperglycemic medication as considered clinically appropriate.
Rescue and treat-to-goal medications indicated as part of the study protocol are explained in 
Section 2.4.2.6.
Lipid, Blood Pressure, and Thyroid Hormone Medications
Concurrent lipid lowering, antihypertensive, and thyroid hormone replacement medications 
are permitted, as detailed above.
Birth Control Medications
These medications are allowed, but patients should be on a stable regimen during placebo 
run-in and are expected to remain on a stable regimen during the double-blind treatment 
period (refer to Section 3.2.3.4 for further detail regarding contraceptive agents).  Note: 
Patients who initiate heterosexual activity during the study may begin hormonal 
contraception as detailed in Section 2.2.
Corticosteroids
Treatment for ≥14 consecutive days or repeated courses of pharmacologic doses of 
corticosteroids (oral, injectable/parenteral) is not permitted during the study.  Oral 
corticosteroids used for physiologic replacement therapy (i.e., in patients with adrenal 
insufficiency) and inhaled, nasal, and topical corticosteroids are allowed.
Note: Use or need for use of excluded medications will require consultation with the study 
investigator and the Sponsor.
Supplements
The use of herbal supplements and other so-called “natural products” should be discouraged 
for the duration of the study.  Patients who do not discontinue the use of such supplements 
should be instructed not to change the use or dose of the supplement for the duration of the 
study.  Patients should be instructed not to initiate new supplements for the duration of the 
study.
3.2.2
Diet/Activity/Other
At Visit 2/Week -1, the patient and parent/guardian will receive individualized diet 
counseling for weight maintenance consistent with the standard guidelines of the country of 
the investigational site (or other similar guidelines such as those from the ADA) for youths 
with T2DM from a dietitian or other qualified health care professional.  Detailed dietary 
information will not be captured in the study database.  Patients and parents/guardians will 
also be counseled to maintain a medically appropriate, routine exercise program; consistency 
and adherence to the recommended regimen of diet and exercise will be encouraged 
throughout the study, with monitoring of diet and exercise occurring at each scheduled study 
visit beginning at Visit 3/Day 1.
 
 
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3.2.3
Procedures
3.2.3.1
Monitoring of Glycemic Control
SMBG
Glucose meters will be supplied to all patients at Visit 2/Week -1 and the patient and 
parent/guardian will be instructed on the procedure for performing fingerstick glucose 
measurements.  The patient may record measurements in the fingerstick glucose log book.  
At a minimum, the patient and parent/guardian will be instructed to monitor fingerstick 
glucose concentrations (1) once daily (including at least 2 measurements a week before 
breakfast) and (2) whenever they have symptoms of hypoglycemia, and (3) during 
intercurrent illnesses. For patients on insulin (at randomization as background therapy, 
or if initiated for Step 2 glycemic rescue or Step 2 Treat to Goal), the investigator will 
counsel the patient and parent/guardian on the required frequency of home glucose 
monitoring based on locally accepted clinical practice guidelines.
During both the pre-randomization and double-blind treatment periods, patients and/or 
parents/guardians will be counseled to contact the study site (1) if patient experiences 
symptoms of low blood sugar or (2) for fingerstick glucose values ≤70 mg/dL (≤3.9 mmol/L) 
with or without symptoms (refer to Section 3.2.3.3).  For patients on insulin therapy, the dose 
of insulin should be down-titrated or interrupted if, in the opinion of the investigator, the 
hypoglycemia occurred in the absence of a readily apparent cause or precipitating factor. 
Further management of insulin doses will be at the investigator’s discretion. In addition, 
patients will be counseled to contact the study site for fasting fingerstick glucose values that 
meet glycemic rescue criteria (refer to Section 2.4.2.6.1) after randomization.
3.2.3.2
Monitoring for Ketonuria/Ketonemia
At Visit 2/Week -1, patients will be supplied with screening strips to monitor for 
ketonuria/ketonemia and the patient and parent/guardian will be instructed on their use.  
Patients and parents/guardians will be instructed to check the patient’s urine for ketones in 
the first morning void or blood for ketonemia at least once a week throughout the study.  
They will also check for ketones during intercurrent illnesses or if the patient’s fingerstick 
blood glucose is ≥400 mg/dL (22.2 mmol/L) at any time during the study.  If urine ketones 
are "moderate” or “large,” or if ketonemia is positive at any time during the study the patient 
and parent/guardian will be instructed to contact the study site immediately for further 
assessment.
3.2.3.3
Assessment and Management of Hypoglycemia
At Visit 2/Week -1, the site will review the symptoms of hypoglycemia with the patient and 
parent/guardian and advise them to promptly manage the hypoglycemia according to local 
clinical practice guidelines.  In addition, the site will counsel the patient and parent/ guardian 
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). However, treatment of the hypoglycemic symptoms should not be 
delayed if a fingerstick glucose measurement cannot be performed immediately.
 
 
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The patient and parent/guardian will be instructed to complete the provided hypoglycemia 
assessment tool(s) for any symptomatic episodes he or she believes may represent 
hypoglycemia.  If a fingerstick glucose has been obtained before or shortly (i.e., within a few 
minutes) after treating, the value should be recorded in the hypoglycemia assessment tool(s).
In addition, patients and parents/guardians will be instructed to record any fingerstick 
glucose values ≤70 mg/dL (≤3.9 mmol/L) on the hypoglycemia assessment tool(s) regardless 
of the presence of clinical symptoms.
Note: The hypoglycemia assessment tool(s) will be available in both an electronic format, 
and a paper format. The paper version consists of two parts: the “Low Blood Sugar 
Calendar” and the “Low Blood Sugar Notepad”. 
Note: The Hypoglycemia assessment tool should also be completed when the patient is away 
from home. If the patient is using the paper Notepad, the information should be transferred to 
the paper Low Blood Sugar Calendar later the same day.
Patients and parents/guardians will be instructed to contact the investigational site to report:

any episode of possible hypoglycemia resulting in symptoms,

any episode of hypoglycemia for which assistance was required (i.e., severe 
hypoglycemia, details provided on the hypoglycemia assessment tool(s), 

any episode of fingerstick glucose ≤70 mg/dL (≤3.9 mmol/L) with or without 
symptoms.
Note:  As indicated, the patients will record symptoms and/or fingerstick glucose 
measurements that they believe are related to hypoglycemia on the hypoglycemia assessment 
tool(s) with the assistance of the parent/guardian.  Each episode should be evaluated by the 
investigator and recorded on the Hypoglycemia Assessment (HA) electronic case report form 
(eCRF).  For episodes determined to be hypoglycemia (symptomatic or asymptomatic), and 
for all glucose values ≤70 mg/dL (3.9 mmol/L), regardless of whether they are considered an 
adverse event, the HA eCRF must also be completed.  Each event of symptomatic 
hypoglycemia must be reported as an adverse event on the adverse event eCRF.  Each 
episode of asymptomatic hypoglycemia considered by the investigator to be an adverse event 
should also be reported on the adverse event eCRF (refer to Section 3.4.7 for guidance on 
reporting). 
 
 
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Patients on Background Insulin Therapy
Patients on insulin should be counseled to contact the site if: a) a patient experiences 2 or 
more episodes of symptomatic hypoglycemia not requiring assistance within a 1-week time 
period; OR, b) patient experiences a single episode of hypoglycemia requiring assistance.
The dose of insulin should be down-titrated or interrupted if, in the opinion of the 
investigator, the hypoglycemia occurred in the absence of a readily apparent cause or 
precipitating factor. Subsequently, if the patient meets criteria for glycemic rescue, rescue 
Step 1 should be initiated in a blinded fashion (refer to Section 2.4.2.6.1) instead of 
increasing the insulin dose to the baseline dose.  After initiating Step 1 rescue, insulin dose 
should be adjusted based on the patients glycemic response; the dose of insulin can be 
increased for Step 2 rescue (refer to Section 2.4.2.6.2). Further management of insulin doses 
will be at the investigator’s discretion.
3.2.3.4
Pregnancy Testing and Contraception
Pregnancy Testing
All females participating in the study will have a urine pregnancy test at visits indicated in 
the Study Flow Chart (if required by an investigational site’s Institutional Review 
Board/Ethics Review Committee (IRB/ERC), a serum pregnancy test can also be obtained in 
addition to the urine pregnancy test).  A positive urine pregnancy test requires immediate 
interruption of study medication until serum -hCG is performed and found to be negative.  
Patients must be discontinued and followed (refer to Section 3.4.5.) if pregnancy is 
confirmed by a positive serum pregnancy test.
Contraception
Non-pregnant, non-breast-feeding females may be enrolled if they are considered unlikely to 
conceive.  Unlikely to conceive is defined as (1) not heterosexually active for the duration of 
this study, or (2) heterosexually active and willing to use adequate contraception.  Birth 
control methods can be either a barrier method and/or a hormonal method to prevent 
pregnancy, used throughout the study as defined in Section 2.2 and for 14 days after the last 
dose of study medication.
The following are considered adequate barrier methods of contraception: intrauterine device 
(IUD), diaphragm with spermicide, contraceptive sponge, or use of condom by partner.  
Appropriate hormonal contraceptives will include any registered and marketed contraceptive 
agent that contains an estrogen and/or a progestational agent (including oral, subcutaneous, 
intrauterine, vaginal, or intramuscular agents).
Patients should be informed that taking the study medication may involve unknown risks to 
the fetus (unborn baby) if pregnancy were to occur during the study and agree that in order to 
participate in the study they must adhere to the contraception requirement (described 
above) for the duration of the study.  If there is any question that a patient will not reliably 
comply with the requirements for contraception, she should not be enrolled into the study.
 
 
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3.2.3.5
Anthropometric Measurements
Body weight will be measured (to be performed in duplicate) using a calibrated digital scale.
Height will be measured (to be performed in triplicate) using a wall-mounted calibrated 
stadiometer.
Blood pressure and heart rate will be measured (to be performed in duplicate) using an 
electronic blood pressure monitor.
Waist circumference will be measured (to be performed in duplicate).
For details on measuring techniques, refer to Appendix 6.1.
3.2.3.6
Laboratory Monitoring
Patients should be fasting for at least 10 hours before Visits 1, 3, 8, 11, Rescue, and 
Discontinuation. Fasting is not required prior to other visits.
All laboratory tests outlined in the Study Flow Chart (e.g., FPG, A1C, CBC, chemistry panel, 
lipid panel, TSH, etc.) and the blood samples for glucose collected during the MTT will be 
performed by the central laboratory (with the exception of the site fingerstick A1C, site and 
patient fingerstick glucose determinations, site dipstick urinalysis, pregnancy test, CD26 
assay and diabetes autoantibody panel).
Glycemic measurements will be masked during the double-blind treatment period for A1C, 
FPG, and MTT measurements.  Masking will occur after Visit 3/Day 1.  However, in order 
for the investigator to perform an evaluation for possible glycemic rescue and/or 
discontinuation, the central laboratory will report to the investigator in an unmasked manner 
any FPG laboratory value (and/or A1C value in Phase B) meeting rescue and/or 
discontinuation criteria (refer to Sections 2.4.2.6 and 2.4.2.7).  In addition, during Phase B, it 
is recommended that the investigator "treat-to-goal" if the patient's A1C is ≥7.0% as 
described in Section 2.4.2.6.3.
Laboratory test results for chemistry (e.g., ALT, AST, creatinine, eGFR) will not be masked, 
but will be flagged by the central laboratory if they meet protocol-specified exclusion and 
discontinuation criteria (refer to Section 2.3 and 2.4.2.7 respectively).
At or after Visit 3/Day 1, ALT and AST elevations greater or equal than 3-times the upper 
limit of normal (ULN) will be flagged by the central laboratory and patients will be retested, 
according to Appendix 6.5.
Further, CD26, IGF-1, IGF-BP3, and biochemical markers of bone turnover will be obtained 
(see Appendix 6.4).  Samples for the measurement of CD-26 expression may not be collected 
in all patients.  Throughout the study, CD26 values will remain masked to the patient and 
investigator. Information regarding any special procedures for the processing of these 
laboratory samples will be communicated separately.
 
 
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3.2.3.7
ECG Procedures
ECGs performed at baseline (performed at or after Visit 2/Week -1 up to and including Visit 
3/Week 0), Visit 8/Week 20, Visit 11/Week 54, Discontinuation Visit (if applicable), and 
Rescue Step 1 or Treat-to-Goal Step 1 Visit (if applicable) will be read locally, and will 
not be sent to a central ECG reading laboratory.
3.2.3.8
Meal Tolerance Test (MTT)
For parent/guardians and patients who agree to participate, an MTT will be performed at 
Randomization Visit 3/Day 1, at Visit 8/Week 20, and at Visit 11/Week 54 (and/or at the 
Rescue [Step 1 or Treat-to-Goal Step 1] Visit or Discontinuation Visit) after a standard 
meal.  Patients who participate in the MTT at Visit 8/Week 20 will be contacted by the site 
the day after the visit to collect the date and time that the first dose of Phase B study 
medication was taken.  The standard meal will consist of 1 can of a nutrition drink and 1 
nutrition bar supplied by the Sponsor (approximate total nutrient content: 460 kcal, 9 g fat, 
75 g carbohydrate, 18 g protein).  For a chart of procedural steps, blood samples and 
collection times for the MTT, refer to Appendix 6.7.
Note:  At Visit 8/Week 20, Visit 11/Week 54 or the Discontinuation Visit, an MTT should 
not be performed if the patient has been previously rescued.  An MTT should not be 
performed if the patient has been off double-blind study medication for ≥5 days, if the study 
medication was discontinued due to an adverse event, or if the visit occurs prior to Visit 
5/Week 4.
Note: Patients on background insulin therapy will not have the MTT performed.
3.2.3.9
Pediatric Quality of Life Inventory
The Pediatric Quality of Life Inventory (PedsQL) is a health-related quality of life measure 
consisting of a 23-item generic core scale plus disease-specific modules to be completed by 
the child and parent individually [58, 65]. The generic core scale and the 28-item diabetes 
module will be used in this study. The generic core scale includes questions on physical 
functioning (8 items), emotional functioning (5 items), social functioning (5 items), and
school functioning (5 items). The diabetes module includes questions on diabetes symptoms 
(11 items), treatment barriers (4 items), treatment adherence (7 items), worry (3 items), and 
communication (3 items).
Data from the PedsQL (Pediatric Quality of Life Inventory) provided at Screening will 
provide valuable quality of life epidemiologic data for this population, which may contribute 
to scientific literature.
The PedsQL will be administered at the baseline visit in countries where local validated 
translations are available.
Note: The PedsQL will not be administered to illiterate parents and their children.
 
 
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3.2.3.10 Tanner Staging Procedures
Tanner Staging will be performed in order to assess the physical measurements of sexual 
development. Tanner Staging will be performed at Visits 3, 8 and 11 or the Discontinuation 
Visit (if applicable), and Rescue [Step 1 or Treat-to-Goal Step 1] Visit (if applicable).  
Refer to Appendix 6.8 for details.
Note: if at any of the evaluations the patient’s sexual maturation is assessed as being Tanner 
Stage V, no further evaluations are needed during the study.
3.2.3.11 Visual Oral Examination Procedures
A visual oral examination (including inspection of the teeth) will be performed at Visits 3, 8,
and 11 or the Discontinuation Visit (if applicable), and Rescue [Step 1 or Treat-to-Goal 
Step 1] Visit (if applicable).  Refer to Appendix 6.10 for visual oral examination procedures 
and to Appendix 6.14 for supplemental dental data sub-study details. 
3.2.3.12 Bone Age Assessment Procedures
An X-ray of the left hand and wrist [standard postero-anterior (PA) view] will be obtained at 
Visits 3, 8, and 11 or the Discontinuation Visit (if applicable), and Rescue [Step 1 or 
Treat-to-Goal Step 1] Visit (if applicable). The bone age will be estimated based on the 
standards of Gruelich and Pyle by a central vendor. Details of the bone age assessment are 
available in a separate Independent Review Charter for this purpose. Baseline (Visit 3) and 
Visit 8 X-rays will be read upon receipt at the Central Vendor; if there is a status of “skeletal 
maturity” for either the Visit 3 or Visit 8 X-ray, then no further X-rays are required during 
the study.  See below for detailed guidance for specific study timepoints.
If a patient is rescued in Phase A:

If before Week 14, then no further X-ray is required for the rest of the study,

If between Week 14 and Week 20, an X-ray should be obtained at the Rescue [Step 
1 or Treat-to-Goal Step 1] Visit but none thereafter.
If a patient is rescued in Phase B:

If before Week 36, then no further X-rays are required for the rest of the study,

If at Week 36 or after, an X-ray should be obtained at the Rescue [Step 1 or Treat-
to-Goal Step 1] Visit but none thereafter.
If a patient is discontinued in Phase A: 

If before Week 14, then no further X-ray is required,

If between Week 14 and Week 20, an X-ray should be obtained at the 
Discontinuation Visit, but none thereafter.
 
 
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If a patient is discontinued in Phase B: 

If before Week 36, then no further X-ray is required,

If at Week 36 or after, an X-ray should be obtained at the Discontinuation Visit, but 
none thereafter.
3.2.3.13 Informed Consent
3.2.3.13.1 General Informed Consent
The investigator must obtain documented consent from the parent/guardian of each potential 
patient in biomedical research or when an investigational drug is administered to patients in 
this clinical study prior to any procedure.  In addition, documented assent forms must be 
obtained from the patients in this clinical study.
Consent must be documented by the dated signature of the parent/guardian of the patient 
along with the dated signature of the person conducting the consent discussion.  If the 
parent/guardian is illiterate, an impartial witness should be present when the entire informed 
consent and other written information is read and explained.  The impartial witness should 
sign and date the informed consent indicating that the explanation of the written information 
was accurate, consent by the parent/guardian was given freely and the parent/guardian 
verbally acknowledged that they understood the information.  Assent must be documented by 
the dated signature of the patient along with the dated signature of the person conducting the 
assent discussion.  A copy of the signed and dated consent and assent forms should be given 
to the patient and/or the parent/guardian before participation in the trial.
When the study population includes non-English speaking people, the information in the 
consent and assent forms should be translated and communicated to the patient in language 
understandable to the patient and parent/guardian.  Either the investigator or Sponsor may take 
the responsibility for the translation; however, documentation must exist to demonstrate who 
performed the translation and that the translation was verified by an individual other than the 
person who performed the translation. Accurately translated consent and assent forms should 
be provided with a written statement by the translator (whether the translator is the 
investigator or a professional translator), indicating that the consent and assent forms are an 
accurate translation of the accompanying English version.
The initial informed consent and assent forms, any subsequent revised written informed 
consent and assent forms, and any written information provided to the patient and/or 
parent/guardian must receive the IRB/IEC’s approval/favorable opinion in advance of use. 
The patient and parent/guardian should be informed in a timely manner if new information 
becomes available that may be relevant to the patient’s and/or parent's/guardian's willingness 
to continue participation in the trial. The communication of this information will be provided 
and documented via revised consent and assent forms or addendum to the original consent 
and assent forms.
 
 
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3.2.3.13.2 Consent and Collection of Specimens for Future Biomedical Research
The investigator or qualified designee will explain the Future Biomedical Research consent 
to the patient, 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 patient.
3.2.3.13.3 Collection of Specimens for Future Biomedical Research from Minors
Patients participating in this study should sign a separate assent form and their parents/ 
guardians should sign a separate consent form for the collection of future biomedical 
research samples.
3.2.3.13.4 Consent for the Supplemental Dental Data Sub-Study
The investigator or qualified designee will explain the Supplemental Dental Data Sub-Study 
to the parent/legal guardian and patient, answer all of his/her questions, and obtain written 
informed consent from the parent/legal guardian and written informed assent from the patient 
(if patient can legally consent, only his/her consent will be obtained), before performing any 
procedure or obtaining any data related to the Supplemental Dental Data Sub-Study.  A copy 
of the informed consent and assent will be given to the parent/legal guardian and patient. 
Refer to Appendix 6.14 for supplemental dental data sub-study details.
3.2.3.14 Future Biomedical Research Collection of Specimens
The following specimens are to be obtained as part of Future Biomedical Research:

Blood for genomics use

Blood for serum and plasma for future use
3.2.3.15 Assignment of Screening Number
A unique screening number will be assigned to all screened patients upon signing the 
informed consent.  The screening number identifies the patients for all procedures that occur 
prior to randomization.  Patients who are re-screened will retain the original screening 
number assigned at the initial screening visit.
3.2.3.16 Patient Identification Cards
All patients will be given a card, at Visit 2/Week -1, identifying them as participants in a 
research study.  The card will contain site contact information (including direct telephone 
numbers) to be utilized in the event of an emergency.
3.2.3.17 Stratification
Randomization at Visit 3 will be stratified by the patient’s insulin use at Visit 1 into the 
following two strata: (1) insulin user; (2) non-insulin user.
3.2.3.18 Randomization/Allocation
A single patient cannot be assigned more than 1 randomization number.
 
 
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3.2.3.19 Post-Study Follow-Up

Post-study Contact for Patients Who Have Completed the Study
Fourteen days after completion of the study, the patient will be contacted by telephone to 
assess for any serious adverse events that occurred after the administration of the last dose of 
study medication. The date of the telephone contact should be recorded and any serious 
adverse events that have occurred should be recorded in the Adverse Event eCRF.
If any serious adverse event requires supplemental procedures, they should be performed as 
medically necessary and recorded in the Procedures eCRF.
For patients who have completed the study prior to approval of amendment 12 (on/off study 
medication), including patients participating in P351, refer to Appendix 6.14 for 
supplemental dental data sub-study details. 

Follow Up of Patients Who Have Discontinued Study Medication Prior to Study 
Completion
Fourteen days after discontinuation of study medication, the patient will be contacted by 
telephone to assess for any serious adverse events that occurred after the administration of
the last dose of study medication.
After the 14 day post-study medication discontinuation telephone contact is made, patients 
who do not withdraw consent should:
1. return to the clinic for key visits (Week 20 and/or Week 54 as applicable) to have 
the following procedures performed: physical examination (including Tanner 
Staging), laboratory assessment of glycemic endpoints (A1C and FPG), and safety 
parameters (CBC, chemistry panel, urine microalbumin to creatinine ratio, and 
dipstick urinalysis), collection of adverse events, VOE, and dental photos (for patients 
who consent, see Section 6.14). Patients who are unable or unwilling to return to the 
clinic at key visits should be contacted by phone to obtain adverse events, 
concomitant medications and weight. For patients unable or unwilling to return to the 
clinic at key visits who receive their diabetes care from the study doctor, the A1C and 
FPG values will be obtained from their records, if available; such patients who 
receive their diabetes care from someone other than the study doctor should have 
their diabetes doctor provide A1C and FPG values, if available.   
2. be contacted by phone in a timeframe similar to their original study visit schedule 
at visits that are not key visits (i.e., not at Week 20 or Week 54), up until the patient 
has reached the Week 54 visit (i.e., the visit that is approximately 54 weeks from 
randomization Visit 3/Day 1). The purpose of these telephone contacts will be to 
assess for serious adverse events that occurred. The date of the telephone contact 
should be recorded and any serious adverse events that have occurred should be 
recorded in the eCRF.
 
 
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Note: Study sites must make all reasonable efforts to counsel the patient to stay in the study 
even if they discontinued the study medication, and make all reasonable efforts to contact the 
patient. Patients must be counseled regarding the importance of complete follow up, even 
when they are not continuing on study medication.  Sites should make at least three attempts 
to make telephone contact. If telephone contacts are not successful, sites should make at least 
two attempts to reach the patient via certified letter before considering the patient as lost to 
follow-up.
If any adverse event requires supplemental procedures, they should be performed as 
medically necessary and recorded in the Procedures eCRF.

Follow Up of Patients Who Have Discontinued From the Study Prior to Study 
Completion
Patients who withdraw consent and discontinue from the study will not be contacted by 
phone for additional follow-up.
Reasons for discontinuation are discussed further in Section 2.4.2.7.
3.2.3.20 Blinding/Unblinding
STUDY TREATMENT IDENTIFICATION INFORMATION IS TO BE UNMASKED 
ONLY IF NECESSARY FOR THE WELFARE OF THE PARTICIPANT. EVERY 
EFFORT SHOULD BE MADE NOT TO UNBLIND.
For emergency situations, where the investigator or delegate needs to identify the drug used 
by a patient and/or the dosage administered he/she will contact the emergency unblinding 
call center by telephone and make a request for emergency unblinding.  As requested by the 
investigator or delegate the emergency unblinding call center will provide the information to 
him/her promptly and report unblinding to the Sponsor.  Prior to contacting the emergency 
unblinding call center to request unblinding of a patient’s treatment assignment, the 
Investigator or delegate should make reasonable attempts to enter the intensity of the AEs 
observed, the relation to study drug, the reason thereof, etc., in the medical chart. If it is not 
possible to record this assessment in the chart prior to the unblinding, the unblinding should 
not be delayed.
In the event that unblinding has occurred, the circumstances around the unblinding (eg, date, 
reason, and person performing the unblinding) must be documented promptly, and the 
Sponsor Clinical Director notified as soon as possible.  Once an emergency unblinding has 
taken place, the principal Investigator, site personnel, and Sponsor personnel may be 
unblinded so that the appropriate follow-up medical care can be provided to the patient.
Patients whose treatment assignment has been unblinded by the Investigator/delegate and/or 
nonstudy treating physician must be discontinued from study drug, but should continue to be 
monitored in the study.  
 
 
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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 patient safety.
3.2.3.21 Interruption/Discontinuation/Withdrawal from Study Medication
If a patient who has initiated Step-1 rescue therapy in Phase A, or is in Phase B of the study 
undergoes an imaging study requiring the use of radiocontrast dye (for example, an 
intravenous pyelogram or computerized tomography study with contrast), all study 
medication should be interrupted for the time of the radiocontrast dye study (refer to the 
metformin label) because the patient may be on metformin (i.e., either on blinded metformin 
or matching metformin placebo). The patient’s renal function should be reassessed 48 hours 
after the procedure: all study medication should be re-instituted (at the same dose as prior to 
its interruption) only after renal function has been evaluated and found not to have been 
reduced by the dye study. In a patient requiring an imaging study, if considered clinically 
appropriate, studies not using radiocontrast dye (e.g., ultrasound, MRI with gadolinium 
contrast, or non-contrast CT studies) should be performed instead of radiocontrast dye 
studies, so as to avoid the interruption of all study medication.
The Sponsor should be immediately contacted when a patient is discontinued or study 
medication is interrupted because of an adverse event or a laboratory safety test abnormality.
Patients may discontinue at any time or be dropped from the study at the discretion of the 
investigator should any untoward effects occur. In addition, a patient may be discontinued by 
the investigator or the SPONSOR if he/she violates the study plan or for administrative 
and/or other safety reasons. The investigator or study coordinator must notify the SPONSOR 
immediately when a patient has been discontinued/ withdrawn due to an adverse event
(telephone or FAX). When a patient discontinues/withdraws prior to study completion, all 
applicable activities scheduled for the final study 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 3.4 SAFETY MEASUREMENTS - DETAILS.
3.2.3.21.1 Withdrawal from Future Biomedical Research
Patients may withdraw their consent for Future Biomedical Research and have their 
specimens and all derivatives destroyed. Patients may withdraw consent at any time by 
writing to the principal investigator for the main trial.  If medical records for the main trial 
are still available, the investigator will contact the Sponsor using the designated mailbox 
(clinical.specimen.management@merck.com), and a form will be provided by the Sponsor to 
obtain appropriate information to complete specimen withdrawal.  Subsequently, the patient'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 patient 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.
 
 
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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 agencies to retain the main trial records) or 
the specimens have been completely anonymized, there will no longer be a link between the 
patient’s personal information and their specimens.  In this situation, the request for 
specimen destruction cannot be processed.
3.2.3.22 Discontinuation Visit Procedures
Discontinuation Visit procedures should be performed on the following patients as soon as 
possible after discontinuing study medication:
-All randomized patients who stop double-blind study medication but remain in the study 
(discontinue from study medication)
-All randomized patients who withdraw consent (discontinue from the study)
At the Discontinuation Visit, patients will undergo the same procedures that they would at 
the final study visit, Visit 11/ Week 54, and at the Rescue [Step 1 or Treat-to-Goal Step 1] 
Visit. Refer to the Study Flow Chart, Section 1.7, for details.
In the subset of patients who have undergone an MTT at baseline, an MTT will be performed 
at the Discontinuation Visit. However, an MTT should not be performed if the patient has 
been rescued. Also, at the Discontinuation Visit, an MTT should not be performed if the 
patient has been off double-blind study medication for ≥5 days, if the study medication was 
discontinued due to an adverse event, or if the visit occurs prior to Visit 5/Week 4.
Note: the Discontinuation Visit is conducted for all patients who stop or discontinue study 
medication, but is only a study discontinuation visit for patients who are stopping study 
medication due to withdrawal of consent. All patients who stop study medication will be 
counseled and encouraged to remain in the study and to return to the site for the Week 20
and Week 54 visits, as applicable (described in Section 3.2.3.19).
3.2.3.23 Collect Substance Use Information
The use of tobacco (pack years) and alcohol should be collected.
3.2.3.24 Supplemental Dental Data Sub-Study
All sub-study procedures are outlined in Appendix 6.14.
EFFICACY MEASUREMENTS
3.3
3.3.1
Clinical and Laboratory Measurements for Efficacy
Efficacy measurements include laboratory assessment of: A1C, FPG, fasting insulin and 
proinsulin, lipid panel. In a subset of patients who agree to undergo the 9-point MTT, 
samples of C-peptide, insulin, and glucose will be collected at all time-points: proinsulin will 
only be collected at time 0.
 
 
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3.3.2
Medication Compliance
Adherence to treatment will be assessed by patient report which may be facilitated by tablet 
count as outlined in the Study Flow Chart (Section 1.7).  Every effort will be made to 
maintain adherence as close to 100% as possible.  If a patient is found to have reduced 
compliance (<85%), site personnel should begin frequent contacts with the patient and the 
parent/guardian to reinforce compliance with study medication.
SAFETY MEASUREMENTS
3.4
3.4.1
Clinical and Laboratory Measurements for Safety

Collection and assessment of adverse events, physical examination, vital signs and body 
weight/BMI/BMI percentile, as indicated in the Study Flow Chart (Section 1.7).

ECG will be collected and read locally.  The assessment of the ECG will be the 
investigator’s responsibility.

A standard hypoglycemia assessment tool(s) will be provided to the patient to collect 
hypoglycemia information.

Laboratory safety studies will include blood chemistry (including ALT, AST, creatine 
phosphokinase [CPK], total bilirubin, and alkaline phosphatase), calcitonin, CD26 assay, 
hematology (including complete blood count [CBC], differential, absolute neutrophil 
count and platelet count), urinalysis, urine microalbumin/creatinine ratio, and urine 
pregnancy testing (performed in all female patients).
For a complete list of laboratory measurements please refer to Appendix 6.4.

Visual oral examination, radiologic assessments (bone age), and growth assessments 
(measurement of height, calculation of growth velocity, TS, and serum IGF-1 and IGF-
BP3).

Biochemical markers of bone turnover:  urine (second AM void) N-terminal cross-linking 
telopeptide of bone collagen (NTX) and creatinine; and serum bone-specific alkaline 
phosphatase (Ostase assay).
3.4.2
Data Monitoring
3.4.2.1
Executive Oversight Committee
The Executive Oversight Committee (EOC) comprises members of Sponsor Senior 
Management.  The EOC will receive and decide upon any recommendations made by the 
Data Monitoring Committee (DMC) regarding the trial.
3.4.2.2
Data Monitoring Committee
To supplement the routine trial monitoring outlined in this protocol, an external DMC will 
monitor the interim data (including data from the Dental Sub-study) from this trial.  The 
voting members of the committee are external to the Sponsor.  The members of the DMC 
must not be involved with the trial in any other way (e.g., they cannot be trial investigators) 
 
 
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and must have no competing interests that could affect their roles with respect to the trial. 
The DMC will include 2 clinicians experienced in pediatric endocrinology and 1 external 
statistician; this is in addition to the unblinded trial statistician who will be a non-voting 
member of the committee.
The DMC will make recommendations to the EOC regarding steps to ensure both patient
safety and the continued ethical integrity of the trial. The DMC can recommend stopping the 
trial for either an unacceptable safety signal in one of the arms of the study or if in its opinion 
continuing double blind treatment is unethical.
Specific details regarding responsibilities and governance, including the roles and 
responsibilities of the various members and the Sponsor protocol team; meeting facilitation; 
the trial governance structure; and requirements for and proper documentation of DMC 
reports, minutes, and recommendations will be described in a separate charter that is 
reviewed and approved by the DMC.  The DMC will monitor the trial at an appropriate 
frequency, as described in the detailed DMC charter.  The DMC will also make 
recommendations to the Sponsor protocol team regarding steps to ensure both patient safety 
and the continued ethical integrity of the trial.
3.4.3
Recording Adverse Events
An adverse event is defined as any untoward medical occurrence in a patient or clinical 
investigation patient 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 
unfavorable 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 (ie, 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.
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 randomization must 
be reported by the investigator if they cause the patient to be excluded from the trial, or are 
the result of a protocol-specified intervention, including but not limited to washout or 
 
 
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discontinuation of usual therapy, diet, placebo treatment or a procedure. From the time of 
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 3.4.6. The investigator will make every 
attempt to follow all patients with non-serious adverse events for outcome.
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).
3.4.4
Definition of an Overdose for This Protocol
An overdose must be reported if any of the following occur during the conduct of the study:

Administration of 2 or more tablets per day (200 mg) of sitagliptin/matching 
placebo for more than 1 day.

Administration of more than 2 tablets per day (>200 mg) of sitagliptin/matching 
placebo.
For recommended management of acute overdose, please refer to the Investigator’s Brochure 
(IB).
Note:  Any overdose meeting above criteria whether or not associated with an adverse event
must be reported to headquarters’ personnel within 24 hours.
Investigators/site personnel are to consult the local, approved metformin product label for 
guidance on the definition of an overdose of metformin.
3.4.4.1
Reporting of Overdose to SPONSOR
If an adverse event(s) is associated with (“results from”) the overdose of test drug or vaccine, 
the adverse event(s) is reported as a serious adverse event, even if no other criteria for serious 
are met.
If a dose of test drug or vaccine meeting the protocol definition of overdose is taken without 
any associated clinical symptoms or abnormal laboratory results, the overdose is reported as 
a non-serious Event of Clinical Interest (ECI), using the terminology “accidental or 
intentional overdose without adverse effect.”
All reports of overdose with and without an adverse event must be reported by the 
investigator within 24 hours to the Sponsor either by electronic media or paper. Electronic 
reporting procedures can be found in the EDC data entry guidelines. Paper reporting 
procedures can be found in the Investigator Trial File Binder (or equivalent).
 
 
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3.4.5
Reporting of Pregnancy to Sponsor
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 patient 
(spontaneously reported to them) that occurs during the trial.
Pregnancies and lactations that occur after the consent form is signed but before 
randomization must be reported by the investigator if they cause the patient 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 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).
3.4.6
Immediate Reporting of Adverse Events to the SPONSOR
3.4.6.1
Serious Adverse Events
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 another 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 3-1 for additional details regarding each of the above criteria.
 
 
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For the time period beginning when the consent form is signed until randomization, any 
serious adverse event, or follow up to a serious adverse event, including death due to any 
cause, that occurs to any patient must be reported within 24 hours to the Sponsor if it 
causes the patient 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 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 patients with serious adverse events must be followed up for outcome.
3.4.6.2
Selected Non-serious Adverse Events
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 randomization, any 
ECI, or follow up to an ECI, that occurs to any patient must be reported within 24 hours 
to the Sponsor if it causes the patient 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 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:
- an overdose of Sponsor's product, as defined in Section 3.4.4 - Definition of an 
Overdose for This Protocol, that is not associated with clinical symptoms or abnormal 
laboratory results.
- an elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of 
normal and an elevated total bilirubin lab value that is greater than or equal to 2X the 
upper limit of normal and, at the same time, an alkaline phosphatase lab value that is less 
than 2X the upper limit of normal, as determined by way of protocol-specified laboratory 
testing or unscheduled laboratory testing.*
 
 
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*Note: These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may require 
an additional evaluation for an underlying etiology. The trial site guidance for assessment 
and follow up of these criteria can be found in the Investigator Trial File Binder (or 
Administrative Binder, or equivalent).
3.4.7
Guidance on Adverse Events Related to Glycemia
3.4.7.1
Hyperglycemia
An adverse event of hyperglycemia requires that a patient have one or more symptoms 
(e.g., increased thirst, polyuria) typically associated with an increased glucose level.  At 
the discretion of the investigator, this may be captured as an adverse event of 
“hyperglycemia.”  This diagnosis may be supported by, but does not require, results from 
a glucose meter or the study central laboratory.  Further, at the discretion of the 
investigator, an elevated blood glucose value without associated symptoms that is 
considered to be an adverse event may be reported as an adverse event of "increased 
blood glucose."  General guidance regarding the determination as to whether an event is 
considered to be an adverse event should be followed (refer to Section 3.4.8).
3.4.7.2
Hypoglycemia
3.4.7.2.1
Documentation
Regardless of whether an episode is considered an adverse event, the HA eCRF must be 
completed for the following:

all episodes determined by the investigator to be hypoglycemia (symptomatic or 
asymptomatic)

all glucose values ≤70 mg/dL (≤3.9 mmol/L)
3.4.7.2.2
Guidance
All episodes considered as likely to represent symptomatic hypoglycemia by the 
investigator must be captured as an adverse event of “hypoglycemia”.  This diagnosis 
may be supported by, but does not require, confirmatory blood glucose results (such as 
those measured using a fingerstick or from a clinical laboratory sample).  Further, at the 
discretion of the investigator, an asymptomatic blood glucose value ≤70 mg/dL 
(3.9 mmol/L) may be reported as an adverse event of “asymptomatic hypoglycemia”.  
General guidance regarding the determination as to whether an event is considered to be 
an adverse event should be followed (refer to Section 3.4.8).
3.4.8
Evaluating Adverse Events
Refer to Table 3-1 for instructions in evaluating adverse events.
 
 
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Table 3-1
An investigator who is a qualified physician, will evaluate all adverse events as to:
Maximum
Mild
awareness of sign or symptom, but easily tolerated  (for pediatric studies, awareness of symptom, but easily tolerated)
Intensity
Moderate
discomfort enough to cause interference with usual activity (for pediatric studies, definitely acting like something is wrong)
Severe
incapacitating with inability to work or do usual activity (for pediatric studies, extremely distressed or unable to do usual activities)
Seriousness
A serious adverse event is any adverse event occurring at any dose that:
†Results in death; or
†Is life threatening; or places the subject/patient, 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 [including hospitalization for an elective procedure] for a preexisting condition which has not worsened 
does not constitute a serious adverse event.); or
†Is a congenital anomaly/birth defect (in offspring of subject/patient 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/patient 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 test drug to be discontinued?
Relationship to 
test drug 
Did the test drug cause the adverse event?   The determination of the likelihood that the test drug 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 test drug and the AE; the greater the correlation with the components and their respective 
elements (in number and/or intensity), the more likely the test drug caused the adverse event (AE):
Exposure
Is there evidence that the subject/patient was actually exposed to the test drug 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 test drug? 
Is the time of onset of the AE compatible with a drug-induced effect?
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 test drug and the AE:  (continued)
to test drug
(continued)
Dechallenge
Was the dose of test drug discontinued or 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 test 
drug; or (3) the study is a single-dose drug study.)
Rechallenge
Was the subject/patient reexposed to the test drug in this study?
      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 study is a single-dose drug study.)
NOTE:  IF A RECHALLENGE IS PLANNED FOR AN ADVERSE EVENT WHICH WAS SERIOUS AND WHICH MAY HAVE BEEN CAUSED BY 
THE TEST DRUG, OR IF REEXPOSURE TO THE TEST DRUG POSES ADDITIONAL POTENTIAL SIGNIFICANT RISK TO THE 
SUBJECT/PATIENT, THEN THE RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE U.S. CLINICAL MONITOR AND THE 
INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE.
Consistency with 
Study Drug 
Profile
Is the clinical/pathological presentation of the AE consistent with previous knowledge regarding the test drug 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 drug relationship).
Yes, there is a reasonable possibility of 
drug relationship.
There is evidence of exposure to the test drug.  The temporal sequence of the AE onset relative to the administration of the test drug is reasonable.  The AE is 
more likely explained by the test drug than by another cause.
Depending on data collection method employed, drug relationship may be further graded as follows:
Definitely related 
There is evidence of exposure to the test drug.  The temporal sequence of the AE onset relative to administration of the test drug is reasonable.   The AE is 
more likely explained by the test drug than by another cause.  Dechallenge is positive.  Rechallenge (if feasible) is positive.  The AE shows a pattern consistent 
with previous knowledge of the test drug or test drug class.
Probably related 
There is evidence of exposure to the test drug.  The temporal sequence of the AE onset relative to administration of the test drug is reasonable.  The AE is more 
likely explained by the test drug than by another cause.  Dechallenge (if performed) is positive.
Possibly related 
There is evidence of exposure to the test drug.  The temporal sequence of the AE onset relative to administration of the test drug is reasonable.  The AE could 
have been due to another equally likely cause.  Dechallenge (if performed) is positive.
No, there is not a reasonable possibility 
of drug 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.)
Depending on data collection method employed, drug relationship may be further graded as follows:
Probably not 
related 
There is evidence of exposure to the test drug.  There is another more likely cause of the AE.  Dechallenge (if performed) is negative or ambiguous.  
Rechallenge (if performed) is negative or ambiguous.
Definitely not 
related 
The subject/patient did not receive the test drug.   OR    Temporal sequence of the AE onset relative to administration of the test drug is not reasonable.   OR   
There is another obvious cause of the AE.
 
 
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3.4.9
SPONSOR Responsibility for Reporting Adverse Events
All adverse events will be reported to regulatory agencies, IRB/IECs, and investigators in 
accordance with all applicable global laws and regulations.
STATISTICAL ANALYSIS PLAN (SAP)
3.5
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, along with an explanation as to when and why they occurred, will be listed in the 
Clinical Study Report (CSR) for the study.  Post-hoc exploratory analyses will be clearly 
identified in the CSR. Details of the analysis of data from the supplemental dental sub-study 
will be provided in a separate document.
3.5.1
Responsibility for Analyses/In-House Blinding
The statistical analysis of the data obtained from this study will be the responsibility of the 
Sponsor. This study (both the Phase A and Phase B periods) will be conducted as a double-
blind study under in-house blinding procedures. At the end of the Phase A period, a copy of 
the database will be frozen after medical/scientific review has been completed, and Phase A 
data have been declared final and complete.  Members of the study team will be unblinded in 
order to review and perform an analysis of all available data at the time of the database lock
as well as author a CSR. This analysis addresses the primary hypothesis and, hence, is not an 
interim analysis. This first CSR will include the analysis of all Phase A (Week 0 to Week 20) 
data and all available data for Phase A+B (Week 0 to Week 54) at the time of this first
database lock.   
A separate, blinded (ie, blinded to participant-level treatment assignment) SPONSOR study 
team that has been identified will continue monitoring the conduct of the remaining Phase B 
study period. All personnel who are unblinded following the first database lock will be 
excluded from any future data review at the individual participant level.  At the end of the 
54-week study, the second database lock will occur after medical/scientific review has been 
performed, and data have been declared final and complete. A separate CSR will be prepared 
after the second database lock. This second CSR will include the analysis of all Phase A+B 
(Week 0 to Week 54) data.     
3.5.2
Hypotheses/Estimation
Objectives and hypotheses of the study are stated in Section 2.1.
3.5.3
Analysis Endpoints
Safety and efficacy endpoints that will be evaluated are listed below. The baseline value will 
be defined as the Visit 3/Week 0/Day 1 (randomization) measurement.  If this measurement 
is not available, the last available pretreatment value will be used as the baseline value.  If no 
 
 
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pre-treatment measurement is available, the baseline value will be treated as missing. The 
primary time point of the study is Week 20.
3.5.3.1
Efficacy Endpoints
The descriptions of the efficacy measurements and time points at which they are measured 
are described in Section 3.3 and Section 1.7 respectively.  The efficacy endpoints to be 
analyzed are listed in Table 3-2. All of these endpoints will be analyzed at the Week 20 and 
Week 54 time points. In addition, change from baseline in A1C will be analyzed at Week 14. 
Week 20 is the primary time point for efficacy analysis.
Table 3-2
Efficacy Endpoints
Endpoint Assessing Primary Hypothesis
Change from baseline in A1C at Week 20
Secondary Endpoints
Change from baseline in A1C at Week 54
Proportion of patients with A1C at goal (<7.0%, <6.5%) at Week 20 and Week 54
Change from baseline in fasting endpoints at Week 20 and Week 54:

FPG

Insulin

Proinsulin

Proinsulin / Insulin Ratio

Homeostatic Model Assessment of β-cell function 

Homeostatic Model Assessment of insulin resistance
Change from baseline in 2-Hour PMG
Change from baseline in AUC endpoints (Total AUC and Excursion AUC) at Week 20 and Week 54: 

Glucose

Insulin

C-peptide

Insulin AUC / Glucose AUC
Proportion of patients initiating glycemic rescue therapy by Week 20 and Week 54
Additional Endpoints
Change from baseline in A1C at Week 14
Time to initiation of glycemic rescue therapy at Week 20 and Week 54
Change from baseline in endpoints using the C-peptide minimal model at Week 20 and Week 54
Change from baseline in endpoints derived from 9-point MTT at Week 20 and Week 54  
Percent change from baseline in lipid panel at Week 20 and Week 54:

Triglycerides

LDL-C

HDL-C

Non-HDL-C

Total cholesterol 
A1C= hemoglobin A1c; AUC=Area under the curve; FPG= fasting plasma glucose; HDL-C= high 
density lipoprotein cholesterol; LDL-C= low density lipoprotein cholesterol; PMG= post meal glucose. 
If FPG is missing at visits where meal tolerance test (MTT) data are collected, FPG will be 
the average of the -10 minute and 0 minute measurements from the MTT.
 
 
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3.5.3.2
Safety Endpoints
The descriptions of the safety measurements and time points at which they are measured are 
described in Section 3.4.1 and Section 1.7 respectively. Tier 1 safety endpoints are listed in 
the Table 3-4.
Part of the assessment of laboratory safety will be accomplished by defining limits of change 
for particular tests such that occurrences of patient values beyond these bounds are considered 
abnormal.  Limits of change criteria are provided in Appendix 6.6.  These criteria are based 
upon elevations considered to be clinically meaningful relative to the laboratory normal 
ranges.
3.5.3.3
Derivation of Efficacy Endpoints
Computational details for efficacy endpoints listed in Table 3-2 are provided below:

HOMA-β = 20×fasting insulin (in mcIU/mL) ÷ {[FPG (in mg/dL)/18] – 3.5}

HOMA-IR = fasting insulin (in mcIU/mL) × FPG (in mg/dL) / (22.5×18)

AUC endpoints will be derived via the trapezoidal rule using 9-point MTT 
measurements.  

Excursion AUC = incremental AUC above the level at the start of the meal.  AUC below 
the level at the start of the meal will not contribute to the Excursion AUC.

2-Hour incremental PMG = Glucose at 120 minutes – glucose at 0 minutes

Endpoints derived from 9-point MTT using the C-peptide minimal model
-
Static sensitivity to glucose (Φs): the effect of glucose concentration on beta-cell 
secretion
-
Dynamic sensitivity to glucose (Φd): the effect of the rate of change of glucose on 
insulin secretion when glucose concentration is increasing and above basal level
-
Overall sensitivity index (Φ): average insulin secretion rate ÷ average glucose 
simulation, calculated as a function of Φs, Φd, and Φb
-
Composite index of insulin sensitivity (ISI): 10,000/sqrt [(FPGFPI) (mean 
glucose concentration during the meal × mean of insulin concentration during the 
meal)]  
-
Disposition indices: beta-cell function accounting for insulin sensitivity

Static (DIs) = sISI

Dynamic (DId ) = dISI 

Overall (DI) = ISI
 
 
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
Insulinogenic index = [insulin (in mcIU/mL) at 30 min. insulin (in mcIU/mL) at 0 min.] 
/ [glucose (in mg/dL) at 30 min. glucose (in mg/dL) at 0 min.]

For analyzing the ratio of proinsulin to insulin, insulin data in mcIU/mL will be 
converted to mmol/L by multiplying by 6.945.
3.5.3.4
Derivation of Safety Endpoints

Bone age: The average of 2 readings at each time point will be used, unless the bone 
age is adjudicated. In situations where adjudication is required, the bone age specified 
by the adjudicator will be used (see details in the Independent Review Charter). 

Growth Velocity for chronologic age = Change from Baseline in Height/Change from 
Baseline in Chronologic Age

Growth Velocity for bone age = Change from Baseline in Height/Change from 
Baseline in Bone Age

BMI percentile: The percentile of BMI derived from the BMI-for-age percentile 
charts defined in Appendix 6.9.

Skeletal maturation = Change from Baseline Bone Age/Change from Chronologic 
Age. 

The derivation of dental safety endpoints will be provided in the P083 Dental 
Analysis Plan.
3.5.4
Analysis Populations
3.5.4.1
Efficacy Analysis Populations
The Full Analysis Set (FAS) population will serve as the primary population for the analysis 
of efficacy data. The FAS population will include all randomized patients who took at least 
one dose of study medication (except as noted in Appendix 6.12 for a patient who was 
randomized twice).  
For analyses using the longitudinal data analysis (LDA) model, patients must also have at 
least one measurement of the relevant analysis endpoint, either at baseline or post-baseline.  
For analyses that use the analysis of covariance (ANCOVA) model, patients must also have a 
baseline measurement. 
All patients randomized within the incorrect stratum for insulin use will be classified 
according to the stratum they should have been randomized to in all analyses that include the 
stratification factor of insulin use. The intended stratum will be derived based on insulin use 
at Visit 1/Screening. An accounting of incorrectly stratified patients will be provided in the 
CSR.
 
 
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For analyses of endpoints unique to the 9-point MTT, the analysis population will include 
only those patients who participated in the 9-point MTT.
For all efficacy analyses, patients will be counted in the treatment group to which they were 
randomized, regardless of the treatment received during the course of the trial.  
3.5.4.2
Safety Analysis Populations
The All Patients as Treated (APaT) population will be used for the analysis of safety data in 
this study.  The APaT population consists of all randomized patients who took at least one 
dose of study treatment (except as noted in Appendix 6.12 for a patient who was randomized 
twice). Patients will be included in the treatment group corresponding to the study treatment 
they actually took for the analysis of safety data using the APaT population.  This will be the 
treatment group to which they were randomized, except for any patients who took incorrect 
study treatment for the entire treatment period.  Such patients 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.
3.5.5
Statistical Methods
Statistical testing and inference for safety analyses are described in Section 3.5.5.2.  Efficacy 
results that will be considered to be statistically significant after consideration of the strategy 
for controlling the Type I error are described in Section 3.5.6, Multiplicity.  Nominal p-
values may be computed for other efficacy analyses as a measure of strength of association 
between the endpoint and the treatment effect rather than formal tests of hypotheses.  All 
statistical tests will be conducted at the α=0.05 (2-sided) level.
Analyses will be performed for Phase A (Week 0 to Week 20) and Phase A+B (Week 0 to 
Week 54). In addition, change from baseline in A1C will be analyzed at Week 14. Between-
group comparisons (sitagliptin vs. placebo) for all efficacy and safety endpoints will be 
performed for Phase A analyses only. The Week in the analysis is derived by mapping the 
relative day ranges listed in Appendix 6.11.
Data from patients already randomized to the metformin arm in P083 under previous 
amendments (from P083-01 to P083-04) will be summarized separately from the summaries 
and analyses addressing the objectives of the current protocol amendment. Data from patients 
who were randomized to placebo in Phase A followed by the sequence of either sitagliptin or 
metformin (for either rescue in Phase A, or the switch in Phase B, whichever is earlier) 
before amendment P083-05 implementation will be combined and included in the Phase A 
analysis as the Placebo Group. The data for patients who were randomized in Phase A to the 
sequence of placebo followed by sitagliptin and who initiated sitagliptin in Phase B before 
amendment P083-05 was initiated will be summarized separately in the Phase A+B analyses.
 
 
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3.5.5.1
Statistical Methods for Efficacy Analyses
There will be two estimands for the analysis of A1C, Treatment Effect (TE) and Treatment 
Policy (TP).  The primary hypothesis will be tested using the TE estimand with the TP 
estimand providing a supplemental analysis, except where regulatory practice requires the TP 
estimand, the TP estimand will constitute the test of the primary hypothesis and the TE 
estimand will be a supplemental analysis. 
The TE estimand consists of the following elements:

Target population: Pediatric patients (age 10 to 17 years, inclusive) with T2DM who 
have inadequate glycemic control

Endpoint: Mean change from baseline in A1C at Week 20  as if all patients remained 
on treatment

Intercurrent event: data obtained after discontinuation of treatment or after taking 
rescue medication are not relevant to this estimand

Measure of intervention effect: difference in endpoint means comparing randomized 
treatments (sitagliptin versus placebo)
The TP estimand consists of the following elements:

Target population: Pediatric patients (age 10 to 17 years, inclusive) with T2DM who 
have inadequate glycemic control

Endpoint: Mean change from baseline in A1C at Week 20 

Intercurrent event: regardless of whether study medication or rescue medication was 
taken up to Week 20

Population level-summary: difference in endpoint means comparing the effect of 
being randomized to treatment (sitagliptin versus placebo)
Accordingly, analyses corresponding to the TE estimand will exclude data after the last dose 
of study medication (plus a 5-day offset) as well as data after the initiation of rescue 
medication.  Analyses corresponding to the TP estimand will include all available data at the 
Week 20 timepoint, including data after the last dose of study medication in any patient who 
remains in the study after discontinuing study medication.
Phase A (Week 0 to Week 20)
The primary efficacy analyses will compare sitagliptin to placebo in change from baseline in 
A1C at Week 20.
Primary Endpoint:  TE Estimand
To address the primary hypothesis using the TE estimand, the mean change from baseline in 
A1C at Week 20 in the sitagliptin group will be compared to that in the placebo group using 
the estimated treatment difference via a constrained longitudinal data analysis (cLDA) 
model, proposed by Liang and Zeger [59].  This cLDA model assumes a common baseline 
 
 
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mean across treatment groups within each stratum (insulin use at screening) and a different 
mean for each treatment at each of the post-baseline time points. In this model, the response 
vector consists of baseline values and the values observed at each post-baseline time point.  
The cLDA model will include terms for treatment, time, baseline BMI percentile, insulin use 
at screening (yes/no), and the interaction of time by treatment, unless the model fails to 
converge.  To ensure model convergence, the stratification factor, insulin use, will be 
removed from the model if necessary.  Time will be treated as a categorical variable so that 
no restriction is imposed on the trajectory of the means over time. The treatment difference in 
terms of mean change from baseline to a given time point will be estimated and tested from 
this model.  An unstructured covariance matrix will be used to model the correlation among 
repeated measurements. 
For the cLDA model, the Kenward-Roger adjustment will be used with restricted (or 
residual) maximum likelihood (REML) to make proper statistical inference. An unstructured 
covariance matrix will be used to model the correlation among repeated measurements and 
hence avoids the potential bias that could result from the use of specific structured covariance 
models. If the unstructured covariance model fails to converge with the default Newton-
Raphson algorithm, the Fisher scoring algorithm or other appropriate methods can be used to 
provide initial values of the covariance parameters. In the rare event that none of the above 
methods yield convergence, a structured covariance such as Toeplitz can be used to model 
the correlation among repeated measurements. In this case, the empirical option will be used 
because the sandwich variance estimator is asymptotically unbiased while the model-based 
variance estimator can substantially overestimate or underestimate the true variance. The 
cLDA model uses the maximum likelihood principle to estimate the parameters and account 
for missing data in an implicit fashion.
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 within each stratum.  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 patients who are 
missing either the baseline or post-baseline measurements, thereby increasing efficiency. 
Change from baseline in A1C at Week 14 will also be assessed from the same cLDA model 
used for the analysis at Week 20.
Primary Endpoint:  TP Estimand
The primary endpoint of A1C will be analyzed using analysis of covariance (ANCOVA) to 
evaluate the TP estimand.  The ANCOVA model will include terms for treatment, insulin use 
at screening (yes/no), and covariates for baseline BMI percentile, and baseline A1C value.  
Any terms dropped from the cLDA model due to convergence issues will also be dropped 
from the ANCOVA model.  A retrieved-dropout (RD) approach for missing data imputation 
 
 
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will be used if feasible. The RD approach will assume that missing Week 20 data for patients 
who discontinued study medication can be represented by the observed Week 20 data for 
patients in the same arm who discontinued study medication but remained in the study.
The RD analysis will use patients who discontinued from study medication but had Week 20 
A1C measurement as reference group to impute the missing Week 20 data for patients who 
were in the same arm and discontinued the study medication and had no Week 20 data.
The following steps will be taken to perform the RD analysis:
1. All patients who did not adhere to study medication prior to Week 20 will be 
classified according to their pattern of protocol deviation (from the assigned treatment 
plan) defined by the time of discontinuation from study medication, and a separate 
A1C profile will be assumed for each deviation pattern for each treatment group. 
There will be four possible deviation patterns by last dose of study medication (A: 
Week 20; B: 14 to <20 weeks; C: 8 to <14 weeks; D: 0 to <8 weeks). 
2. Assume that the repeated A1C measures follow a multivariate normal distribution 
with a different mean profile and common variance covariance matrix for each 
deviation pattern and each treatment group.
3. For each deviation pattern and each treatment group, assume that the distribution of 
missing values is same as the distribution of observed values among patients who did 
not adhere to study medication but remained in the study and had an observed A1C 
value at Week 20.
4. Based on the assumptions and the non-informative prior distributions for the mean 
profiles and variance-covariance matrix described above, the imputed Week 20 
values for each patient will be drawn from the posterior distribution of missing 
values.
5. A set of K (K=100) ‘complete’ datasets will be created from the imputation. An 
ANCOVA model as presented previously will be used to analyze each of the 
‘complete’ datasets and perform the final inference, combining the resulting 
parameter estimates and standard errors following Rubin’s rule.
In order to perform the RD analysis, each reference group (combination of deviation pattern 
and treatment group) that has one or more patients with missing data must contain at least 
one RD patient.
In these studies, patients were not required to return for clinic visits when discontinued from 
study medication until the implementation in September 2015 of amendment P083-09. Thus, 
the RD analysis may not be feasible due to insufficient observed Week 20 data post-
discontinuation of study medication. In this case, the primary analysis will use the Return-to-
Baseline (RTB) approach for missing data imputation. The RTB analysis assumes patients 
who discontinued the study medication prematurely would have a ‘washout’ of any potential 
effect of the assigned study medication. 
 
 
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The RTB analysis will include all patients with a baseline A1C measurement.  Missing A1C 
values at Week 20 will be imputed from a normal distribution with the expected value set to 
the patient’s baseline value plus a shift and standard deviation computed based on the root 
mean squared error from the ANCOVA model described above.  For patients with missing 
data at Week 20, one hundred imputations will be performed based on the distribution 
specified previously.  Each of the 100 resulting datasets will contain the original non-missing 
A1C data and the imputed data for the missing values at Week 20. The 100 datasets will be 
analyzed using the ANCOVA model described above.  The 100 ANCOVA-based estimates 
of the treatment difference will be combined using PROC MIANALYZE based on Rubin’s 
rule which accounts for between and within imputation variability.
Two sensitivity analyses of TP estimand for change from baseline in A1C will be performed 
to assess the impact of missing data imputation. Both analyses will include measurements 
collected after discontinuation of study medication or initiation of rescue. One approach will 
use a jump to reference (J2R) pattern mixture model and the other approach will use a pattern 
mixture model in conjunction with the tipping point approach.  
In the J2R analysis, the missing data due to dropout will be handled using J2R imputation, 
which falls under the category of pattern mixture models known as reference-based 
imputation. 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 will be used [66].  Specifically, based on its definition, the 
overall mean treatment difference (estimand) for J2R can be written as
Where
is the proportion of completers in the sitagliptin group, t is the last time point (i.e., 
Week 20), and
and
are the hypothetical means at last time point for the two groups 
under MAR.  These means will be estimated based on Restricted Residual Maximum 
Likelihood (REML) from the primary cLDA model and will be used to compute 
.  The variance for J2R estimate of the treatment difference can be 
approximated by, 
where n is sample size in the sitagliptin group.  The first term
can be 
computed based on the REML from the cLDA model.
 
 
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In the pattern mixture model in conjunction with the tipping point approach, the 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 from the primary cLDA model. For each imputed value, a positive 
adjustment will be added for the sitagliptin group (to the detriment of sitagliptin). The 
inference will be carried out for a range of values of . The smallest value of that renders 
the significant result into non-significant is the tipping point value, which provides a measure 
of robustness of the primary result. 
All p-values are based upon a ‘t-distribution’ with Kenward-Rogers degrees of freedom 
adjustments derived from the primary cLDA model.
Secondary Endpoints
All other continuous efficacy endpoints except triglycerides will be analyzed using the cLDA 
model described above for A1C. For analyses of lipid endpoints, the response vector will 
consist of log-transformed baseline and post-baseline values.  The treatment difference in 
terms of mean percent changes from baseline to a given time point will be estimated and 
tested from this model through back-transformations.
Summary statistics will be provided using observed data for change from baseline in 2-hour 
PMG, AUC endpoints, and endpoints derived from 9-point MTT at Week 20.
Triglycerides will be analyzed using a nonparametric method: an ANCOVA based upon 
Tukey’s normalized ranks on the percent change from baseline [60].  This model will have 
the same terms as the ANCOVA model described above.  For this analysis, within-treatment 
effects will be estimated using medians, and between-treatment effects will be estimated 
using the Hodges-Lehmann estimate [61] with a corresponding distribution-free 95% 
confidence interval (CI) based on Wilcoxon’s rank sum test.  The standard deviation of the 
median will be computed as (Q3-Q1)/1.075, where Q3 and Q1 represent the 75th and 25th
percentiles, respectively.  Missing values will be imputed from the last observed post-
baseline measurement, if available.
Analyses of the percentages of patients at the A1C goals of <7.0% and <6.5% at Week 20 
will be conducted using the M&N method [62], an unconditional, asymptotic method, 
stratified by baseline BMI percentile (≥ or < median), insulin use at screening (yes/no), and 
baseline A1C (> or ≤ median). If necessary due to sparse cells, stratification factors will be 
removed. The differences in percentages along with the corresponding 95% CIs will be 
provided.  The multiple imputation (MI) method will be used to determine whether a patient 
has met the goal when the A1C result at Week 20 is not available.  Imputations of the 
missing data will be based on the marginal univariate normal distributions with means equal 
to the predicted values and variances equal to the squared standard errors for the predicted 
values from the cLDA model. Ten sets of imputations of each missing value will be 
constructed from the cLDA model.  The seed for the random number generator will be 
0431083.  Patients with missing Week 20 data will be categorized as “at” or “not at” the A1C 
goals (<7.0% or <6.5%) at Week 20 after imputation. To estimate the within-group response 
 
 
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rates and between-group rate difference, each of the 10 imputed data sets will be summarized 
to obtain the proportion of responders within each group. The estimated proportions of 
responders from the 10 imputed data sets will be combined using standard multiple 
imputation techniques to yield an overall estimate of 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 intervals for between-group rate difference via the M&N 
method.  In addition, as a sensitivity analysis the Cochran-Mantel- Haenszel method will be 
used to analyze the percentages of patients at the A1C goals of < 7.0% and < 6.5% at Week 
20 in the ‘all patients randomized’ population, with missing data imputed as ‘not at goal’. 
Furthermore, an additional sensitivity analysis for A1C < 7.0% goal will be performed for 
patients with a baseline A1C ≥ 7.0%.
A time-to-event analysis will be performed for the initiation of glycemic rescue therapy up to 
Week 20. Patients will be considered as rescued if they initiated protocol prespecified rescue 
therapy. Patients with no events will be censored at the completion of Phase A or 
discontinuation from the study during Phase A. The protocol prespecified rescue therapy will 
pertain to Step 1 rescue (see Section 2.4.2.6 of protocol). The proportion of patients initiating 
glycemic rescue therapy by Week 20 in each treatment group will be summarized. A plot of 
the Kaplan-Meier estimate of the distribution of the time-to-initiation of glycemic rescue 
therapy during Week 0 to Week 20 will be provided for each treatment arm and a log-rank 
test, comparing the time-to-initiation distribution of sitagliptin versus placebo will be 
conducted. Table 3-3 summarizes the analysis strategy for efficacy endpoints at Week 20.
 
 
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Table 3-3
Analysis Strategy for Efficacy Variables at Week 20
Endpoint/Variable
Approach
Statistical Method
Analysis 
Population
Missing Data Approach
Primary Endpoint
Change from baseline in A1C 
P (TE)
cLDA
FAS
Model-based
P (TP)
ANCOVA
FAS
RD/RTB†
Sen (TP)
cLDA
FAS
J2R
Sen (TP)
cLDA
FAS
Tipping Point
Secondary Endpoints
Change from baseline in FPG
P (TE)
cLDA
FAS
Model-based
Proportion of patients with A1C at 
Goal (<7.0%, <6.5%) at Week 20
P
S
S
M&N
CMH
M&N
FAS
FAS
FAS/Subgroup‡
Multiple Imputation
“not at goal”
Multiple Imputation
Other Endpoints
Percent change from baseline in 
lipid parameters (other than 
triglycerides)
P
cLDA
FAS
Model-based
Percent change from baseline in 
triglycerides
P
Non-parametric method
FAS
LOCF
Change from baseline in Insulin, 
Proinsulin, Proinsulin / Insulin Ratio
P
cLDA
FAS
Model-based
Change from baseline in HOMA-β 
and HOMA-IR
P
cLDA
FAS
Model-based
Time to initiation of glycemic rescue 
therapy during Week 0 to Week 20
P
Kaplan-Meier
FAS
DAO
Proportion initiating glycemic 
rescue therapy during Week 0 to 
Week 20
P
Summary statistics
FAS
DAO
ANCOVA= analysis of covariance; cLDA= constrained longitudinal data analysis; DAO=data as observed; FAS= full 
analysis set; J2R=Jump-to-reference; P=Primary approach; RD= Retrieved-Dropout; RTB=Return-to-Baseline; 
S=Secondary approach; Sen=Sensitivity approach; TE=Treatment effect; TP=Treatment policy.
† If RD is not feasible due to insufficient data post discontinuation from study medication, RTB imputation will serve as 
the primary approach for TP. If RD is feasible, RTB will be performed as a secondary approach.
‡ Subgroup=patients with baseline A1C ≥7.0% (applicable to A1C goal <7.0% analysis).
Week 0 to Week 54 Analyses
The statistical analyses at Week 54 will be analogous to those at Week 20 except that no 
between-group comparisons will be provided for Week 54. The efficacy endpoints will be 
summarized for within-group mean change from baseline with estimates and 95% confidence 
intervals calculated from the analysis model. 
Additionally, for triglycerides, within-treatment effects will be estimated using medians, and 
between-treatment effects will not be estimated.  The standard deviation of the median will 
be computed as (Q3-Q1)/1.075, where Q3 and Q1 represent the 75th and 25th percentiles, 
respectively.  Missing values will be imputed from the last observed post-baseline 
measurement.
 
 
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3.5.5.2
Statistical Methods for Safety Analyses
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
adverse events (AEs), PDLCs, laboratory tests, vital signs, waist circumference, BMI, growth 
velocity, Tanner Staging data, urine microalbumin/creatinine ratio, and CD26.  All safety 
endpoints will be analyzed using summary statistics. For the Week 20 analysis, the following 
analysis approaches will be used:

For all safety endpoints except hypoglycemia, data will be summarized including data 
following the initiation of rescue or intensification therapy (IR).

Hypoglycemia endpoints will be summarized excluding data measured following the 
initiation of rescue therapy or intensification therapy (ER). 
The Treatment Period will include all data from randomization up to 14 days after the last 
dose of study medication.  All safety endpoints will be analyzed for the time frame consisting 
of the Treatment Period + 14 day post treatment follow up, and for SAEs an additional 
analysis including all post-randomization follow-up will be performed. For Phase A analyses, 
the 14-day post Treatment Period window will exclude the Phase B Treatment Period for 
patients who enter Phase B; ie, events that occur during the first 14 days of Phase B will not 
be counted. 
For the Week 54 analysis, the same approaches from Week 20 will be applied except that the 
primary approach for SAEs at Week 54 will include all post-randomization follow-up, 
without an upper day limit.
Listings of all AEs (regardless of seriousness) reported more than 14 days after the end of the 
Treatment Period and of PDLCs occurring beyond the Treatment Period will be provided.
The analysis of safety results will follow a tiered approach (Table 3-4).  The tiers differ with 
respect to the analyses that will be performed.  Safety parameters or adverse events of special 
interest that are identified a priori constitute “Tier 1” safety endpoints that will be subject to 
inferential testing for statistical significance with p-values and 95% confidence intervals 
provided for between-group comparisons.  Other safety parameters will be considered Tier 2 
or Tier 3.  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.
Adverse events (summary measures, specific terms, system organ class terms) and 
predefined limits of change in laboratory and vital signs parameters that are not pre-specified 
as Tier 1 endpoints 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 patients in any 
treatment group exhibit the event; all other adverse events and predefined limits of change 
will belong to Tier 3.
 
 
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The threshold of at least 4 patients with events has been chosen because the 95% confidence 
interval for the between-group difference in percent incidence will always include zero when 
treatment groups of equal size have less than 4 patients with 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, and not as a formal 
method for assessing the statistical significance of the between-group differences in adverse 
events and predefined limits of change.
The continuous endpoints waist circumference and BMI will be considered Tier 2 safety 
parameters.  The endpoints IGF-1, IGF-BP3, Bone Age (as Bone Age/Chronologic Age), 
Growth Velocity Percentile (for both bone age and chronologic age), biochemical markers of 
bone turnover [Urine NTx/Creatinine ratio; Bone specific Alkaline Phosphatase] and 
calcitonin, urine albumin/creatinine ratio, percentage change from baseline in CD26 and 
endpoints in accessing Tanner staging will be considered Tier 3 safety parameters. Changes 
from baseline in laboratory parameters, vital signs and urine parameters that are not pre-
specified as Tier 1 or Tier 2 endpoints will also be considered Tier 3 safety parameters.  
Summary statistics for baseline, on-treatment, and change (or percentage change) from 
baseline values will be provided in table format at Week 20 and 54.  Mean change from 
baseline over time will be plotted with the corresponding standard errors for both Week 20 
and 54.
The data from the oral examination case report forms will be summarized.
Adverse events of symptomatic hypoglycemia and selected gastrointestinal (GI) adverse 
events (i.e., nausea, vomiting, abdominal pain or discomfort, diarrhea) are Tier 1 endpoints. 
p-values (Tier 1 only) and 95% confidence intervals for between-treatment differences in the 
percentages of patients with events will be calculated using the M&N method [62], an 
unconditional, asymptotic method. For continuous Tier 2 safety parameters, change from 
baseline or percent change from baseline will be analyzed using the same cLDA model 
described in Section 3.5.5.1. Only 95% confidence interval will be provided.  For Tier 2 AEs, 
95% confidence intervals for between-treatment differences will be provided using the M&N
method.
Table 3-4 summarizes the analysis strategy for safety endpoints for the Phase A and Phase 
A+B analysis.  The strategy to address multiplicity issues with regard to multiple endpoints is 
described in Section 3.5.6, Multiplicity.
 
 
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Table 3-4
Analysis Strategy for Safety Parameters in Phase A and A+B
Tier
Safety Endpoint
p-Value
95% CI for Treatment 
Comparison
Descriptive
Statistics
Tier 1
Any AE of symptomatic hypoglycemia
X
X
X
Selected 
gastrointestinal 
events 
(Diarrhea, 
Nausea, 
Abdominal Pain†, Vomiting) 
X
X
X
Tier 2 ‡
AE summary measures
X
X
Specific AEs§, SOCs, and PDLCs
X
X
Any AE of hypoglycemia
X
X
AEs of severe hypoglycemia
X
X
Any
Requiring medical assistance
Not requiring medical assistance
Change from baseline in BMI, BMI percentile and waist 
circumference  
X
X
Tier 3
Specific AEs, SOCs or PDLCs (incidence < 4 patients in 
all of the treatment groups)
X
Change from Baseline Results (Labs and Vital signs) 
Percent change from baseline in IGF-1 and IGF-BP3
Bone Age (as Bone Age/Chronologic Age)
Growth Velocity Percentile (for both bone age and 
chronologic age)
Change from baseline in markers of bone turnover [Urine 
NTx/Creatinine ratio, Bone specific Alkaline 
Phosphatase] and  Calcitonin
Change from baseline Urine albumin/creatinine ratio
Change from baseline in endpoints for accessing Tanner 
Stage
Percentage change from baseline in CD26
X
AE= adverse event; BMI= body mass index; PDLC= predefined limits of change; SOC= system organ class.
† Includes abdominal pain lower, abdominal pain upper, abdominal pain, abdominal discomfort and epigastric discomfort.
‡ Endpoints listed here will qualify for Tier 2 only if the incidence is ≥4 patients in at least one of the treatment groups.
§ Among those endpoints not pre-specified as Tier 1 endpoints.
SAE=Serious adverse event; SOC=System Organ Class; PDLC=Pre-Defined Limit of Change; X = results will be provided.
Analysis of Hypoglycemia
Separate analyses of hypoglycemia will be performed for patients on background insulin and 
for patients not on background insulin at screening.
The Tier 1 analysis for hypoglycemia will include the numbers and percentages of patients 
experiencing one or more adverse events of symptomatic hypoglycemia, regardless of 
glucose value.
The Tier 2 analysis for hypoglycemia will include the numbers and percentages of patients 
experiencing one or more of each the following, regardless of glucose value:

Adverse events of hypoglycemia (symptomatic or asymptomatic)
 
 
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
Adverse events of severe hypoglycemia, defined as adverse events of symptomatic 
hypoglycemia that required assistance, either medical or non-medical, regardless of 
whether such assistance was obtained.  These events will be further sub-classified as:
o
Those that required medical assistance.  Adverse events of symptomatic 
hypoglycemia that included a markedly depressed level of consciousness, loss of 
consciousness, or seizure will be classified as having required medical assistance, 
whether or not medical assistance was obtained.
o
Those that did not require medical assistance (i.e., those episodes that required non-
medical assistance to treat).
The Tier 3 summary of hypoglycemia will include the following, based on episodes 
classified by the investigator as adverse events:

The numbers and percentages of patients with each of the following, overall and by 
lowest reported glucose category (<50 mg/dL [<2.8 mmol/L], ≤70 mg/dL [≤3.9 mmol/L], 
>70 mg/dL [>3.9 mmol/L], or unknown).  A patient's lowest glucose category will be 
classified as unknown only if no glucose measurements are available for that patient.
1. any episodes (symptomatic or asymptomatic)
2. symptomatic episodes
3. asymptomatic episodes

The numbers and percentages of patients with episodes having precipitating factors, 
overall and separately by factor

The number of episodes per patient

The number of each of the following (summed across all patients).  The overall summary 
will include an indication of whether precipitating factors were present.
1. all episodes (symptomatic or asymptomatic)
2. symptomatic episodes
3. asymptomatic episodes
Exposure-adjusted incidence rates (i.e., number of patients with ≥1 event, per 100 patient-
years) may also be provided for selected endpoints defined above.
A summary of patients with episodes that were reported on the hypoglycemia assessment 
(HA) eCRF but were not classified by the investigator as adverse events will also be 
provided.  If a substantial number of patients had episodes that were not classified as adverse 
events, then additional summaries may be provided for the Tier 3 endpoints above, including 
all episodes reported on the HA eCRF (i.e., not restricted to adverse events).  It is expected 
that all symptomatic hypoglycemia episodes will be classified by the investigator as adverse 
events and, thus, that any episodes that are not classified as adverse events will be 
asymptomatic episodes.
 
 
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3.5.5.3
Summaries of Baseline Characteristics, Demographics, and Other Analyses
Demographic and Baseline Characteristics
The comparability of the treatment groups at baseline for each relevant characteristic will be 
assessed by the use of tables and/or graphs.  No statistical tests will be performed on these 
characteristics.  The number and percentage of patients screened, randomized, the primary 
reasons for screen failure, and the primary reason for discontinuation will be displayed.  
Medical history and prior and concomitant therapies will be summarized by treatment either 
by 
descriptive 
statistics 
or 
categorical 
tables. 
 
In 
addition, 
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, standard deviation [SD], median, 
range and proportion will be provided.

Continuous baseline demographic variables: age (years), weight (kg), height (cm), time 
since diagnosis of T2DM (days), body mass index (BMI; kg/m2) and BMI percentile for 
age and sex.

Categorical baseline demographic variables: gender (male, female), and race (White, 
Black, Asian, American Indian or Alaska Native or Other), ethnicity (Hispanic/Latino or 
not) and Baseline BMI percentile (<95% and ≥95%).

Baseline A1C, and distribution of A1C at baseline (≥ or < median A1C).

Baseline FPG

Time since diagnosis of T2DM (> or ≤ median)

Insulin use at Visit 1(yes/no)

Baseline substance use (tobacco/alcohol)

Baseline skeletal maturation status (skeletally mature: yes/no)

PedsQL at screening
3.5.6
Multiplicity
As there is only one hypothesis in the study, no multiplicity control is needed for the study 
hypotheses.  Comparisons involving other efficacy endpoints and time points are considered 
supportive and will be made at the α=0.05 nominal level (two-sided).  No multiplicity 
adjustment will be performed on these other comparisons.
From a safety standpoint, application of a multiplicity adjustment could potentially mask a 
safety concern.  Thus, no control of Type I error rate beyond the per-comparison α=0.05 
nominal level will be applied to the safety analyses, with the realization that spurious 
statistical significance may be observed for some endpoints.
 
 
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3.5.7
Sample Size and Power Calculations
This study will randomize approximately 190 patients, but no more than 220 patients,
including approximately 10 to 11 patients randomized to the metformin arm prior to its 
removal from the study design in amendment 5 to this protocol (P083-05). Therefore, there 
will be approximately 180 to 210 patients randomized
to the sitagliptin and 
placebo/metformin (Phase A/Phase B) treatment groups in a 1:1 ratio. Power calculations are 
based on 90 patients in each of the sitagliptin and placebo treatment groups.  
A sample size of 90 per treatment group will be equivalent to an effective sample size of 
approximately 82 per treatment group at Week 20 in the power calculation for the primary 
hypothesis test using the cLDA model in the FAS population. An effective sample size of 82 
per treatment will provide 82% power to detect a between-group difference of -0.5% in A1C 
reduction at Week 20 assuming the conditional standard deviation is 1.1%. The half-width of 
the 95% CI is expected to be 0.34%. 
These calculations were based upon the following assumptions:

Cumulative attrition rates at Weeks 8, 14, and 20 are 0.07, 0.10, and 0.15, 
respectively 

A conditional correlation matrix at Weeks 8, 14, and 20 is 
The correlation matrix assumptions above are based on data from MK-0431 PN036.
Table 3-5 shows the power using α=0.05 (two-sided). The observed between-group 
difference (sitagliptin minus placebo) in change from baseline in A1C in adult ranges 
from -0.50% to -1.03% after 18 to 24 weeks of treatment. The observed standard deviation in 
adults with the similar A1C entry criteria ranges from 0.65% to 1.09%. Unpublished internal 
analyses of analyses of previous sitagliptin studies suggest that the SD may be higher in a 
younger population.  Therefore, the assumed SD for this study is 1.1% for A1C change from 
baseline.  
Table 3-5
Power for Superiority in Change from Baseline in A1C (%) 
82 Effective Patients Per Group and α = 0.05 (two-sided)
Difference (%) 
Standard Deviation (%) 
Power (%) 
0.6 
1.1 
93% 
0.5
1.1
82%










1
93
.0
74
.0
93
.0
1
87
.0
74
.0
87
.0
1
 
 
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3.5.8
Subgroup Analyses
To assess whether the treatment effect at Week 20 is consistent across various subgroups, 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 the following classification 
variables with a minimum of 8 patients per treatment group in each subgroup:

Baseline A1C: ≥ or < median

Gender

Race (White, Black, Asian, Other)

Ethnicity (Hispanic or Latino, Not Hispanic or Latino)

Age: ≤14 or >14

Baseline BMI percentile > or ≤Median

Time since diagnosis of diabetes at baseline: > or ≤1 year

Background insulin (yes/no)
The treatment effect across trial centers will be summarized for A1C at Week 20 with 
descriptive statistics.
The consistency of the treatment effect will be assessed in the context a repeated measures 
ANCOVA (RMANCOVA) method, which is a generalization of the standard ANCOVA to 
accommodate repeated measurements.  The RMANCOVA model will adjust for baseline 
A1C, treatment, baseline BMI, subgroup, insulin use at screening (yes/no), and treatment-by-
subgroup interaction.  If necessary due to sparse cells, the stratification factor will be 
removed from the model. 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.  For subgroup analyses based on factors that are already in 
the main model, the respective term will appear in the model only once.  Treatment effects 
and nominal 95% confidence intervals 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.
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% confidence intervals will usually be wide in the subgroup analyses.  
3.5.9
Interim Analyses
No interim analyses of efficacy are planned for this trial. The external DMC (see Section 
3.4.2.2) will monitor interim data to ensure both patient safety and continued ethical integrity 
of the trial. 
 
 
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Data will be analyzed and a study report generated when the last patient completes Phase A 
(ie, after all randomized patients complete Visit 8/Week 20 or have discontinued from Phase 
A of the study).   Investigators and patients will remain blinded to study drug treatment 
assignment until all patients have completed the trial (ie, all randomized patients complete 
Visit 11/Week 54 or have discontinued from the study) and the second database is locked.  
The first unblinding and analysis is not an interim analysis because it includes the complete 
data for analysis of the primary efficacy endpoint.  
3.5.10 Medication Adherence
The computation of medication adherence will be based on the study medication case report 
form. A day within the Double-blind Treatment Period will be considered an adherent day if 
the patient reports one tablet from each column (labeled as A, B, C, D, E) in the prescribed 
blister card (a total of 5 tablets in a day).
If the study medication eCRF indicates general adherence problems with any double-blinded 
therapy, the patient will be considered non-adherent for that day regardless of the number of 
tablets for the assigned treatment(s) and any matching placebo reported.
For each patient, two rates will be calculated. The adherence rate summarizes adherence to 
assigned study medication over the patient’s duration of study participation. The compliance 
rate summarizes the adherence with study medication during the Treatment Period only. 
Adherence Rate (%) =
Number of Adherent Days
× 100% 
Number of Days in the Study
Compliance Rate (%) =
Number of Adherent Days
× 100% 
Number of Days in the Double-blind Treatment Period
The “Number of Days in the Study” is the total number of days from Day 1 (or the 
randomization day for non-treated patients) to the day of study completion or study 
discontinuation excluding the 14 days of post-study follow-up.
For a patient who is followed for the entire study period, the "Number of Days in Double-
blind Treatment Period" is the total number of days from the first dose of double-blind study 
medication to the last scheduled day for treatment administration for that patient. For a 
patient who discontinues from the study prematurely, the "Number of Days in Double-blind 
Treatment Period" is the total number of days from the first dose of double-blind study 
medication to the date of the last dose of study medication.
Summary statistics will be provided on percent adherence and compliance by treatment 
group.
 
 
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3.5.11 Extent of Exposure
The extent of exposure to study treatment will be evaluated by summary statistics and 
frequencies for the "Number of Days on Therapy" by treatment group.
LABELING, PACKAGING, STORAGE, DISPENSING, AND RETURN OF 
3.6
CLINICAL SUPPLIES
3.6.1
Product Descriptions
Investigational materials will be provided by the Sponsor as summarized in Table 3-6. Blister 
card configuration is summarized in Table 3-7. 
Table 3-6
Product Descriptions
Product Name & Potency
Dosage Form
Sitagliptin 100 mg (as sitagliptin phosphate) 
Tablet
Placebo to match sitagliptin 100 mg (as sitagliptin phosphate)
Tablet
Metformin hydrochloride 500 mg
Tablet
Placebo to match metformin hydrochloride 500 mg
Tablet
Table 3-7
Blister Card Configuration
Blister 
Card 
Column 
Label
Product Name & Potency
Dosage 
Form
Dose Regimen
A
Sitagliptin 100 mg (as Sitagliptin Phosphate) or Placebo
Tablet
One tablet daily prior to morning 
meal
B
Metformin Hydrochloride 500 mg, or Placebo
Tablet
One tablet daily prior to morning 
meal
C
Metformin Hydrochloride 500 mg, or Placebo
Tablet
One tablet daily prior to morning 
meal
D
Metformin Hydrochloride 500 mg, or Placebo
Tablet
One tablet daily prior to evening meal
E
Metformin Hydrochloride 500 mg, or Placebo
Tablet
One tablet daily prior to evening meal
All placebos were created by the Sponsor in the image of the active product.
Insulin will be supplied by the investigator site as needed.  The investigator or designee will 
record the lot number, expiration date, and drug dispensed.
 
 
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3.6.2
Packaging Information
Patients will receive blinded blister packs for both Run-in and Blinded Treatment.  Run-in 
blister packs will be received in a weekly kit containing 2 blister cards.  Blinded Treatment 
will be received in monthly kits containing 5 blister cards.
Supplies will be affixed with a clinical label in accordance with regulatory requirements.
3.6.3
Clinical Supplies Disclosure
The emergency unblinding call center will use the randomization schedule for the trial to 
unblind patients 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 randomization 
system (IVRS/IWRS) should be used in order to unblind patients and to unmask treatment 
identity.  The Sponsor will provide random code/disclosure envelopes or lists to the 
emergency unblinding call center.
Treatment identification information is to be unmasked ONLY if necessary for the welfare of 
the patient.  Every effort should be made not to unblind the patient 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 patient’s code 
should be unblinded.  Trial site personnel and Sponsor personnel directly associated with the 
conduct of the trial should not be unblinded.
3.6.4
Storage and Handling Requirements
The storage conditions will be indicated on the label.
The clinical supplies storage area at the site must be monitored by the site staff for 
temperature consistency with the acceptable storage temperature range as specified on the 
label or in the product label attached to the protocol.  Documentation of temperature 
monitoring should be maintained.
3.6.5
Returns and Reconciliation
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 patients and the 
amount remaining at the conclusion of the trial.
For all trial sites, the country Sponsor personnel or designee will provide appropriate 
documentation that must be completed for drug accountability and return.
3.6.6
Comparator Statement
At the close of the study after unblinding, a letter is to be sent by the investigator to those 
patients who received placebos in the image of the competitor’s product to provide the 
following information:
 
 
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“You have participated in a study conducted by the Sponsor. This is to advise you that 
you were among those who received a look-alike tablet created by the Sponsor to 
resemble the drug Metformin Hydrochloride as much as possible. You may also have 
received the active drug Metformin Hydrochloride as manufactured by Aurobindo.”
3.6.7
Distributing to Sites and Dispensing to Patients
Study personnel will have access to IVRS to allocate patients, to assign drug to patients 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.
DATA MANAGEMENT
3.7
Information regarding Data Management procedures for this protocol will be provided by the 
SPONSOR.
BIOLOGICAL SPECIMENS
3.8
Information regarding biological specimens for this protocol will be provided by the 
Sponsor.
 
 
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4. ADMINISTRATIVE AND REGULATORY DETAILS
CONFIDENTIALITY
4.1
4.1.1
Confidentiality of Data
For Studies Conducted Under the U.S. IND
Particular attention is drawn to the regulations promulgated by the Food and Drug 
Administration under the Freedom of Information Act providing, in part, that information 
furnished to clinical investigators and Institutional Review Boards will be kept confidential 
by the Food and Drug Administration only if maintained in confidence by the clinical 
investigator and Institutional Review Board.
For All Studies
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, 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 study 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.
4.1.2
Confidentiality of Patient Records
For All Studies
By signing this protocol, the investigator agrees that the SPONSOR (or SPONSOR 
representative), Institutional Review Board/Independent Ethics Committee (IRB/IEC), or 
Regulatory Agency representatives may consult and/or copy study documents in order to 
verify worksheet/case report form data. By signing the consent form, the patient agrees to 
this process. If study documents will be photocopied during the process of verifying 
worksheet/case report form information, the patient will be identified by unique code only; 
full names/initials will be masked prior to transmission to the SPONSOR.
For Studies Conducted Under the U.S. IND
By signing this protocol, the investigator agrees to treat all patient data used and disclosed in 
connection with this study in accordance with all applicable privacy laws, rules and 
regulations, including all applicable provisions of the Health Insurance Portability and 
Accountability Act and its implementing regulations, as amended from time to time 
(“HIPAA”).
 
 
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4.1.3
Confidentiality of Investigator Information
For All Studies
By signing this protocol, the investigator recognizes that certain personal identifying 
information with respect to the investigator, and all subinvestigators and study site personnel, 
may be used and disclosed for study management purposes, as part of a regulatory 
submissions, and as required by law. This information may include:

name, address, telephone number, and email address;

hospital or clinic address and telephone number;

curriculum vitae or other summary of qualifications and credentials; and

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 agencies or to other investigators. 
By signing this protocol, the investigator expressly consents to these uses and disclosures.
For Multicenter Studies
In order to facilitate contact between investigators, the SPONSOR may share an 
investigator’s name and contact information with other participating investigators upon 
request.
COMPLIANCE WITH LAW, AUDIT, AND DEBARMENT
4.2
By signing this protocol, the investigator agrees to conduct the study in an efficient and 
diligent manner and in conformance with this protocol; 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 study.
The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by Merck Sharp & Dohme Corp., a 
subsidiary of Merck & Co., Inc., is attached.
The investigator also agrees to allow monitoring, audits, Institutional Review Board/ 
Independent Ethics Committee review, and regulatory agency inspection of trial-related 
documents and procedures and provide for direct access to all study-related source data and 
documents.
 
 
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The investigator agrees not to seek reimbursement from patients, their insurance providers, or 
from government programs for procedures included as part of the study reimbursed to the 
investigator by the SPONSOR.
The investigator shall prepare and maintain complete and accurate study documentation in 
compliance with Good Clinical Practice standards and applicable federal, state, and local 
laws, rules and regulations; and, for each patient participating in the study, provide all data, 
and upon completion or termination of the clinical study submit any other reports to the 
SPONSOR as required by this protocol or as otherwise required pursuant to any agreement 
with the SPONSOR.
Study documentation will be promptly and fully disclosed to the SPONSOR by the 
investigator upon request and also shall be made available at the investigator’s site upon 
request for inspection, copying, review, and audit at reasonable times by representatives of 
the SPONSOR or any regulatory agencies. 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 study documentation and worksheets/case report forms.
International Conference of Harmonization Good Clinical Practice guidelines (Section 4.3.3) 
recommend that the investigator inform the patient’s primary physician about the patient’s 
participation in the trial if the patient has a primary physician and if the patient agrees to the 
primary physician being informed.
According to European legislation, a SPONSOR must designate a principal or coordinating 
investigator (CI) to review the report (summarizing the study results) and confirm that to the 
best of his/her knowledge the report accurately describes conduct and results of the study. 
The SPONSOR may consider one or more factors in the selection of the individual to serve 
as the CI (e.g., thorough understanding of clinical trial methods, appropriate enrollment of 
patient cohort, timely achievement of study milestones, and availability of the CI during the 
anticipated review process).
The investigator will promptly inform the SPONSOR of any regulatory agency inspection 
conducted for this study.
Persons debarred from conducting or working on clinical studies by any court or regulatory 
agency will not be allowed to conduct or work on this SPONSOR’s studies. The investigator 
will immediately disclose in writing to the SPONSOR if any person who is involved in 
conducting the study 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 site’s IRB/IEC.
 
 
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COMPLIANCE WITH FINANCIAL DISCLOSURE REQUIREMENTS
4.3
By signing this protocol, the investigator agrees to provide to the SPONSOR accurate 
financial information to allow the SPONSOR to submit complete and accurate certification 
and disclosure statements as required by U.S. Food and Drug Administration regulations (21 
CFR Part 54). The investigator further agrees to provide this information on a Financial 
Disclosure/Certification Form that is provided by Merck Sharp & Dohme Corp., a subsidiary 
of Merck & Co., Inc. This requirement also extends to subinvestigators. The investigator also 
consents to the transmission of this information to Merck Sharp & Dohme Corp., a subsidiary 
of Merck & Co., Inc. in the United States for these purposes. This may involve the 
transmission of information to countries that do not have laws protecting personal data.
QUALITY CONTROL AND QUALITY ASSURANCE
4.4
By signing this protocol, the SPONSOR agrees to be responsible for implementing and 
maintaining quality control and quality assurance systems with written 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 study.
COMPLIANCE WITH INFORMATION PROGRAM ON CLINICAL TRIALS 
4.5
FOR SERIOUS OR LIFE THREATENING CONDITIONS
Under the terms of The Food and Drug Administration Modernization Act (FDAMA), the 
SPONSOR of the study is solely responsible for determining whether the study is subject to 
the requirements for submission to the Clinical Trials Data Bank, http://clinicaltrials.gov/.  
Merck, as SPONSOR of this study, will review this protocol and submit the information 
necessary to fulfill this requirement.  Merck entries are not limited to FDAMA mandated 
trials.  Merck’s voluntary listings, beyond those mandated by FDAMA, will be in the same 
format as for treatments for serious or life-threatening illnesses.  Information posted will 
allow patients to identify potentially appropriate trials for their disease conditions and pursue 
participation by calling a central contact number for further information on appropriate study 
locations and site contact information.
By signing this protocol, the investigator acknowledges that the statutory obligation under 
FDAMA is that of the SPONSOR and agrees not to submit any information about this study 
to the Clinical Trials Data Bank.
PUBLICATIONS
4.6
This study 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 study results within 12 months after the last 
data become available, which may take up to several months after the last patient visit in 
some cases such as vaccine trials.  However, manuscript submission timelines may be 
extended on OTC studies.  For studies intended for pediatric-related regulatory filings, the 
 
 
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investigator agrees to delay publication of the study results until the SPONSOR notifies the 
investigator that all relevant regulatory requirements on the study drug have been fulfilled 
with regard to pediatric-related regulatory filings.  Merck will post a synopsis of study results 
for approved products on www.clinicalstudyresults.org and www.clinicaltrials.gov by 12 
months after the last patient's last visit or within 7 days of product approval in any major 
markets (United States, Europe or Japan), 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.
For multicenter studies, subsequent to the multicenter publication (or after public disclosure 
of the results online at www.clinicalstudyresults.org if a multicenter manuscript is not 
planned), an investigator and his/her colleagues may publish their data independently.  In 
most cases, publication of individual site data does not add value to complete multicenter 
results, due to statistical concerns.  In rare cases, publication of single site data prior to the 
main paper may be of value.  Limitations of single site observations in a multicenter trial 
should always be described in such a manuscript.
Authorship credit should be based on 1) substantial contributions to conception and design, 
or acquisition of data, or analysis and interpretation of data; 2) drafting the article or revising 
it critically for important intellectual content; and 3) final approval of the version to be 
published. Authors should meet conditions 1, 2, and 3.  Significant contributions to study 
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 study, final decisions on authorship 
and the order of authors’ names will be made based on participation and actual contributions 
to the study and writing, as discussed above. The first author is responsible to defend 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 study 60 days prior to submission for publication/ presentation. 
Any information identified by the SPONSOR as confidential must be deleted prior to 
submission. SPONSOR review can be expedited to meet publication timelines.
 
 
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Lobstein T, Jackson-Leach R. Estimated burden of paediatric obesity and co-morbidities 
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10. Pinhas-Hamiel O, Zeitler P. The global spread of type 2 diabetes mellitus in children and 
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13. Dabelea D, DeGroat J, Sorrelman C, Glass M, Percy CA, Avery C, et al. Diabetes in 
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16. Liu LL, Yi JP, Beyer J, Mayer-Davis EJ, Dolan LM, Dabelea D, et al. Type 1 and Type 
2 Diabetes in Asian and Pacific Islander - U.S. youth The SEARCH for diabetes in 
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Diabetes in African American youth prevalence, incidence, and clinical characteristics: 
the SEARCH for diabetes in youth study. Diabetes Care 2009;32(Suppl 2):S112-S122.
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characteristics of type 2 diabetes mellitus in overweight European Caucasian 
adolescents. Exp Clin Endocrinol Diabetes 2005;113:167-70.
20. Weigand S, Maikowski U, Blankenstein O, Biebermann H, Tarnow P, Grüters A. Type 
2 diabetes and impaired glucose tolerance in European children and adolescents with 
obesity – a problem that is no longer restricted to minority groups. Eur J Endocrinol
2004;151:199-206.
21. Harron KL, Feltbower RG, McKinney PA, Bodansky HJ, Campbell FM, Parslow RC.  
Rising rates of all types of diabetes in south Asian and non-south Asian children and 
young people aged 0-29 years in West Yorkshire, U.K., 1991-2006. Diabetes Care 
2011;34(3):652-4.
22. Hannon TS, Rao G, Arslanian SA. Childhood obesity and type 2 diabetes mellitus. 
Pediatrics 2005;116:473-80.
23. Lee S, Gungor N, Bacha F, Arslanian SA. Racial differences in adiponectin in youth. 
Diabetes Care 2006;29(1):51-6.
24. Jacobson-Dickman E, Levitsky L. Oral agents in managing diabetes mellitus in children 
and adolescents. Pediatr Clin N Am 2005;52:1689-703.
 
 
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25. American Diabetes Association. Type 2 diabetes in children and adolescents. Diabetes 
Care 2000;23(3):381-9.
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polycystic ovary syndrome:  roles of insulin resistance and risk of cardiovascular 
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27. Desai M, Gayle D, Babu J, Ross MG. Programmed obesity in intrauterine growth-
restricted newborns:  modulation by newborn nutrition. Am J Physiol Regul Interg 
Comp Physiol 2005;288:R91-R96.
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weight, type 2 diabetes, and insulin resistance in Pima Indian children and young adults. 
Diabetes Care 1999;22(6):944-50.
29. DeFronzo RA. Lilly lecture 1987.  The triumvirate: β-cell, muscle, liver.  A collusion 
responsible for NIDDM. Diabetes 1988;37:667-87.
30. Weiss R, Dziura JD, Burgert TS, Taksali SE, Tamborlane WV, Caprio S. Ethnic 
differences in beta cell adaptation to insulin resistance in obese children and adolescents. 
Diabetologia 2006;49:571-9.
31. Caprio S. Insulin resistance in childhood obesity. J Pediatr Endocrinol Metab 
2002;15:487-92.
32. Druet C, Tubiana-Rufi N, Chevenne D, Rigal O, Polak M, Levy-Marchal C. 
Characterization of insulin secretion and resistance in type 2 diabetes of adolescents. J 
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33. Weiss R, Caprio S, Trombetta M, Taksali SE, Tamborlane WV, Bonadonna R. β-cell 
function across the spectrum of glucose tolerance in obese youth. Diabetes 
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34. Weiss R, Taksali SE, Tamborlane WV, Burgert TS, Savoye M, Caprio S. Predictors of 
changes in glucose tolerance status in obese youth. Diabetes Care 2005;28(4):902-9.
35. Rosenbloom AL, Joe JR, Young RS, Winter WE. Emerging epidemic of type 2 diabetes 
in youth. Diabetes Care 1999;22(2):345-54.
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Retinopathy and nephropathy in youth-onset compared with adult-onset type 2 diabetes. 
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youth-onset type 2 diabetes mellitus on incidence of end-stage renal disease and 
mortality in young and middle-aged Pima Indians. JAMA 2006;296(4):421-6.
39. Eppens MC, Vraig ME, Cusumano J, Hing S, Chan AKF, Howard NJ, et al. Prevalence 
of diabetes complications in adolescents with type 2 compared with type 1 diabetes. 
Diabetes Care 2006;29(6):1300-6.
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lipids and glucose control. Arch Pediatr Adolesc Med 2007;161:159-65.
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adolescents with type 2 diabetes. Ann Pharmacother 2006;40:1517-21.
42. Gungor N, Thompson T, Tyrrell KS, Janosky J, Arslanian S. Early signs of 
cardiovascular disease in youth with obesity and type 2 diabetes. Diabetes Care 
2005;28(5):1119-221.
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disease in patients with type 1 diabetes. N Engl J Med 2005;353(25):2643-53.
44. Urakami T. How should we treat type 2 diabetes in youth? Pediatric Endocrinology 
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children. Ped Diabetes 2007;8(Suppl 9):16-27.
46. Bobo N, Evert A, Gallivan J, Imperatore G, Kelly J, Linder B, et al. Commentaries: An 
update on type 2 diabetes in youth from the National Diabetes Education Program. 
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47. Canadian Diabetes Association. Type 2 diabetes in children and adolescents. Clin Pract 
Guidelines 2003:S91-S93.
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pediatric patients with type 2 diabetes. Diabetes Care 2002;25:89-94.
49. Weiss R, Dufour S, Taksali SE, Tamborlane WV, Petersen KF, Bonadonna RC, et al. 
Prediabetes in obese youth: a syndrome of impaired glucose tolerance, severe insulin 
resistance, and altered myocellular and abdominal fat partitioning. Lancet 
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50. Yeckel CW, Taksali SE, Dziura J, Weiss R, Burgert TS, Sherwin RS, et al. The normal 
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51. Zuhri-Yafi M, Brosnan PG, Hardin DS. Treatment of type 2 diabetes mellitus in children 
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2007;132:2131-57.
53. Silverstein JH, Rosenbloom AL. Treatment of type 2 diabetes mellitus in children and 
adolescents. J Pediatr Endocrinol Metab 2000;13:1403-9.
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56. Farah SE, Wals KT, Friedman IB, Pisacano MA, DiMartino-Nardi J. Prevalence of 
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Presentation of youth with type 2 diabetes in the pediatric diabetes consortium.  
Pediatric Diabetes 2016;17:266-273.  
58. Toffolo G, et al. Quantitative indexes of Beta-cell function during graded up and down 
glucose infusion from C-peptide minimal models.  Am J Physiol 2001;280:E2-E10.
59. Liang K, Zeger S. Longitudinal data analysis of continuous and discrete responses for 
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63. National High Blood Pressure Education Program Working Group on High Blood 
Pressure in Children and Adolescents.  The fourth report in the diagnosis, evaluation, and 
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64. De Onis M Onyango AW, Borghi E, Siyam A, Nishida C, Siekmann J. Development of 
a WHO growth reference for school-aged children and adolescents. Bulletin of the 
World Health Organization 2007;85:660-7.
 
 
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65. Varni JW, Burwinkle TM, Jacobs JR, Gottschalk M, Kaufman F, Jones KL. The 
PedsQL in type 1 and type 2 diabetes: reliability and validity of the Pediatric Quality of 
Life Inventory Generic Core Scales and type 1 Diabetes Module. Diabetes Care, 
2003;26(3) 631-7.
66. Liu G and Pang L (2015). On Analysis of Longitudinal Clinical Trials with Missing 
Data Using Reference-Based Imputation. Journal of Biopharmaceutical Statistics. 
 
 
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6. APPENDICES
BLOOD PRESSURE AND ANTHROPOMETRIC MEASUREMENTS
6.1
Blood Pressure
Ensure patient has not had any caffeine or tobacco within 30 minutes.  BP should be 
measured in the sitting position.  The patient will remain in the sitting position for at least 5 
minutes before any blood pressure readings are recorded.  The same arm, preferably the non-
dominant arm, should be used for all blood pressure determinations at each visit.  Systolic and 
diastolic BP will be determined by obtaining two measurements, 1-2 minutes apart.  The 
consecutive systolic BP readings should be within 5 mm Hg of each other and the 
consecutive diastolic BP readings should be within 5 mm Hg of each other.  The final 
BP measurement must be recorded.
Body Mass Index
The Body Mass Index will be calculated using the following equation:
BMI =
Body weight in Kilograms
(Height in meters)2
Note:
1 kg = 2.2 pounds
1 m = 3.28 feet
Weight
Weight will be taken on the same calibrated digital scale throughout the study, after voiding 
and while wearing only a gown and underwear (no street clothes, no shoes or socks).  
Patients should step gently onto the scale, place both feet together in the center of the scale 
and stand straight with eyes directed ahead.  Patients should be instructed to stand still 
and not sway.  Measurement will be recorded after the weight has stabilized.
Weight will be measured after voiding (to the nearest 0.2 kg).  Measurements will be 
collected until 2 consecutive measurements do not differ by more than 0.2 kg from each 
other.  The final weight measurement must be recorded.  The same digital scale must be 
used throughout the study.
The SPONSOR will provide a scale and/or 10-kg certified weight to study sites that do not 
have them. The scale must be calibrated according to the manufacturer’s instructions at 
set-up and when it is transferred or moved.  Additional calibration should be 
performed according to the manufacturer’s instructions.
 
 
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Height
Standing height will be measured without shoes using a stadiometer.
Standing height will be assessed through maximum vertical stature for persons who can stand 
unassisted.  Hair ornaments, barrettes, braids, jewelry, or cornrows should be moved or 
removed from the top of the head before the measurement is taken.
A fixed stadiometer with vertical backboard, fixed floorboard and movable headboard must 
be used.  Patients should stand with the heels of their feet against the vertical backboard with 
feet pointing outward at approximately a 60-degree angle.  Body weight should be distributed 
evenly with both feet flat on the floor.  The examiner should check several contact points 
with the vertical backboard, including heels, buttocks, shoulder blades, and the back of the 
head.  This may be difficult for patients with certain body shapes.  However, the head should 
be in the Frankfort plane (an imaginary line from the ear canal to just below the lower orbit 
of the eye should be parallel to the floor).  Patient should be looking straight ahead, and be 
asked to take a deep breath and stand tall.  Once the patient is positioned, the headboard will 
be placed on top of the head, with sufficient pressure to compress the hair.  The measurement 
is recorded in cm, to the nearest mm.  Measurements will be collected until 3 consecutive 
measurements do not differ by more than 1.0 cm from each other.  The final height 
measurement must be recorded.  Some patients may have physical conditions that may 
limit the ability to measure height accurately (e.g., kyphosis).  In such cases, height should be 
measured to the best of the examiner’s ability, a note should be made of the condition and 
measurements should be repeated in the same manner for the rest of study.
The stadiometer must be calibrated upon mounting the stadiometer to the wall, and 
according to the manufacturer’s instructions thereafter. 
Waist Circumference
Instructions for using tension-controlled measuring tapes:
The tape measure used should be a non-stretching, non-metallic retractable tape.
The tape is placed around the patient’s trunk at the appropriate level for waist measurement. 
The tape’s “zero line” is aligned alongside of the tape graduations on the Metric side of the 
tape. The zero end of the tape is held in the left hand above the remaining part of the tape 
held by the right hand. The measurement is read next to the tape’s “zero line” and recorded in 
centimeters to the nearest millimeter.
Waist circumference will be measured according to the National Health and Nutrition 
Examination Survey (NHANES) III protocol.  The measuring tapes may be provided by the 
Sponsor.  It is advisable that the patient’s waist measurement be obtained by the same 
study personnel at each visit in order to provide consistency.  Waist circumference will 
be measured after voiding, in gown, underwear and socks but without shoes.
 
 
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To define the level at which waist circumference is measured, a bony landmark is located and 
marked.  The patient stands and the examiner, positioned at the right of the patient, palpates 
the upper hip bone to locate the right iliac crest.  Just above the uppermost lateral border of 
the right iliac crest, a horizontal mark is drawn using a black pen, and then crossed with a 
vertical mark on the midaxillary line.  The measuring tape is placed in a horizontal plane 
around the abdomen at the level of this marked point on the right side of the trunk.  The plane 
of the tape is parallel to the floor and the tape is snug, but does not compress the skin.  The 
measurement is made at the end of normal minimal respiration (in duplicate). Measurements 
will be collected until two consecutive measurements do not differ by more than 1 cm.
The average of these two measurements will be reported.
 
 
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BLOOD PRESSURE TABLE FOR GENDER/AGE/HEIGHT FOR BOYS AGE 10 TO17
6.2
Age
(Years)
Blood
Pressure
Systolic Blood Pressure by
Percentile of Height (mmHg)
Diastolic Blood Pressure by
Percentile of Height (mmHg)
Percentile
5%
10%
25%
50%
75%
90%
95%
5%
10%
25%
50%
75%
90%
95%
10
90th
111
112
114
115
117
119
119
73
73
74
75
76
77
78
95th
115
116
117
119
121
122
123
77
78
79
80
81
81
82
99th
122
123
125
127
128
130
130
85
86
86
88
88
89
90
11
90th
113
114
115
117
119
120
121
74
74
75
76
77
78
78
95th
117
118
119
121
123
124
125
78
78
79
80
81
82
82
99th
124
125
127
129
130
132
132
86
86
87
88
89
90
90
12
90th
115
116
118
120
121
123
123
74
75
75
76
77
78
79
95th
119
120
122
123
125
127
127
78
79
80
81
82
82
83
99th
126
127
129
131
133
134
135
86
87
88
89
90
90
91
13
90th
117
118
120
122
124
125
126
75
75
76
77
78
79
79
95th
121
122
124
126
128
129
130
79
79
80
81
82
83
83
99th
128
130
131
133
135
136
137
87
87
88
89
90
91
91
14
90th
120
121
123
125
126
128
128
75
76
77
78
79
79
80
95th
124
125
127
128
130
132
132
80
80
81
82
83
84
84
99th
131
132
134
136
138
139
140
87
88
89
90
91
92
92
15
90th
122
124
125
127
129
130
131
76
77
78
79
80
80
81
95th
126
127
129
131
133
134
135
81
81
82
83
84
85
85
99th
134
135
136
138
140
142
142
88
89
90
91
92
93
93
16
90th
125
126
128
130
131
133
134
78
78
79
80
81
82
82
95th
129
130
132
134
135
137
137
82
83
83
84
85
86
87
99th
136
137
139
141
143
144
145
90
90
91
92
93
94
94
17
90th
127
128
130
132
134
135
136
80
80
81
82
83
84
84
95th
131
132
134
136
138
139
140
84
85
86
87
87
88
89
99th
139
140
141
143
145
146
147
92
93
93
94
95
96
97
Note: country-specific blood pressure norms may be used if available – otherwise, these guidelines should be used.
Ref [63]
 
 
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BLOOD PRESSURE TABLE BY GENDER/AGE/HEIGHT FOR GIRLS AGE 10 TO 17
6.3
Years of
Age 
Blood 
Pressure
Systolic Blood Pressure by Percentile 
of Height (mmHg)
Diastolic Blood Pressure by Percentile 
of Height (mmHg)
Percentile
5%
10%
25%
50%
75%
90%
95%
5%
10%
25%
50%
75%
90%
95%
10
90th
112
112
114
115
116
118
118
73
73
73
74
75
76
76
95th
116
116
117
119
120
121
122
77
77
77
78
79
80
80
99th
123
123
125
126
127
129
129
84
84
85
86
86
87
88
11
90th
114
114
116
117
118
119
120
74
74
74
75
76
77
77
95th
118
118
119
121
122
123
124
78
78
78
79
80
81
81
99th
125
125
126
128
129
130
131
85
85
86
87
87
88
89
12
90th
116
116
117
119
120
121
122
75
75
75
76
77
78
78
95th
119
120
121
123
124
125
126
79
79
79
80
81
82
82
99th
127
127
128
130
131
132
133
86
86
87
88
88
89
90
13
90th
117
118
119
121
122
123
124
76
76
76
77
78
79
79
95th
121
122
123
124
126
127
128
80
80
80
81
82
83
83
99th
128
129
130
132
133
134
135
87
87
88
89
89
90
91
14
90th
119
120
121
122
124
125
125
77
77
77
78
79
80
80
95th
123
123
125
126
127
129
129
81
81
81
82
83
84
84
99th
130
131
132
133
135
136
136
88
88
89
90
90
91
92
15
90th
120
121
122
123
125
126
127
78
78
78
79
80
81
81
95th
124
125
126
127
129
130
131
82
82
82
83
84
85
85
99th
131
132
133
134
136
137
138
89
89
90
91
91
92
93
16
90th
121
122
123
124
126
127
128
78
78
79
80
81
81
82
95th
125
126
127
128
130
131
132
82
82
83
84
85
85
86
99th
132
133
134
135
137
138
139
90
90
90
91
92
93
93
17
90th
122
122
123
125
126
127
128
78
79
79
80
81
81
82
95th
125
126
127
129
130
131
132
82
83
83
84
85
85
86
99th
133
133
134
136
137
138
139
90
90
91
91
92
93
93
Note: country-specific blood pressure norms may be used if available – otherwise, these guidelines should be used.
Ref [63]
 
 
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LABORATORY EVALUATIONS
6.4
Fasting plasma glucose (FPG) test (Visits 1, 3, 8, 11, Rescue, and Discontinuation)
Whole blood hemoglobin A1c (A1C) test (Visits 1, 3, 6, 7, 8, 9, 10, 11, Rescue, and 
Discontinuation)
Note:  Do not collect A1C at Rescue or Discontinuation Visits if the occurs before 
Visit 6/Week 8.
Fasting Serum C-Peptide Test (Visit 1) 
Diabetes Autoantibody Panel (Visit 1)
Glutamic acid decarboxylase 65- kDa autoantibody (GAD65-Ab)
Insulinoma-associated protein-2 autoantibody (IA2 Ab)
Fasting Serum Insulin and Proinsulin Tests (Visits 3, 8, 11, Rescue [Step 1 or Treat-to-
Goal Step 1], and Discontinuation)
If a patient is undergoing the MTT, then do not obtain fasting insulin and proinsulin.
Do not perform fasting serum insulin and proinsulin tests on patients on background insulin 
therapy.
9-Point MTT in a subset of patients (Visits 3, 8, 11, Rescue [Step 1 or Treat-to-Goal 
Step 1] and Discontinuation)
Glucose
Insulin
C-peptide
Proinsulin (only at time zero)
Note:  An MTT should not be performed at the Visit 8/Week 20, Visit 11/Week 54 or the 
Discontinuation Visit if the patient has been rescued.  Also, an MTT should not be 
performed at the Discontinuation Visit if the patient has been off double-blind study 
medication ≥5 days, if the study medication was discontinued due to an adverse event, or if 
the visit occurs prior to Visit 5/Week 4.
The MTT will not be performed for patients on background insulin therapy.
Lipid Analyses (Visits 1, 3, 8, 11, Rescue [Step 1 or Treat-to-Goal Step 1] and 
Discontinuation)
Total cholesterol
Triglycerides (TG)
HDL cholesterol
LDL cholesterol-calculated
Non-HDL cholesterol – calculated
 
 
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Hematology (Visits 1, 3, 5, 8, 11, Rescue [Step 1 or Treat-to-Goal Step 1] and 
Discontinuation)
Hemoglobin, hematocrit, and red blood cell count
Mean corpuscular hemoglobin concentration and mean corpuscular volume
White blood cell count and differential
Platelet count
Absolute neutrophil count
Blood Chemistry (Visits 1, 3, 5, 8, 9, 10, 11, Rescue [Step 1 or Treat-to-Goal Step 1], and 
Discontinuation)
Serum sodium test
Serum potassium test
Serum chloride test
Serum bicarbonate test
Serum calcium test
Serum phosphorus test
Serum albumin test
Serum alkaline phosphatase test
Serum uric acid test
Total serum protein test
Serum alanine aminotransferase test (ALT)
Serum aspartate aminotransferase test (AST)
Serum creatine phosphokinase test (CPK)
Total serum bilirubin test
Serum blood urea nitrogen test
Serum creatinine test
Urine Pregnancy Test (Visits 1, 3, 5, 6, 7, 8, 9, 10, 11, Rescue and Discontinuation) for all 
females performed at the investigator’s site
Serum beta-human chorionic gonadotropin (-hCG) test in all randomized patients with a 
positive urine pregnancy test.
Dipstick Urinalysis (Visits 1, 2, 3, 8, 11, Rescue [Step 1 or Treat-to-Goal Step 1], and 
Discontinuation)
If dipstick urinalysis (midstream) is positive for blood, leukocyte esterase, nitrites, or protein, 
then a complete urinalysis (dipstick and microscopy) must be sent to the central laboratory.
Dipstick should not be performed if patient is menstruating.
Urine microalbumin/creatinine ratio (Visits 3, 8, 11, Rescue [Step 1 or Treat-to-Goal 
Step 1] and Discontinuation)
The urine sample for microalbumin/creatinine ratio should not be collected if the patient is 
menstruating, has vigorously exercised within 24 hours, or had fever or an active infection 
within two days of the visit.
 
 
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Thyroid Function Test (Visit 1)
Serum thyroid-stimulating hormone (TSH) test
CD26 Assay (Visit 3, 8, 11, Rescue [Step 1 or Treat-to-Goal Step 1] and 
Discontinuation)
CD26
CD3
CD8
If the Rescue [Step 1 or Treat-to-Goal Step 1] Visit occurs prior to Visit 8, a sample for the 
CD26 assay should be obtained at that time instead of at Visit 8/Week 20. For patients who 
have not received rescue therapy in Phase B, if a sample for CD26 was not obtained or 
analyzed at Visit 8, it can still be obtained at or prior to Visit 9.
IGF-1 and IGF-BP3 (Visit 3, 8, 11, Rescue [Step 1 or Treat-to-Goal Step 1] and 
Discontinuation)
Biochemical Markers of Bone Turnover and Calcitonin (Visit 3, 8, 11, Rescue [Step 1 or 
Treat-to-Goal Step 1] and Discontinuation)
Urine (second AM void) N-terminal cross-linking telopeptide of bone collagen (NTX) and 
creatinine
Serum calcitonin
Serum bone-specific alkaline phosphatase (Ostase assay)
Future Biomedical Research Samples
Serum (SST) and Plasma (EDTA) Samples (Visits 3, 8, 11, Rescue [Step 1 or Treat-to-
Goal Step 1] and Discontinuation)
Blood (DNA) for FBR (Visit 5).
 
 
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STANDARD OPERATING PROCEDURES FOR LIVER ENZYME 
6.5
ELEVATIONS
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 (for age and sex), 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 3.4.6.2).  Alkaline phosphatase reference 
ranges for age and sex are listed in the table below.
Alkaline Phosphatase Reference Ranges by Age and Sex1
Age Range (years)
Reference Ranges for 
Females (U/L)
Reference Ranges for 
Males (U/L)
10 – 12
51 - 332
42 - 362
13 – 15
50 - 162
74 - 390
16 – 17
47 - 119
52 - 171
≥18 
30 – 115
43 - 115
1 If testing is performed by a local laboratory, then reference ranges from that local 
laboratory should be used 
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 (see 
Section 3.4.6.2).
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.
 
 
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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); and (c) Hepatitis C (antibody).
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 study medication 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 study medication 
therapy interrupted immediately.
Once interrupted, reinstatement of therapy must occur only after consultation with a 
Merck Clinical Monitor. 
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 Merck Clinical Monitor 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 Merck Clinical Monitor.
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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PREDEFINED LIMITS OF CHANGE (PDLC)
6.6
The following predefined limits of change will be assessed in the statistical analysis, as 
described in Section 3.5.
Laboratory Test
Predefined Limits of Change† Criterion
Categories Assessed for Each Criterion
At Least One Value
Last On-Treatment 
Value
Laboratory – Hematology
Hemoglobin (g/dL)
1.  Decrease ≥1.5 g/dL
N
Y
WBC Count (103/microL)
1.  Decrease ≥50% and value < LLN
Y
Y
2.  Increase ≥20% and value > ULN
Y
Y
Neutrophil Count (103/microL)
1.  Decrease ≥20%  and value < LLN
Y
Y
2.  Increase ≥20% and value > ULN
Y
Y
Lymphocyte Count (103/microL)
1.  Decrease ≥20% and value < LLN
Y
Y
2.  Increase ≥20% and value > ULN
Y
Y
Platelet Count (103/microL)
1.  Decrease ≥25% and value < LLN 
Y
Y
2.  Increase ≥100% and value > ULN
Y
Y
Laboratory – Chemistry
BUN (mg/dL)
1.  Increase ≥50% and value > ULN
N
Y
Serum Creatinine (mg/dL)
1.  Increase ≥0.3 mg/dL
N
Y
Total Bilirubin (mg/dL)
1.  Value ≥2×ULN
Y
Y
Direct Bilirubin (mg/dL)
1.  Increase ≥50% and value > ULN
Not applicable for 
this study
Not applicable for 
this study
AST (IU/L)
1.  Value ≥3×ULN
Y
Y
2.  Value >5×ULN
Y
Y
3.  Value >10×ULN
Y
Y
4.  Value >20×ULN
Y
Y
ALT (IU/L)
1.  Value ≥3×ULN
Y
Y
2.  Value >5×ULN
Y
Y
3.  Value >10×ULN
Y
Y
4.  Value >20×ULN
Y
Y
AST (IU/L) or ALT (IU/L)
1.  Value ≥3×ULN
Y
Y
2.  Value >5×ULN
Y
Y
3.  Value >10×ULN
Y
Y
4.  Value >20×ULN
Y
Y
AST (IU/L) or ALT (IU/L)+
Total Bilirubin (mg/dL)
1.  ALT ≥3×ULN or AST ≥3×ULN with 
Bilirubin ≥2×ULN
Y
Y
Alkaline Phosphatase (IU/L)
1.  Value >1.5×ULN
Y
Y
Serum Uric Acid (mg/dL)
1.  Increase ≥50% and value > ULN
Y
Y
Serum Sodium (mEq/L)
1.  Decrease ≥10 mEq/L and value < LLN
N
Y
2.  Increase ≥10 mEq/L and value > ULN
N
Y
Serum Potassium (mEq/L)
1.  Decrease ≥1.0 mEq/L and value < LLN
N
Y
2.  Increase ≥1.0 mEq/L and value > ULN
N
Y
Serum Calcium (mg/dL)
1.  Increase ≥1.0 mg/dL and value > ULN
N
Y
2.  Decrease ≥1.0 mg/dL and value < LLN
N
Y
†  Increases and decreases are relative to baseline.
LLN = Lower limit of normal; ULN = upper limit of normal; WBC = white blood cell; BUN = blood urea nitrogen; AST = 
aspartate aminotransferase; ALT = alanine aminotransferase.
 
 
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MEAL TOLERANCE TEST (MTT) BLOOD SAMPLES, COLLECTION 
6.7
TIMES AND PROCEDURE
Blood Samples and Collection Time (Minutes From Start of Meal) 
-10
0 
10 
20 
30 
60 
90 
120 
180 
9-point MTT
Glucose
X
X
X
X
X
X
X
X
X
Insulin 
X
X
X
X
X
X
X
X
X
C-Peptide
X
X
X
X
X
X
X
X
X
Proinsulin
X
Note: The MTT will not be performed on patients on background insulin therapy.
9-point MTT
Samples will be collected 10 minutes before ingesting the meal (T = -10 min), immediately 
prior to start of ingesting the meal (T=0 min), at 10 minutes (T=10 minutes) after the start of 
the meal, at 20 minutes (T=20 minutes) after the start of the meal, at 30 minutes (T=30 
minutes) after the start of the meal, at 60 minutes after the start of the meal (T=60 min), at 90 
minutes (T=90 minutes) after the start of the meal, at 120 minutes after the start of the meal 
(T=120 min), and at 180 minutes at the start of the meal (T=180 minutes).
Note: At Visit 8, patients will take the dose of double-blind study medication from the 
previous visit’s blister-pack (Phase A) as a witnessed dose 30 minutes prior to the start of the 
standard meal for the MTT (T= -30 minutes).
Samples for glucose, insulin, and C-peptide will be collected at all time points. Proinsulin 
will be collected only at time zero (T=0 min).
Note: All blood samples for the 9-point MTT should be carefully timed, and the label 
with the appropriate time point should be placed on the blood sample tubes.
An MTT should not be performed at Visit 8/Week 20, Visit 11/Week 54, or the 
Discontinuation Visit if the patient has been rescued.  Also, an MTT should not be 
performed at the Discontinuation Visit if the patient has been off double-blind study 
medication ≥5 days, if the study medication was discontinued due to an adverse event, or if 
the visit occurs prior to Visit 5/Week 4.
Meal Tolerance Test Procedures
The following procedures should be performed in the order specified:
1) An indwelling catheter to obtain samples is preferred (using either a heparin lock or an 
infusion IV with saline to keep the vein open and catheter used only for blood sampling).
2) Fasting blood samples obtained (See Study Flow Chart [Section 1.7] for specific samples 
to obtain).
 
 
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3) Dosing of Study Medication:
Visit 3/Day 1: First dose of double-blind study medication should be taken after all 
blood samples for the MTT are obtained (i.e., after the 180 minute sample is drawn).
Visit 8/Week 20 and Visit 11/Week 54 (or at Discontinuation Visit/Rescue [Step 1 or 
Treat-to-Goal Step 1] Visit):  Patients will take the dose of double-blind study 
medication from the previous visit’s blister-pack as a witnessed dose exactly 30 minutes 
prior to ingesting the standard meal for the MTT (T=-30 minutes).  Patients who 
participate in the MTT at Visit 8/Week 20 will be contacted by the site the day after the 
visit to collect the date and time that study medication was taken.
4) Meal administered immediately after time “0” blood samples for glucose, insulin, and 
proinsulin are obtained.
5) Carefully draw timed blood samples for glucose, insulin, C-peptide and proinsulin (time 
zero only) relative to the start of the meal:  -10, 0 (immediately prior to eating), 10, 20, 
30, 60, 90, 120, and 180 minutes. The “0” time should be considered from when the 
patient starts eating.  Blood samples should be carefully timed and the label with the 
appropriate time point should be placed on the blood tubes.
The patient should remain sitting or supine during the period of the test, with the 
exception of going to the restroom. The patient should be encouraged to eat the standard 
meal (see below for description of standard meal), over a period of up to 15 minutes. At 
the Visit 3/Day 1 MTT, if the patient is unable to finish the meal in 15 minutes, the 
period may be extended to 20 minutes. If the entire meal (bar and drink) is not eaten in 20 
minutes, the amount of the bar and drink ingested should be documented, and a similar 
amount of the bar and drink should be provided at Visit 8/ Week 20 and Visit 11/Week 
54 (or at Discontinuation Visit/Rescue [Step 1 or Treat-to-Goal Step 1] visit) MTTs
and should be consumed in a similar period of time.
If the patient is unable or unwilling to ingest the meal or finishes only a minimal amount 
(e.g., <50%), the MTT should be stopped without further sample collection.  If the patient 
was unable or unwilling to complete the MTT at Visit 3/ Day 1, the patient should not 
have a MTT performed at Visit 8/Week 20 or Visit 11/Week 54 (or at Discontinuation 
Visit/Rescue [Step 1 or Treat-to-Goal Step 1] visit). Patients with hypersensitivity or 
dietary restrictions to the contents of the nutrition drink or bars will omit the protocol-
specified MTT.
 
 
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TANNER STAGING
6.8
Tanner Stages of Maturation
In male patients, Tanner Staging will be assessed by testicular volume and pubic hair 
distribution as denoted in the listings below. An orchidometer (Prader) will be used to 
evaluate testicular volume. The testes will be palpated with a gloved hand and the wooden 
ball of the orchidometer that most closely matches the testicular size is determined. For each 
male patient, Tanner Staging will be recorded for both pubic hair and testicular volume.
In female patients, Tanner Staging will be evaluated by the stage of breast development and 
pubic hair distribution as denoted in the listings below.  If breast development is 
asymmetrical, the development should be characterized using the more advanced stage. 
Additionally, each female patient will be asked at each visit if menarche has occurred and 
this information will be captured at each visit.  For each female patient, Tanner Staging will 
be recorded for both pubic hair and breast.
Pubic hair (both male and female) 

Tanner I -- none (prepubertal state)

Tanner II -- small amount of long, downy hair with slight pigmentation at the base

Tanner III -- hair becomes more coarse and curly, and begins to extend laterally

Tanner IV -- adult-like hair quality, extending across pubis but sparing medial thighs

Tanner V -- hair extends to medial surface of the thigh
Genitals (male) 

Tanner I -- prepubertal (testicular volume less than 1.5 ml; small penis)

Tanner II -- testicular volume between 1.6 and 6 ml; skin on scrotum thins, reddens 
and enlarges; penis length unchanged

Tanner III -- testicular volume between 6 and 12 ml; scrotum enlarges further; penis 
begins to lengthen

Tanner IV -- testicular volume between 12 and 20 ml; scrotum enlarges further and 
darkens; penis increases in length and circumference

Tanner V -- testicular volume greater than 20 ml; adult scrotum and penis
 
 
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Breasts (female) 

Tanner I -- no glandular tissue; areola follows the skin contours of the chest 
(prepubertal)

Tanner II -- breast bud forms, with small area of surrounding glandular tissue; breast 
bud within area of areola; areola begins to widen

Tanner III -- breast begins to become more elevated, and extends beyond the borders 
of the areola, which continues to widen but remains in contour with surrounding 
breast

Tanner IV -- increase breast size and elevation; areola and papilla form a secondary 
mound projecting from the contour of the surrounding breast

Tanner V -- breast reaches final adult size; areola returns to contour of the 
surrounding breast, with a projecting central papilla
 
 
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BMI-FOR-AGE CHARTS
6.9
Sites should follow their approved country specific BMI-for-age percentile charts, if 
available (e.g., sites within the United States will refer to the Centers for Disease Control 
charts). If an approved country-specific BMI-for-age percentile chart is not available, refer to 
the World Health Organization charts shown in the figures below.
Instructions for obtaining the body mass index-for-age percentile:

Find the child’s age on the horizontal axis.

Find the BMI measurement on the vertical axis (to determine BMI, please refer to 
Appendix 6.1).

The body mass index-for-age percentile will be at the intersection of the child’s age and 
BMI measurement.
BMI-for-Age—Girls, 5 to 19 Years (Percentiles)
2007 WHO Reference [64]
 
 
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BMI-for-Age—BOYS, 5 to 19 years (percentiles)
2007 WHO Reference [64]
 
 
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VISUAL ORAL EXAMINATION PROCEDURES
6.10
The investigator will perform a visual oral examination* by completing the following steps.  
The evaluation will be recorded on the eCRFs.
1. Patient brushes their teeth without toothpaste.  The investigator observes whether the 
gums bleed.
2. The investigator wipes teeth with gauze.
3. The investigator uses a flashlight and mirror to visually evaluate the gums (start top 
right to left then bottom left to right) and each tooth (same sequence).
*: Investigators have been trained to perform the VOE through materials specifically 
designed for this purpose.  This training will be repeated periodically. 
 
 
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MAPPING OF RELATIVE DAY RANGES TO WEEKS
6.11
The following rules will be used to map the relative day ranges to weeks for A1C, vitals, and 
laboratory parameters for summaries and analyses that are based on individual time points. If 
a patient has multiple observations within a day range, the observation that is closest to the 
target day (calculated as target week 7) will be used in the analyses. For summaries and 
analyses that are not based on individual time points (e.g., AEs and PDLCs), all results will 
be included without mapping to individual time points.
Required Phase
Relative Day Range 
prior amendment 05
Relative Day Range 
amendment 05 and beyond
Week
Day Relative to Start of Trial†
Day Relative to Start of Trial†
Any
Day ≤1
Day ≤1
0
A
43≤ Day ≤70
43≤ Day ≤70
8
A
71≤ Day ≤105
71≤ Day ≤119
14
A
Day 106
Day 120
20
Day Relative to Start of Phase B‡
Day Relative to Start of Phase B‡
B
1< Day ≤112
1< Day ≤112
30
B
113≤ Day ≤196
113≤ Day ≤196
42
B
Day 197
Day 197
54
†Start of Phase A is defined as first dose of Phase A study medication for all treated patients and the randomization day for 
patients who did not take any dose of study medication.
‡Start of Phase B is defined as first dose day of Phase B study medication or Visit 8 day for patients who entered Phase B 
off study medication.
In addition, the following will be used to map the relative day ranges to weeks for other 
endpoints. The following will be used to map the relative day ranges to weeks for FPG, 
Tanner 
staging, 
growth 
velocity, 
lipids, 
ECG, 
waist 
circumference, 
urine 
microalbumin/creatinine ratio, insulin related parameters, physical exams, and CD26.
Required Phase
Relative Day Range 
Week
Day Relative to Start of Trial†
Day ≤1
Day 70
Any
0
A
20
Day Relative to Start of Phase B‡
Day 119
B
54
† Start of Phase A is defined as first dose of Phase A study medication for all treated patients and the randomization day for 
patients who did not take any dose of study medication.
‡ Start of Phase B is defined as first dose day of Phase B study medication or Visit 8 day for patients who entered Phase B off 
study medication.
For the additional analysis that includes data collected after discontinuation of study 
medication, the same day ranges will be applied, regardless of trial Phase.  If a patient does 
not have a Week 20 visit, the Week 20 date will be imputed as 140 days after randomization 
prior to applying the day ranges in Phase B for the additional data beyond Week 20. 
 
 
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PATIENT RANDOMIZED TWICE
6.12
One patient is known to have been randomized twice. This patient consented to amendment 
083-05 but was given a randomization number belonging to amendment 083-01 because the 
site had not activated amendment 083-05 in IVRS prior to this randomization. This patient 
received study medication under the first randomization number for 6 days prior to being 
discontinued from the study. The patient was randomized a second time under amendment 
083-05, 3 days after the discontinuation from the study and was given a second
randomization number. The patient received study medication and continued participation in 
the study under the second randomization number.
In the clinical study report, both randomization numbers will be presented in tabulations of 
study disposition.  Data associated with the second randomization number will be included in 
demographic, safety, and efficacy tables. No adverse events were reported and no post-
randomization efficacy and safety data were collected under the first randomization number. 
 
 
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COLLECTION AND MANAGEMENT OF SPECIMENS FOR FUTURE 
6.13
BIOMEDICAL RESEARCH 
6.13.1 Scope of Future Biomedical Research
The DNA, serum, and plasma specimens collected in the current trial will be used to study 
various causes for how patients may respond to a drug.  The DNA, serum, and plasma 
specimens will be stored to provide a resource for future studies conducted by Merck focused 
on the study of biomarkers responsible for how a drug enters and is removed by the body, 
how a drug works, other pathways a drug may interact with, or other aspects of disease.
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, 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 Merck or designees and research will be monitored and 
reviewed by a committee of our scientists and clinicians.
6.13.2 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 response.2
c.
Pharmacogenetics:  A subset of pharmacogenomics, pharmacogenetics is the influence of 
variations in DNA sequence on drug response.2
d. DNA:  Deoxyribonucleic acid.
e.
RNA:  Ribonucleic acid.
6.13.3 Summary of Procedures for Future Biomedical Research
a.
Patients for Enrollment
All patients enrolled in the clinical trial will be considered for enrollment in the Future 
Biomedical Research sub-study.
                                                
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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b. Informed Consent
Informed consent for specimens (i.e., DNA, RNA, protein, etc) will be obtained during 
screening for protocol enrollment from all patients or legal guardians, at a study visit by 
the investigator or his or her designate.  Informed consent for Future Biomedical 
Research should be presented to the patients on Visit 1.  If delayed, present consent at 
next possible Patient Visit.  Informed consent must be obtained prior to collection of all 
Future Biomedical Research specimens.
Patients are not required to participate in the Future Biomedical Research sub-study in 
order to participate in the main trial.
Consent forms signed by the patient will be kept at the clinical trial site under secure 
storage for regulatory reasons.  Information contained on the consent form alone cannot 
be traced to any specimens, test results, or medical information once the specimens have 
been rendered de-identified.  Patients who decline to sign the Future Biomedical 
Research informed consent will not have the specimen collected nor will they be 
discontinued from the main study.
A template of each study site’s approved informed consent will be stored in the Sponsor’s 
clinical document repository.  Each consent will be assessed for appropriate specimen 
permissions.
Each informed consent approved by an ethics committee is assigned a unique tracking 
number.  The tracking number on this document will be used to assign specimen 
permissions for each specimen into the Entrusted Keyholder’s Specimen Database.
c.
eCRF Documentation for Future Biomedical Research Specimens
Documentation of both consent and acquisition of Future Biomedical Research 
specimens will be captured in the electronic Case Report Forms (eCRFs).  Reconciliation 
of both forms will be performed to assure that only appropriately-consented specimens 
are used for this sub-study's research purposes. Any specimens for which such an 
informed consent cannot be verified will be destroyed.
d. Future Biomedical Research Specimen Collections
Blood specimens for DNA or RNA isolation will usually be obtained at a time when the 
patient is having blood drawn for other study purposes.  Specimens like tissue and bone 
marrow will usually be obtained at a time when the patient is having such a procedure for 
clinical purposes.
Specimens will be collected and sent to the laboratory designated for the trial where they 
will be processed (e.g., DNA or RNA extraction, etc) following the Merck approved 
policies and procedures for specimen handling and preparation.
 
 
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6.13.4 Confidential Patient 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 patient' clinical information with future test results. In fact 
little or no research can be conducted without connecting the clinical study data to the 
specimen. The clinical data allow specific analyses to be conducted. Knowing patient 
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, Merck has developed secure policies and procedures.  All specimens will be de-
identified as described below.
At the clinical 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 patient identifiers and this first unique code will be held at the study site.  No 
personal identifiers will appear on the specimen tube.
This first code will be replaced with a second code at a Merck designated storage/lab facility.  
The second code is linked to the first code via a second key. The specimen is now double 
coded.  Specimens with the second code are sometimes referred to as de-identified 
specimens. The use of the second code provides additional confidentiality and privacy 
protection for patients over the use of a single code.  Access to both keys would be needed to 
link any data or specimens back to the patient's identification.
The second code is stored separately from the first code and all associated personal specimen 
identifiers.  A secure link, the second key, will be utilized to match the second code to the 
first code to allow clinical information collected during the course of the study to be 
associated with the specimen.  This second key will be transferred under secure procedures 
by the Merck designated facility to an Entrusted Keyholder at Merck.  The second code will 
be logged into the primary biorepository database at Merck and, in this database, this 
identifier will not have identifying demographic data or identifying clinical information (i.e., 
race, sex, age, diagnosis, lab values) associated with it. The specimen will be stored in a 
designated biorepository site with secure policies and procedures for specimen storage and 
usage.
The second key can be utilized to reconstruct the link between the results of future 
biomedical research and the clinical information, at the time of analysis.  This linkage would 
not be possible for the scientist conducting the analysis, but can only be done by the Merck 
Entrusted Keyholder under strict security policies and procedures.  The Merck Entrusted 
Keyholder will link the information and then issue a de-identified data set for analysis.  The 
only other circumstance by which future biomedical research data would be directly linked to 
the full clinical data set would be those situations mandated by health authorities (e.g., 
EMEA, FDA), whereby this information would be directly transferred to the health authority.
 
 
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6.13.5 Biorepository Specimen Usage
Specimens obtained for the Merck Biorepository will be used for analyses using good 
scientific practices.  However, exploratory analyses will not be conducted under the highly 
validated conditions usually associated with regulatory approval of diagnostics.  The scope of 
research performed on these specimens is limited to the investigation of the variability in 
biomarkers that may correlate with a clinical phenotype in patients.
Analyses utilizing the Future Biomedical Research specimens may be performed by Merck, 
or an additional third party (e.g., a university investigator) designated by Merck.  The 
investigator conducting the analysis will be provided with double coded specimens.  Re-
association of analysis results with corresponding clinical data will only be conducted by the 
Merck Entrusted Keyholder.  Any contracted third party analyses will conform to the specific 
scope of analysis outlined in this sub-study.  Future Biomedical Research specimens 
remaining with the third party after the specific analysis is performed will be returned to the 
sponsor or destroyed and documentation of destruction will be reported to Merck.
6.13.6 Withdrawal From Future Biomedical Research
Patients may withdraw their consent for Future Biomedical Research and have their 
specimens and all derivatives destroyed.  Patients may withdraw consent at any time by 
writing to the principal investigator for the main study.  If medical records for the main study 
are still available, the Investigator will contact MERCK using the designated mailbox 
(clinical.specimen.management@merck.com) and a form will be provided by MERCK to 
obtain appropriate information to complete specimen withdrawal.  Subsequently, the patient's 
specimens will be removed from the biorepository and be destroyed.  A letter will be sent 
from MERCK to the investigator confirming the destruction.  It is the responsibility of the 
Investigator to inform the patient 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 study data and results.  No 
new analyses would be generated after the request is received.
In the event that the medical records for the main study are no longer available (e.g., if the 
investigator is no longer required by regulatory agencies to retain the main study records) or 
the specimens have been completely anonymized, there will no longer be a link between the 
patient’s personal information and their specimens. In this situation, the request for specimen 
destruction cannot be processed.
6.13.7 Retention of Specimens
Future Biomedical Research specimens will be stored in the biorepository for potential 
analysis for up to 20 years from acquisition.  Specimens may be stored for longer if a 
regulatory or governmental agency has active questions that are being answered.  In this 
special circumstance, specimens will be stored until these questions have been adequately 
addressed.
 
 
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Specimens from the site will be shipped to a central laboratory and then shipped to the Merck 
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 Merck policies and procedures and this destruction will be 
documented in the biorepository database.
6.13.8 Data Security
Separate databases for specimen information and for results from the Future Biomedical 
Research sub-study will be maintained by Merck.  This is done to separate the future 
exploratory test results (which include genetic data) from the clinical trial database thereby 
maintaining a separation of patient number and these results.  The separate databases are 
accessible only to the authorized sponsor and the designated study administrator research 
personnel and/or collaborators.  Database user authentication is highly secure, and is 
accomplished using network security policies and practices based in international standards 
(e.g., ISO17799) to protect against unauthorized access.  The Merck Entrusted Keyholder 
maintains control over access to all specimen data.  These data are collected for future 
biomedical research purposes only as specified in this sub-study will not be used for any 
other purpose.
6.13.9 Reporting of Future Biomedical Research Data to Patients
There is no definitive requirement in either authoritative ethical guidelines or in relevant 
laws/regulations globally that research results have to be, in all circumstances, returned to 
study participant.  Some guidelines advocate a proactive return of data in certain instances.  
No information obtained from exploratory laboratory studies will be reported to the patient or 
family, and this information will not be entered into the clinical database maintained by 
Merck on patients.  Principle reasons not to inform or return results to the patient include: 
lack of relevance to patient health, limitations of predictive capability, concerns of 
misinterpretation, and absence of good clinical practices standards in exploratory research 
typically used for diagnostic testing.
If any exploratory results are definitively associated with clinical significance for patients 
while the clinical trial is still ongoing, investigators will be contacted with information as to 
how to offer clinical diagnostic  testing (paid for by Merck) to patients enrolled and will be 
advised that  counseling should be made available for all who choose to participate in this 
diagnostic testing.
If any exploratory results are definitively associated with clinical significance after 
completion of a clinical trial, Merck will publish the results without revealing specific patient 
information, inform all sites who participated in the Merck clinical trial, and post 
anonymized results on our website or other accredited website(s) that allow for public access 
(e.g., Disease societies who have primary interest in the results) in order that physicians and 
patients may pursue clinical diagnostic testing if they wish to do so.
 
 
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6.13.9.1 Gender, Ethnicity, and Minorities
Although many diagnoses differ in terms of frequency by ethnic population and gender, 
every effort will be made to recruit all patients diagnosed and treated on Merck clinical trials 
for future biomedical research.  When studies with specimens are conducted and patients 
identified to serve as controls, every effort will be made to group specimens from patients 
and controls to represent the ethnic and gender population representative of the disease under 
current investigation.
6.13.10 Risks Versus Benefits of Future Biomedical Research 
For future biomedical research, risks to the patient 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 study.
Merck has developed strict security, policies and procedures to address patient 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.
It is necessary for patient-related data (i.e., ethnicity, diagnosis, drug therapy and dosage, 
age, toxicities, etc.) to be reassociated to double coded specimens at the time of data analysis.  
These patient data will be kept in a separate, secure Merck database, and all specimens will 
be stripped of patient identifiers.  No information concerning results obtained from future 
biomedical research will be entered into clinical records, nor will it be released to outside 
persons or agencies, in any way that could be tied to an individual patient.
6.13.11 Self-Reported Ethnicity
Parents/guardians of patients who participate in future biomedical research will be asked to 
provide ethnicity of the patient.  Patients who do not wish to provide this data may still 
participate in future biomedical research.
Questions
Any questions related to the future biomedical research should be e-mailed directly to 
clinical.specimen.management@merck.com.
 
 
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SUPPLEMENTAL DENTAL DATA SUB-STUDY
6.14
Note: Procedures for the Supplemental Dental Data Substudy do not apply to Brazil and 
Serbia.
6.14.1 Sub-Study Objective
The purpose of this sub-study is to enhance the dental data collected from the visual oral 
examination to support secondary objectives to summarize data on the change from baseline 
in measures of dentition at Week 20 and Week 54 (Section 2.1.2).
6.14.2 Sub-Study Design and Procedures
New and ongoing patients (on or off study medication) participating in the main study, P083, 
will be asked to participate in this sub-study to collect supplemental dental data.  Patients 
who previously completed 54 weeks of the main study (on or off study medication) are also 
eligible to participate. Patients who have withdrawn consent from P083 are not eligible.  
Note: Patients currently enrolled in MK-0431 P351 are also eligible to be contacted to 
participate in this sub-study.
For all patients participating in the sub-study, supplemental dental data will consist of: 
1. The patient’s dental records for dental exams performed prior to the study (closest 
available record prior to randomization), during the study, at completion of the 
study, and after completion of the study (for patients who have completed the study 
prior to the approval of the dental sub-study amendment).
2. Dental photographs taken at the time points indicated in the sub-study flow charts 
(Table 6-1, Table 6-2, and Table 6-3).  
Details regarding procedures for dental records and photographs can be found in the separate 
instruction document provided to the investigator.
Note: These dental assessments as part of the dental data sub-study are in addition to the 
VOE procedures listed in the main protocol conducted by the investigator.  
For patients who have completed 54 weeks of the main study prior to entering the sub-study, 
supplemental dental data will also include:
1. A visual oral examination (including inspection of teeth) performed by the 
investigator as described in Appendix 6.10.  
2. Collection of events and medications of particular dental interest starting at Week 54 
of the main study until the post main study Dental Visit (Table 6-3).  Serious AEs are 
to be recorded as described in Section 3.4.6.1. Procedure-related adverse events 
occurring on the day of the post-study dental exam will be recorded on the Adverse
Events eCRF.  Non-serious dental events occurring after completion of the main 
study through the Dental Visit will be recorded on the Medical History – New 
Conditions eCRF.
 
 
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Independent Reviewer Assessment
A Dental Charter will define how the independent reviewer will evaluate all relevant, 
available data for each patient (including but not limited to VOE, dental records and dental 
photographs) and determine if there has been an overall change in the patient’s dental status.
All personnel involved in the review process will remain blinded to treatment allocation 
throughout the trial. 
6.14.3 Sub-Study Sample Size
There is no predetermined sample size for this sub-study.  All eligible patients randomized 
into the main study and who consent to participate will be included in this sub-study.   
6.14.4 Sub-Study Inclusion Criteria
1. Patient was randomized into P083 and has taken at least one dose of study 
medication, including new and ongoing patients (on or off study medication), and 
patients who previously completed 54 weeks of the main study (on or off study 
medication). 
Note:  Patients currently enrolled in MK-0431 P351 are also eligible to be contacted 
to participate in this sub-study. 
2. a) Patient who can legally consent, understands the sub-study procedures, and 
voluntarily agrees to participation by giving informed written consent; or b) Patient 
who cannot legally consent, has an age-appropriate understanding of the study 
procedures, and gives informed written assent and their parent/guardian agrees to 
participation by giving informed written consent. If the parent/guardian is illiterate, 
see Section 3.2.3.13.1 for details. 
6.14.5 Sub-Study Patient Definition
New Patients – Patients who have been randomized after the approval of amendment 12.  
Ongoing Patients – Patients who were randomized prior to approval of amendment 12 
AND: 

are continuing on study medication, or

have discontinued study medication and are within 54 weeks of randomization 
Completed Patients - Patients who completed 54 weeks from date of randomization to P083 
(includes patients on or off study medication and patients participating in P351).   
 
 
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6.14.6 Sub-Study Flow Charts
Sub-study flow charts for new patients, ongoing patients, and patients who previously 
completed 54 weeks of the main study are outlined in Table 6-1, Table 6-2, and Table 6-3.  
Note:  For all new and ongoing patients, sub-study visits will be combined with the pre-
existing visits for the main study.  No new or additional visits are required.  
Table 6-1
Sub-Study Flow Chart for New Patients
Screening
Week 0/
Day 1
Week 
20
Week 
54
Rescue Step 1 or Treat 
to Goal Step 1 or 
Discontinuation
Obtain informed consent and assent1
X
Evaluate inclusion criteria
X
Dental photographs
X
X
X
X
Collection of dental records
X2
X3 
X3 
X3 
X3 
1.
Consent/assent forms must be signed prior to any sub-study specific procedures.    
2.
The patient’s parent/guardian and/or the patient will be asked if the patient has had any dental exams prior 
to screening. If so, the closest available record before randomization will be obtained from the patient’s 
personal dentist (if consent/assent provided).
3.
The patient’s parent/guardian and/or the patient will be asked if the patient has had any dental exams since 
the last study visit.  If so, these records will be obtained from the patient’s personal dentist (if 
consent/assent provided).
Table 6-2
Sub-Study Flow Chart for Ongoing Patients 
First Clinic Visit 
Following Dental 
Sub-Study 
Amendment 
Approval 1
Week 20
Week 54
Rescue Step 1 or 
Treat to Goal Step 
1 or 
Discontinuation
Obtain informed consent and assent2
X
Evaluate inclusion criteria
X
Dental photographs
X
X
X
X
Collection of dental records
X3
X4
X4
X4
1.
Ongoing patients will be able to participate in this sub-study starting at their first clinic visit (per the main 
protocol) following dental sub-study amendment approval at the site.  For patients who have discontinued 
study medication, this First Clinic Visit would be either Week 20 or Week 54.
2.
Consent/assent forms must be signed prior to any sub-study specific procedures.     
3.
The patient’s parent/guardian and/or the patient will be asked if the patient has had any dental exams prior 
to the first clinic visit after this sub-study approval at the site. If so, the closest available record before 
randomization and all available records since randomization will be obtained from the patient’s personal 
dentist (if consent/assent provided).
4.
The patient’s parent/guardian and/or the patient will be asked if the patient has had any dental exams since 
the last study visit.  If so, these records will be obtained from the patient’s personal dentist (if 
consent/assent provided). 
 
 
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Table 6-3
Sub-Study Flow Chart for Patients who Completed 54 weeks of the Main Study 
Dental Visit
(Post Main Study)
Obtain informed consent and assent1
X
Evaluate inclusion criteria
X
Collect post treatment dental events and medications2
X
Monitor for adverse events3
X
Visual oral examination (including inspection of teeth)4
X
Dental photographs
X
Collection of dental records5,6
X
1.
Consent/assent forms must be signed prior to any sub-study specific procedures.   
2.
Collect events and medications of particular dental interest. 
3.
The AE reported should occur in conjunction with the dental sub-study visit.    
4.
Patients returning after completing P083 will have a visual oral examination (see Appendix 6.10).   
5.
The patient’s parent/guardian and/or the patient will be asked if the patient has had any dental exams prior 
to randomization to P083. If yes, the closest available dental record prior to randomization will be collected
from the patient’s personal dentist (if consent/assent provided). 
6.
The patient’s parent/guardian and/or the patient will be asked if the patient has had any dental exams during 
his/her participation in P083 and after completion of 54 weeks of this main study. If so, these records will 
be collected from the patient’s personal dentist (if consent/ assent provided).  
 
 
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LIST OF PRIOR AMENDMENTS
6.15
Amendment 01 dated 14-Jan-2013, Global.
Amendment 02 dated 30-Apr-2013, Country-specific, Germany.
Amendment 03 dated 30-Mar-2013, Country-specific, Mexico.
Amendment 04 dated 29-Apr-2013, Country-specific, Brazil.
Amendment 05 dated 19-Feb-2014, Global.
Amendment 06 dated 06-Mar-2014, Country-specific, Germany.
Amendment 07 dated 01-Dec-2014, Global.
Amendment 08 dated 07-Jan-2015, Country-specific, Germany.
Amendment 09 dated 27-Aug-2015, Global
Amendment 10 dated 16-Oct-2015, Country-specific, Germany
Amendment 11 not released.
Amendment 12 dated 27-Jan-2017, Global.
Amendment 13 dated 20-Feb-2017, Country-specific, Germany.
Amendment 14 not released.
Amendment 15 not implemented. 
 
 
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7. ATTACHMENTS
Merck & Co., Inc. Code of Conduct for Clinical Trials
Pharmacogenomics Informational Brochure for IRBs/IECs & Investigational Site Staff
 
 
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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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8. SIGNATURES
SPONSOR’S REPRESENTATIVE
8.1
TYPED NAME
SIGNATURE
DATE
INVESTIGATOR
8.2
I agree to conduct this clinical study 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); deviations from the protocol are acceptable only with a 
mutually agreed upon protocol amendment. I agree to conduct the study 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 the SAFETY MEASUREMENTS section of this protocol. 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 study 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
SIGNATURE
DATE
 
 
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