Clinical trial NCT01760447
Conditions: Type 2 Diabetes Mellitus
Sponsor: Merck Sharp & Dohme LLC
Start date: 2011-12-07; Completion date: 2019-09-17
Enrollment: 223 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to assess the effect of the addition of sitagliptin (administered as MK-0431A or MK-0431A XR) relative to the addition of placebo on glycated hemoglobin (A1C), and the safety and tolerability of the addition of sitagliptin, in pediatric participants (ages 10-17 years) with type 2 diabetes mellitus with inadequate glycemic control on metformin therapy (alone or in combination with insulin). The primary hypothesis is that the addition of sitagliptin reduces glycated hemoglobin (A1C) more than the addition of placebo after 20 weeks of treatment.

Detailed description:

Arms: arm 1: Participants received one tablet of sitagliptin/metformin and one tablet of metformin-placebo, administered twice daily prior to the morning and evening meals, for up to 20 weeks in the base study alone, or for up to 54 weeks if the participant also entered the extension study. Participants in this arm were enrolled in protocol MK-0431A-170. arm 2: Participants received one tablet of metformin and one tablet of placebo to sitagliptin/metformin, administered twice daily prior to the morning and evening meals, for up to 20 weeks in the base study alone, or for up to 54 weeks if the participant also entered the extension study. Participants in this arm were enrolled in protocol MK-0431A-170. arm 3: Participants received two tablets of sitagliptin/metformin XR and two tablets of metformin XR placebo, administered once daily with a meal, for up to 54 weeks. Participants in this arm were enrolled in protocol MK-0431A-289. arm 4: Participants received two tablets of metformin XR and two tablets of placebo to sitagliptin/metformin XR, administered once daily with a meal, for up to 54 weeks. Participants in this arm were enrolled in protocol MK-0431A-289.
Interventions: intervention 1: Sitagliptin plus metformin intervention 2: Placebo to metformin intervention 3: Metformin intervention 4: Placebo to sitagliptin plus metformin intervention 5: Sitagliptin plus metformin XR intervention 6: Placebo to metformin XR intervention 7: Insulin intervention 8: Placebo to sitagliptin plus metformin XR intervention 9: Metformin XR
Intervention descriptions: intervention 1: Participants received 2 tablets daily, one taken with a morning meal and one taken with an evening meal, to provide a total daily dose of 100 mg of sitagliptin and 1000 mg, 1700 mg or 2000 mg of metformin. Dosage of metformin was based on each participant's daily metformin dose prior to enrollment. intervention 2: Participants received 2 tablets daily, one taken with a morning meal and one taken with an evening meal. Each tablet contained placebo to metformin. intervention 3: Participants received 2 tablets daily, one taken with a morning meal and one taken with an evening meal, to provide a total daily dose of 1000 mg, 1700 mg or 2000 mg of metformin. Dosage was based on each participant's daily metformin dose prior to enrollment. intervention 4: Participants received 2 tablets daily, one taken with a morning meal and one taken with an evening meal. Each tablet contained placebo to sitagliptin plus metformin. intervention 5: Participants received 2 tablets daily, both taken together with a meal, to provide a total daily dose of 100 mg of sitagliptin and 1000 mg, 1500 mg or 2000 mg of metformin. Dosage of metformin XR was based on each participant's daily metformin dose prior to enrollment. intervention 6: Participants received 2 tablets daily, both taken together with a meal. Each tablet contained placebo to metformin XR. intervention 7: Participants who met protocol-specific glycemic rescue criteria received insulin as glycemic rescue therapy; participants on background insulin had their insulin dose increased for glycemic rescue. During Weeks 20-54, for participants who were not on background insulin or rescued with insulin during Weeks 0-20 in the "Sitagliptin/Metformin" and "Metformin" arms (protocol MK-0431A-170), and during Weeks 0-54 for participants not on background insulin in the "Sitagliptin/Metformin XR" and "Metformin XR" arms (protocol MK-0431A-289), the type of insulin for glycemic rescue was specified to be insulin glargine. intervention 8: Participants received 2 tablets daily, both taken together with a meal. Each tablet contained placebo to sitagliptin plus metformin XR. intervention 9: Participants received 2 tablets daily, both taken together with a meal, to provide a total daily dose of 1000 mg, 1500 mg or 2000 mg of metformin XR. Dosage was based on each participant's daily metformin dose prior to enrollment.

Protocol documents:
Prot_SAP_000.pdf: 
Official Protocol Title: 
NCT number: 
NCT01760447 
Document Date: 
03-Apr-2018
A Phase III Multicenter, Double-Blind, Randomized, Placebo-Controlled 
Clinical Trial to Evaluate the Safety and Efficacy of MK-0431A XR (a Fixed-
Dose Combination Tablet of Sitagliptin and Extended-Release Metformin) in 
Pediatric Patients with Type 2 Diabetes Mellitus With Inadequate Glycemic 
Control on Metformin Therapy (Alone or in Combination with Insulin)


Product:  MK-0431A
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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 MK-0431A XR (a Fixed-Dose Combination Tablet of 
Sitagliptin and Extended-Release Metformin) in Pediatric Patients with Type 2 Diabetes 
Mellitus With Inadequate Glycemic Control on Metformin Therapy (Alone or in 
Combination with Insulin)
INVESTIGATOR:
PRIMARY:
CLINICAL PHASE: III
US IND NUMBER:
101,964
EudraCT NUMBER: 2012-004035-23
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.................................................................................................................11
1.1
TITLE ....................................................................................................................11
1.2
INDICATION........................................................................................................11
1.3
SUMMARY OF RATIONALE.............................................................................11
1.4
SUMMARY OF STUDY DESIGN ......................................................................11
1.5
SAMPLE ...............................................................................................................12
1.6
DOSAGE/DOSAGE FORM, ROUTE, AND DOSE REGIMEN.........................13
1.7
STUDY FLOW CHART.......................................................................................14
2. CORE PROTOCOL.....................................................................................................18
2.1
OBJECTIVES AND HYPOTHESES ...................................................................18
2.1.1
Primary ...........................................................................................................18
2.1.2
Secondary .......................................................................................................18
2.1.3
Exploratory:....................................................................................................19
2.2
PATIENT INCLUSION CRITERIA.....................................................................20
2.3
PATIENT EXCLUSION CRITERIA....................................................................22
2.4
STUDY DESIGN AND DURATION...................................................................28
2.4.1
Summary of Study Design..............................................................................28
2.4.2
Treatment Plan................................................................................................28
2.4.2.1
Study Visits General Information ...........................................................31
2.4.2.2
Visit 1/Screening Visit............................................................................32
2.4.2.3
Visit 2 Single-Blind Placebo Run-In ......................................................32
2.4.2.4
Visit 3/Randomization Visit to Visit 6/Week 20:  Phase A 
Double-Blind Treatment Period..............................................................33
2.4.2.5
Visit 6/Week 20 through Visit 9/Week 54:  Phase B Double-
blind Treatment Period............................................................................33
2.4.2.6
Glycemic Rescue – Phase A ...................................................................34
2.4.2.7
Discontinuation.......................................................................................35
2.4.2.7.1
The Reason for Protocol-Specified Discontinuation From 
the Study is Listed Below................................................................36
2.4.2.7.2
Reasons for Protocol-Specified Discontinuation From Study 
Medication Are Listed Below .........................................................36
2.4.2.8
Mandatory Post-study Telephone Follow-up..........................................38
2.4.3
Beginning and End of Study Definition.........................................................38
2.5
LIST OF EFFICACY/PHARMACOKINETIC/IMMUNOGENICITY, 
ETC., MEASUREMENTS....................................................................................38
2.6
LIST OF SAFETY MEASUREMENTS...............................................................38
2.7
STATISTICAL ANALYSIS PLAN SUMMARY................................................38
2.7.1
Efficacy Analyses...........................................................................................38
2.7.2
Safety Analyses ..............................................................................................39
 
 
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2.7.3
Power and Sample Size ..................................................................................39
2.7.4
Interim Analysis .............................................................................................40
3. PROTOCOL DETAILS...............................................................................................41
3.1
RATIONALE ........................................................................................................41
3.1.1
Background and Rationale for this Study.......................................................41
3.1.2
Rationale for Efficacy Endpoints ...................................................................42
3.1.3
Rationale for Selection of Study Population ..................................................42
3.1.4
Rationale for Dose Regimen ..........................................................................43
3.1.5
Rationale for Placebo Use ..............................................................................46
3.1.6
Future Biomedical Research...........................................................................46
3.2
STUDY PROCEDURES.......................................................................................47
3.2.1
Concomitant Medication(s)/Treatment(s) ......................................................47
3.2.2
Diet/Activity/Other.........................................................................................48
3.2.3
Procedures ......................................................................................................48
3.2.3.1
Monitoring of Glycemic Control ............................................................48
3.2.3.2
Monitoring for Ketones...........................................................................49
3.2.3.3
Assessment and Management of Hypoglycemia ....................................49
3.2.3.4
Pregnancy Testing and Contraception ....................................................51
3.2.3.5
Anthropometric Measurements...............................................................51
3.2.3.6
Laboratory Monitoring............................................................................52
3.2.3.7
ECG Procedures......................................................................................52
3.2.3.8
Assessment of Swallowing Ability.........................................................52
3.2.3.9
Tanner Staging........................................................................................53
3.2.3.10 Collect Substance Use Information.........................................................53
3.2.3.11 Informed Consent....................................................................................53
3.2.3.11.1 General Informed Consent ..............................................................53
3.2.3.11.1.1 Consent and Collection of Specimens for Future 
Biomedical Research ...............................................................54
3.2.3.11.1.2 Collection of Specimens for Future Biomedical 
Research from Minors .............................................................54
3.2.3.11.1.3 Future Biomedical Research....................................................54
3.2.3.12 Assignment of Screening Number..........................................................54
3.2.3.13 Patient Identification Cards.....................................................................54
3.2.3.14 Stratification............................................................................................54
3.2.3.15 Randomization/Allocation ......................................................................54
3.2.3.16 Poststudy Follow-Up...............................................................................55
3.2.3.16.1 Poststudy Contact for Patients Who Have Completed the 
Study................................................................................................55
3.2.3.16.2 Follow-Up of Patients Who Have Discontinued Study 
Medication Prior to Study Completion ...........................................55
3.2.3.17 Blinding/Unblinding ...............................................................................56
3.2.3.18 Interruption/Discontinuation/Withdrawal from Study Medication.........57
3.2.3.18.1 Withdrawal from Future Biomedical Research...............................57
3.2.3.19 Discontinuation Visit Procedures............................................................58
3.2.3.20 Collect Substance Use Information.........................................................58
 
 
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3.3
EFFICACY/PHARMACOKINETIC/IMMUNOGENICITY, ETC. 
MEASUREMENTS...............................................................................................58
3.3.1
Clinical and Laboratory Measurements for Efficacy .....................................58
3.3.2
Medication Compliance..................................................................................58
3.4
SAFETY MEASUREMENTS ..............................................................................59
3.4.1
Clinical and Laboratory Measurements for Safety.........................................59
3.4.1.1
Assessment of Swallowability of MK-0431A XR tablets ......................59
3.4.2
Data Monitoring Committee...........................................................................60
3.4.2.1
Executive Oversight Committee.............................................................60
3.4.2.2
Data Monitoring Committee...................................................................60
3.4.3
Recording Adverse Events .............................................................................60
3.4.4
Definition of an Overdose for This Protocol..................................................61
3.4.4.1
Reporting of Overdose to SPONSOR.....................................................62
3.4.5
Reporting of Pregnancy to SPONSOR...........................................................62
3.4.6
Immediate Reporting of Adverse Events to the SPONSOR ..........................62
3.4.6.1
Serious Adverse Events ..........................................................................62
3.4.6.2
Selected Nonserious Adverse Events......................................................63
3.4.7
Guidance on Adverse Events Related to Glycemia........................................64
3.4.7.1
Hyperglycemia........................................................................................64
3.4.7.2
Hypoglycemia.........................................................................................65
3.4.7.2.1
Documentation ................................................................................65
3.4.7.2.2
Guidance..........................................................................................65
3.4.8
Evaluating Adverse Events.............................................................................65
3.4.9
SPONSOR Responsibility for Reporting Adverse Events.............................68
3.5
STATISTICAL ANALYSIS PLAN (SAP)...........................................................68
3.5.1
Responsibility for Analyses/In-House Blinding.............................................68
3.5.2
Hypotheses/Estimation...................................................................................68
3.5.3
Analysis Endpoints.........................................................................................68
3.5.3.1
Efficacy Endpoints..................................................................................69
3.5.3.2
Safety Endpoints .....................................................................................69
3.5.3.3
Derivation of Efficacy Endpoints ...........................................................70
3.5.4
Analysis Populations ......................................................................................70
3.5.4.1
Efficacy Analysis Populations ................................................................70
3.5.4.2
Safety Analysis Populations....................................................................71
3.5.5
Statistical Methods .........................................................................................71
3.5.5.1
Statistical Methods for Efficacy Analyses..............................................71
3.5.5.2
Statistical Methods for Safety Analyses .................................................78
3.5.5.3
Summaries of Baseline Characteristics and Demographics....................83
3.5.6
Multiplicity.....................................................................................................83
3.5.7
Sample Size and Power Calculations .............................................................83
3.5.7.1
Sample Size and Power for Efficacy Analyses.......................................83
3.5.7.2
Sample Size and Power for Safety Analyses ..........................................85
3.5.8
Subgroup Analyses.........................................................................................85
3.5.9
Interim Analyses.............................................................................................86
3.5.10 Compliance (Medication Adherence).............................................................86
3.5.11 Extent of Exposure .........................................................................................87
 
 
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3.6
LABELING, PACKAGING, STORAGE, DISPENSING, AND RETURN 
OF CLINICAL SUPPLIES ...................................................................................87
3.6.1
Patients and Replacement Information...........................................................87
3.6.2
Product Descriptions ......................................................................................87
3.6.3
Primary Packaging and Labeling Information ...............................................88
3.6.4
Clinical Supplies Disclosure...........................................................................89
3.6.5
Storage and Handling Requirements..............................................................89
3.6.6
Standard Policies / Return of Clinical Supplies .............................................89
3.6.7
Comparator Statement....................................................................................90
3.7
DATA MANAGEMENT ......................................................................................90
3.8
BIOLOGICAL SPECIMENS................................................................................90
4. ADMINISTRATIVE AND REGULATORY DETAILS............................................91
4.1
CONFIDENTIALITY ...........................................................................................91
4.1.1
Confidentiality of Data...................................................................................91
4.1.2
Confidentiality of Patient Records .................................................................91
4.1.3
Confidentiality of Investigator Information ...................................................92
4.2
COMPLIANCE WITH LAW, AUDIT, AND DEBARMENT.............................92
4.3
COMPLIANCE WITH FINANCIAL DISCLOSURE REQUIREMENTS..........93
4.4
QUALITY CONTROL AND QUALITY ASSURANCE ....................................94
4.5
COMPLIANCE WITH INFORMATION PROGRAM ON CLINICAL 
TRIALS FOR SERIOUS OR LIFE THREATENING CONDITIONS ................94
4.6
PUBLICATIONS ..................................................................................................94
5. LIST OF REFERENCES.............................................................................................96
6. APPENDICES ...........................................................................................................102
6.1
BMI-FOR-AGE CHARTS ..................................................................................102
6.2
BLOOD PRESSURE TABLE FOR GENDER/AGE/HEIGHT FOR 
BOYS AGE 10-17...............................................................................................105
6.3
BLOOD PRESSURE TABLE BY GENDER/AGE/HEIGHT FOR GIRLS 
AGE 10-17...........................................................................................................106
6.4
STANDARD OPERATING PROCEDURES FOR LIVER ENZYME 
ELEVATIONS ....................................................................................................107
6.5
COLLECTION AND MANAGEMENT OF SPECIMENS FOR FUTURE 
BIOMEDICAL RESEARCH ..............................................................................110
6.5.1
Scope of Future Biomedical Research .........................................................110
6.5.2
Definitions....................................................................................................110
6.5.3
Summary of Procedures for Future Biomedical Research ...........................110
6.5.4
Confidential Patient Information for Future Biomedical Research..............112
6.5.5
Biorepository Specimen Usage ....................................................................113
6.5.6
Withdrawal From Future Biomedical Research...........................................113
6.5.7
Retention of Specimens................................................................................113
6.5.8
Data Security ................................................................................................114
6.5.9
Reporting of Future Biomedical Research Data to Patients.........................114
6.5.10 Gender, Ethnicity, and Minorities ................................................................115
6.5.11 Risks Versus Benefits of Future Biomedical Research................................115
 
 
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6.5.12 Self-Reported Ethnicity................................................................................115
6.5.13 Questions......................................................................................................115
6.6
BLOOD PRESSURE AND ANTHROPOMETRIC MEASUREMENTS .........116
6.7
LABORATORY EVALUATIONS.....................................................................119
6.8
MAPPING OF RELATIVE DAY RANGES TO WEEKS.................................121
6.9
PREDEFINED LIMITS OF CHANGE (PDLC).................................................122
6.10 CONSTRAINED LONGITUDINAL DATA ANALYSIS (CLDA) 
METHOD (WITH ADJUSTMENT FOR BASELINE VALUES) –
TECHNICAL DETAILS FOR MODEL SPECIFICATION, 
ASSUMPTIONS, AND SAS IMPLEMENTATION CODES............................123
6.11 TANNER STAGING...........................................................................................125
6.12 List of Prior Amendments ...................................................................................127
7. ATTACHMENTS......................................................................................................128
8. SIGNATURES...........................................................................................................140
8.1
SPONSOR’S REPRESENTATIVE ....................................................................140
8.2
INVESTIGATOR................................................................................................140
 
 
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SUMMARY OF CHANGES
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 post study reporting 
activities initiated.
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. 
-To define estimands as recommended by 
ICH E9 (R1).
-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.
1.6
Dosage/Dosage Form, 
Route, and Dose Regimen
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.
- To ensure patient laboratory results for 
eligibility assessment are recent. 
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.
To ensure patient laboratory results for 
eligibility assessment are recent.
2.4.1
Summary of Study Design
The number of patients per group was 
removed from the Study Design figure.
The sample size was modified. 
2.4.2.1
Study Visits General 
Information
-Clarified that patients should also 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.
-To clarify the duration of the placebo run-
in period and to harmonize with the current 
guidance to investigators.
 
 
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Section 
Number
Section Title
Description of Change
Rationale
2.4.2.3
Visit 2 Single-Blind 
Placebo Run-In
Emphasized completion of procedures 
before dosing.
To ensure that results from procedures are 
not affected by administration of study 
medication. This approach is also used at 
the placebo-run in Visit to maintain 
consistency with other visits. 
2.4.2.4
Visit 3/Randomization 
Visit to Visit 6/Week 20
2.4.2.5
Visit 6/Week 20 through 
Visit 9/Week 54
2.7.3
Power and Sample Size
Power and sample size were updated. 
To reflect revised sample size.
3.1.4
Rationale for Dose 
Regimen
Updated information on study P296.
Study P296 has completed.
3.2.3.6
Laboratory Monitoring
Clarified that patients should only be 
fasting for Visits 1, 3, 6, 9, Rescue, and 
Discontinuation, but not for other visits.
To limit patient burden of fasting for visits 
where fasting is not required. 
3.2.3.17
Blinding/Unblinding
Text on unblinding of patients was 
updated.
To reflect protocol template updates. 
3.5.1
Responsibility for 
Analyses/In-House 
Blinding
Added that 1 CSR will be written for this 
study, and pooled analyses with P170 
(base and extension) will be included in a 
separate report.
To clarify the reporting plan. 
3.5.4.1
Efficacy Analysis 
Populations
Completers population was removed.
The population not related to estimands.
3.5.5.2
Statistical Methods for 
Safety Analyses
Changed safety analyses approach –
primary approach will include data after 
rescue except for hypoglycemia endpoints.
Simplification of analysis approach.
3.5.7.1
Sample Size and Power for 
Efficacy Analyses
Updated sample size and power 
information.
To reflect revised sample size. 
 
 
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Section 
Number
Section Title
Description of Change
Rationale
3.5.7.2
Sample Size and Power for 
Safety Analysis
Updated sample size.
To reflect revised sample size.
3.5.8
Subgroup Analyses
Subgroup analyses for P289 alone were
removed.
Subgroup analyses will be based on pooled 
data instead of P289 alone.
3.5.10
Compliance (Medication 
Adherence)
Adherence definition was added.
To reflect compliance based on time in 
study.
3.6.1
Patients and Replacement 
Information
Updated sample size.
To reflect revised sample size. 
5
List of References
List of references was updated.
Deleted references that are no longer 
applicable.
6.8
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
List of Prior Amendments
List was updated.
Update.
Entire 
document
-The word ‘subject’ was replaced with the 
word ‘patient’.
-Editorial and formatting changes.
Consistency throughout the document.
 
 
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1. SUMMARY
1.1
TITLE
A Phase III Multicenter, Double-Blind, Randomized, Placebo-Controlled Clinical Trial to 
Evaluate the Safety and Efficacy of MK-0431A XR (a Fixed-Dose Combination Tablet 
of Sitagliptin and Extended-Release Metformin) in Pediatric Patients with Type 2 
Diabetes Mellitus With Inadequate Glycemic Control on Metformin Therapy (Alone or in 
Combination with Insulin)
1.2
INDICATION
For the treatment of pediatric patients (10-17 years of age, inclusive) with type 2 diabetes 
mellitus (T2DM) with inadequate glycemic control on metformin therapy (alone or in 
combination with insulin).
1.3
SUMMARY OF RATIONALE
This study, MK-0431A P289, is designed to assess the safety and efficacy of the addition 
of sitagliptin (administered as MK-0431A extended-release [XR]) compared with the 
addition of placebo to therapy with extended-release metformin (metformin XR) for the 
treatment of T2DM in pediatric patients (10-17 years of age, inclusive) who have
inadequate glycemic control on metformin therapy (alone or in combination with insulin).
Based on data from adult patients, the safety and efficacy of the addition of sitagliptin is 
not expected to differ based on the background metformin therapy; therefore, the safety 
and tolerability of the addition of sitagliptin to metformin XR are expected to be similar 
to that of adding sitagliptin to metformin.  Hence, the data from the P170 base study and 
from the first 20 weeks of P289 will be combined for the primary analyses of each study.
A separate study, MK-0431A P170 base study, is a 20-week study to assess the safety 
and efficacy of sitagliptin added to ongoing metformin therapy compared with the 
addition of placebo to ongoing metformin therapy for the treatment of T2DM in pediatric 
patients (10-17 years of age, inclusive) with inadequate glycemic control on metformin
(alone or in combination with insulin). MK-0431A P170 has an extension study to the 
original 20-week P170 base study and is designed to provide an assessment of safety for 
an additional 34 weeks in patients from the P170 base study who agree to participate in 
the extension study. Week 0 to Week 54 data from P289 will be combined with Week 0 
to Week 54 data from P170 (base + extension) for this longer-term assessment. Refer to 
Sections 3.1 and 3.5 for additional details.
1.4
SUMMARY OF STUDY DESIGN
This is a multinational, randomized, double-blind, parallel-group study.  The study will 
be approximately 56 weeks in duration, including a screening period of 1 week (Visits 1 
to 2), a 1-week single-blind placebo run-in period (Visits 2 to 3), and a 54-week double-
blind treatment period (Visits 3 to 9).  The treatment periods will consist of Phase A (a 
20-week placebo-controlled period [Visits 3 to 6]) and Phase B (a 34-week active-
 
 
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controlled period [Visits 6 to 9]), as shown in Figure 2-1 (Section 2.4.1).  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 medication) to assess for 
any serious adverse events (SAEs). Please refer to Section 3.2.3.16.2 for details.
At Visit 1, patients 10-17 years of age (inclusive) with T2DM on a stable dose of 
metformin (≥1500 mg/day, for ≥12 weeks) without insulin or those on stable doses of 
metformin (≥1500 mg/day, for ≥12 weeks) and insulin (of any type, variance in dose to 
be ≤15% of total daily dose, for ≥12 weeks) will be eligible to be screened.  
At Visit 2, eligible patients with inadequate glycemic control (hemoglobin A1c [A1C] of 
≥6.5% and ≤10.0% on metformin monotherapy and ≥7.0% or ≤10.0% for those on dual 
therapy with metformin and insulin at Visit 1) will undergo diet and exercise counseling.  
Based on their current dose of metformin (immediate-release [IR] or XR), patients will be 
switched to the appropriate corresponding dose of Sponsor-supplied metformin XR and 
initiate MK-0431A XR placebo. Those patients who enter the study on background 
insulin will continue their insulin throughout the study.
At Visit 3/Day 1, patients will be randomized in a 1:1 ratio to treatment with either MK-
0431A XR and metformin XR placebo or with metformin XR and MK-0431A XR 
placebo.  Randomization will be stratified by the following:  1) dose of metformin at 
Visit 1 and 2) insulin use at Visit 1.  The dose of double-blind study medication will 
remain stable for the duration of the study.  At Visit 6/Week 20 (end of Phase A 
treatment period, beginning of Phase B) and subsequent visits in Phase B, all patients will 
remain on their randomized double-blind study medication and if their glycemic values 
meet the protocol-specified thresholds (Section 2.4.2), patients on background insulin 
will uptitrate their background insulin and patients not on background insulin will initiate 
insulin glargine.   
1.5
SAMPLE
At least 90 patients, but no more than 110 patients (10 to 17 years of age, inclusive) with 
T2DM who have inadequate glycemic control will be eligible to participate if they meet 
ONE of the following enrollment criteria:  

A1C of ≥6.5% and ≤10.0% at Visit 1 on a stable dose of metformin (≥1500 
mg/day, for ≥12 weeks) without insulin.
OR

A1C ≥7.0% and ≤10.0% at Visit 1 on stable doses of metformin (≥1500 mg/day, 
for ≥12 weeks) and insulin (of any type, variance in dose to be ≤15% of total 
daily dose, for ≥12 weeks). 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. 
 
 
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Note: Patients on stable doses of metformin ≥1000 mg and <1500 mg/day (±insulin) for 
≥12 weeks can participate if there is documentation in the patient’s medical records that 
they cannot tolerate higher doses of metformin. 
At least 30% of the randomized patients will be 10 to 14 years of age.  
1.6
DOSAGE/DOSAGE FORM, ROUTE, AND DOSE REGIMEN 
MK-0431A XR (sitagliptin/metformin XR: 50/500 mg, 50/1000 mg tablets), metformin 
XR (500 and 1000 mg tablets), and their matching placebos, will be supplied by the 
Sponsor (see Table 2-2). All insulin will be sourced locally.  
During the 1-week single-blind placebo run-in period, patients will receive the following 
treatments:

two tablets of metformin XR (500 mg x 2; 500 mg and 1000 mg; or 1000 mg x 2) 
and two tablets of MK-0431A XR placebo (matching the metformin XR dose), 
administered once daily with a meal, preferably in the evening
During the 54-week double-blind treatment period, patients will receive one of the 
following treatments:

two tablets of MK-0431A XR (50/500 mg x 2; 50/500 mg and 50/1000 mg; or 
50/1000 mg x 2) and two tablets of metformin XR placebo (matching the 
metformin dose in MK-0431A XR), administered once daily with a meal, 
preferably in the evening 

two tablets of metformin XR (500 mg x 2; 500 mg and 1000 mg; or 1000 mg x 2) 
and two tablets of MK-0431A XR placebo (matching the metformin XR dose), 
administered once daily with a meal, preferably in the evening 
Open-label insulin (for background) and open-label insulin glargine will be sourced 
locally and administered subcutaneously based on instructions provided by the 
Investigator (based on accepted local, national or international guidelines for use of 
insulin).  
Doses of background insulin should remain stable (of any type, variance in dose to be 
≤15% of total daily dose) for the duration of the trial (See Section 2.4.2.5 and 2.4.2.6 for 
uptitration, Section 3.2.3.1 for down-titration of insulin, and Section 1.5 for insulin stable 
regimen definition).
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.
 
 
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1.7
STUDY FLOW CHART
Screening
Run-In
Random-
ization
Double-Blind Treatment
Phase A
Double-Blind Treatment
Phase B
Post-Study
Phone 
Contact
V.1
V.2
Wk -1
V.3
Day 1
TC
Wk 2
TC
Wk 4
V.4
Wk 6
V.5
Wk 12
TC
Wk 16
V.6
Wk 20
TCs1
V.7
Wk 28
V.8
Wk 40
V.9
Wk 54
Visit
Rescue2/
D/C3
Wk 56 or
14 days post-
discon.
Study Procedures
Obtain informed consent and assent4
X
Obtain informed consent and assent for Future 
Biomedical Research (FBR)
X
Dispense patient identification card
X
Evaluate Inclusion/Exclusion criteria
X
X
X
Monitor for Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
X
X5
Collect medical history6
X
Review prior/concomitant medication
X
X
X
X
X
X
X
X
X
X
Perform physical exam
X
X
X
X
Perform Tanner Staging
X
X
X
X
Measure vital signs (HR, BP measured twice)
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)
X7
X
X
X
Site Assessment of Swallowability
X
X
X
Swallowing Ability Questionnaire
X
X
X
X
X
X
X
X
X
Diet/exercise counseling8
X
Diet/exercise monitoring and re-inforcement
X
X
X
X
X
X
X
X
X
Dispense hypoglycemia assessment tool(s)9
X
X
X
X
X
X
Instruct on hypoglycemia symptoms and management
X
X
X
X
X
X
X
X
X
X
Review of  hypoglycemia assessment tool(s) 
X
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)  
X
Dispense ketone testing kit and provide instructions
X
Review thresholds for rescue (Phase A) and initiating 
insulin glargine (Phase B)10
X
X
X
X
X
X
X
X
X
Witness Dose
X
X
X
Dispense single-blind placebo medication
X
Assess for single-blind medication compliance
X
Dispense double-blind study medication
X
X
X
X
X
X
Initiate insulin glargine11
(X)
(X)
(X)
 
 
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Screening
Run-In
Random-
ization
Double-Blind Treatment
Phase A
Double-Blind Treatment
Phase B
Post-Study
Phone 
Contact
V.1
V.2
Wk -1
V.3
Day 1
TC
Wk 2
TC
Wk 4
V.4
Wk 6
V.5
Wk 12
TC
Wk 16
V.6
Wk 20
TCs1
V.7
Wk 28
V.8
Wk 40
V.9
Wk 54
Visit
Rescue2/
D/C3
Wk 56 or
14 days post-
discon.
Study Procedures
Assess/Reinforce double-blind medication compliance
X
X
X
X
X
X
X
X
X
X
X
Review/Reinforce SMBG measurements
X
X
X
X
X
X
X
X
X
X
X
X
Monitoring and Central Laboratory Procedures
Site fingerstick A1C12
X
X
(X)
(X)
Fasting plasma glucose13
X
X
X
X
X
A1C
X
X
X
X
X14
X
X
X14
X15
Site fingerstick glucose
X
X
(X)
(X)
Fasting C-peptide13
X
Complete Blood Count (CBC)/Differential
X
X
X
X
X
X
X
Chemistry panel
X
X
X
X
X
X
X
Fasting Insulin and  Proinsulin16
X
X
X17
Lipid panel13
X
X
X
X
X
TSH
X
Dipstick Urinalysis18
X
X
X
X
X
Urine microalbumin/creatinine ratio19
X
X
X
X
Urine Pregnancy test (for all females)20
X
X
X
X
X
X
X
X
X
Blood sample (serum and plasma) for FBR21
X
X
X
X
Blood sample (for genetics) for FBR22
X
 
 
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  NOTE:  Clinic Visit 4, Visit 5, Visit 7, and Visit 8 may be performed by a qualified health professional at the patient’s home/location other than the site if approved by the country and local IRB/EC.
1.
Perform telephone contacts to the patient weekly between the visit at which insulin/insulin glargine is uptitrated/initiated and the next clinic visit; additional phone contacts may be done at the discretion    
of the investigator.
2.
All rescue procedures should be performed prior to the initiation of rescue therapy.  If the Rescue Visit occurs on a scheduled study visit, all procedures for that visit should be performed. If the 
Discontinuation Visit occurs on a scheduled study visit, all Visit 9 procedures should be performed. If the Rescue or Discontinuation Visit is performed at an unscheduled visit within 4 weeks of Visit 3
or Visit 6, do not perform a physical examination, Tanner Staging, height and waist circumference measurements, ECG,  hematology, chemistry, and lipid blood panel measurements, dipstick urinalysis, 
urine microalbumin/creatinine measurements,  urine pregnancy test, and FBR sampling. 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 3.2.3.16.2).
3.
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 at key visits 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 (ie, not at week 20 or 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 3.2.3.16.2 for further details. 
4.
Consent form must be signed prior to any study specific procedures; informed consent will be obtained from the parent/legal guardian and assent will be obtained from the patient.
5.
Collect serious adverse events only.
6.
Male and female patients 10 to ≤14 years collect up to 5 years of relevant medical history. Male and female patients 15-17 years collect up to 7 years of relevant medical history.
7.
The ECG may be done at Visit 2 or at Visit 3, but must be read and evaluated for study eligibility before the patient receives double-blind study medication at Visit 3.  
8.
Patients will be seen by a dietitian or qualified health professional for diet/exercise counseling at Visit 2.
9.
The hypoglycemia assessment tool(s) will be provided as paper or as an electronic device, per site approval, and will be reviewed at each visit.  The tool(s) will be dispensed at Visit 2 and re-dispensed as 
needed per molality. The paper Low Blood Sugar Calendar and Notepad will be collected at each visit and a new Low Blood Sugar Calendar will be dispensed as needed during the trial.  The Low Blood 
Sugar Calendar from the previous visit will be re-dispensed at Visit 3.
10. The patient and parent/guardian will be informed of the fingerstick glucose rescue threshold that is applicable until the next visit and will be instructed to call the site if the fasting fingerstick glucose (FFSG) value is greater 
than this threshold on 3 consecutive days. Patients and parents should be counseled that if one FFSG value is above the threshold for rescue, the FFSG has to be checked the following morning. If the FFSG value is above the 
threshold for rescue on two consecutive days, the FFSG has to be checked on the third day as well, and the site called if all three values are above the thresholds for rescue.  After the patient/parent/guardian calls the site with 
FFSG values that exceed the thresholds for 3 consecutive days, and after assessing for compliance with study medication, an FPG will be performed, and the patient will be rescued if the FPG is greater than the threshold 
specified in Table 2-3.  For reference, site personnel will record the threshold for rescue in the fingerstick glucose log book.  In Phase B, the patient and parent/guardian will be instructed to call the site if the FFSG value is 
>130mg/dL on 2 consecutive days.  After the patient/parent/guardian calls the site with FFSG values that are >130 mg/dL for 2 consecutive days, an unscheduled visit will be scheduled, and patients will be instructed to either 
uptitrate their background insulin or initiate insulin glargine if their FFSG and A1C meet the thresholds at the unscheduled visit.
11. Beginning at Visit 6/Week 20 or at any visit thereafter, patients who have not been rescued in Phase A will either uptitrate their background insulin or initiate insulin glargine if their FFSG >130 mg/dL 
(7.2 mmol/L) and their FS A1C >7.5% at the visit.  See Section 2.4.2.5.
12. At Visit 1, a site fingerstick A1C may be used, at the discretion of the investigator, for screening purposes; a laboratory A1C must be used to meet inclusion criteria for eligibility.  At Visit 6/Week 20, a 
site fingerstick A1C must be performed as part of the assessment for uptitration of background insulin or initiation of insulin glargine.  If background insulin is not uptitrated or if insulin glargine is not 
started at Visit 6/Week 20, a site fingerstick A1C must be done at all subsequent visits until the background insulin is uptitrated, or until insulin glargine is initiated or the study is completed.  See Section 
2.4.2.5.
13. If the patient is not fasting at Visit 1/Screening Visit, a fasting lipid profile, FPG, and fasting C peptide should be obtained at or prior to Visit 2 rather than at Visit 1.
14. For patients who agree to continued follow-up and further data collection after discontinuing study medication, the investigator will record A1C values obtained from other sources (if available) around 
Week 20 and Week 54.
15. Blood sample for A1C should not be collected if the Discontinuation Visit or Rescue Visit occurs prior to Week 8.
16.
Samples for fasting insulin and proinsulin should not be collected on patients on insulin (background, rescue [Phase A], or glycemic therapy [Phase B]).  
17. Perform only if Rescue or Discontinuation occurs prior to Visit 6/Week 20.
 
 
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18. If dipstick (midstream urine specimen) is positive for blood, WBC (eg, 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.
19. 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.
20. 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.
21. Serum and plasma for future biomedical research will be obtained for randomized patients who sign the FBR consent.
22. Informed consent for future biomedical research samples must be obtained before the DNA sample.  DNA sample for analysis should be obtained predose, on Day 1 (or with the next scheduled blood draw), as 
the last sample drawn, on randomized patients only, or at a later date as soon as the informed consent is obtained.
 
 
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2. CORE PROTOCOL
2.1
OBJECTIVES AND HYPOTHESES
Section 3.1.1 presents the rationale for pooling data from the two studies.
2.1.1
Primary
For MK-0431A XR P289:
(1) Objective: Over 54 weeks, to assess the safety and tolerability of the addition of 
sitagliptin (administered as MK-0431A XR) in pediatric patients (ages 10-17 years) 
with T2DM with inadequate glycemic control on metformin therapy (alone or in 
combination with insulin).  
For the pooled study population (patients from MK-0431A XR P289 Phase A and 
MK-0431A P170 base study):
(2) Objective: after 20 weeks, to assess the effect of the addition of sitagliptin 
(administered as MK-0431A or MK-0431A XR) relative to the addition of placebo on 
A1C in pediatric patients (ages 10-17 years) with T2DM with inadequate glycemic 
control on metformin therapy (alone or in combination with insulin).
Hypothesis: The addition of sitagliptin reduces A1C more than the addition of 
placebo after 20 weeks.
For the pooled study population (patients from MK-0431A XR P289 Phases A+B 
and MK-0431A P170 base and extension studies):
(3) Objective:  Over 54 weeks, to assess the safety and tolerability of the addition of 
sitagliptin (administered as MK-0431A or MK-0431A XR) in pediatric patients (ages 
10-17 years) with T2DM with inadequate glycemic control on metformin therapy
(alone or in combination with insulin).
2.1.2
Secondary
For the pooled study population (patients from MK-0431A XR P289 Phase A and 
MK-0431A P170 base study):
(1) Objective:  After 20 weeks, to assess the effect of the addition of sitagliptin 
(administered as MK-0431A or MK-0431A XR) relative to placebo on fasting plasma 
glucose (FPG) in pediatric patients (ages 10-17 years) with T2DM with inadequate 
glycemic control on metformin therapy (alone or in combination with insulin).
(2) Objective:  After 20 weeks, to assess the effect of the addition of sitagliptin 
(administered as MK-0431A or MK-0431A XR) relative to placebo on the proportion 
of patients initiating glycemic rescue therapy in pediatric patients (ages 10-17 years) 
with T2DM with inadequate glycemic control on metformin therapy (alone or in 
combination with insulin).
 
 
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(3) Objective:  After 20 weeks, to assess the effect of the addition of sitagliptin 
(administered as MK-0431A or MK-0431A XR) relative to placebo on the proportion 
of patients with A1C at goal (<7.0%) in pediatric patients (ages 10-17 years) with 
T2DM with inadequate glycemic control on metformin therapy (alone or in 
combination with insulin).
For the pooled study population (patients from MK-0431A XR P289 Phases A+B 
and MK-0431A P170 base and extension studies):
(4) Objective:  After 54 weeks, to assess the effect of the addition of sitagliptin 
(administered as MK-0431A or MK-0431A XR) on the change from baseline in A1C 
in pediatric patients (ages 10-17 years) with T2DM with inadequate glycemic control 
on metformin therapy (alone or in combination with insulin).
(5) Objective:  After 54 weeks, to assess the effect of the addition of sitagliptin 
(administered as MK-0431A or MK-0431A XR) on the change from baseline in FPG, 
in pediatric patients (ages 10-17 years) with T2DM with inadequate glycemic control 
on metformin therapy (alone or in combination with insulin).
(6) Objective:  After 54 weeks, to assess the effect of the addition of sitagliptin 
(administered as MK-0431A or MK-0431A XR) on the proportion of patients with 
A1C at goal (<7.0%) in pediatric patients (ages 10-17 years) with T2DM with 
inadequate glycemic control on metformin therapy (alone or in combination with 
insulin).
2.1.3
Exploratory:
For MK-0431A XR P289:
(1) Objective:  After 20 weeks, to assess the effect of the addition of sitagliptin 
(administered as MK-0431A XR) relative to placebo on the change from baseline in 
A1C and FPG in pediatric patients (ages 10-17 years) with T2DM with inadequate 
glycemic control on metformin therapy (alone or in combination with insulin).
(2) Objective:  After 20 weeks and after 54 weeks, to assess the effect of the addition of 
sitagliptin (administered as MK-0431A XR) relative to placebo on growth velocity 
and Tanner Staging in pediatric patients (ages 10-17 years) with T2DM with 
inadequate glycemic control on metformin therapy (alone or in combination with 
insulin).  
For the pooled study population (patients from MK-0431A XR P289 Phase A and 
MK-0431A P170 base study):
(3) Objective:  After 20 weeks, to assess the addition of sitagliptin (administered as MK-
0431A or MK-0431A XR) relative to placebo on growth velocity and Tanner Staging 
in pediatric patients (ages 10-17 years) with T2DM with inadequate glycemic control 
on metformin therapy (alone or in combination with insulin).
 
 
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For the pooled study population (patients from MK-0431A XR P289 Phases A+B 
and MK-0431A P170 base and extension studies):
(4) Objective:  After 54 weeks, to assess the addition of sitagliptin (administered as MK-
0431A or MK-0431A XR) relative to placebo on growth velocity and Tanner Staging 
in pediatric patients (ages 10-17 years) with T2DM with inadequate glycemic control 
on metformin therapy (alone or in combination with insulin).
2.2
PATIENT INCLUSION CRITERIA
All laboratory measurements (to determine eligibility) must be performed by the central 
laboratory after an overnight fast ≥10 hours in duration. A patient with screening 
values/findings outside ranges described in the protocol may, at the discretion of the 
investigator, have one repeat determination performed.  If the repeat value satisfies the 
criterion, the patient may continue in 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.
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 diagnosed by American Diabetes Association (ADA) criteria 
(eg, 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) documented in medical record.
b) Patient is assessed as having a clinical profile consistent with T2DM (eg, based 
upon body weight, family history, presentation).
c) Patient has BMI ≥85th percentile for age and sex at screening (or patient has a 
history of being overweight or obese at time of diagnosis of T2DM).  See 
Appendix 6.1.
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 must be included 
in the source documents at the site.
2.  Patient has
i)
T2DM for ≥2 years
 
 
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OR
ii) T2DM for <2 years and a fasting C-peptide value >0.6 ng/mL at Screening 
Visit/Visit 1.
Note: All patients on background insulin (see below) should have a fasting C-
peptide value >0.6 ng/mL at Screening Visit/Visit 1 regardless of duration of 
T2DM
3. (a) Patient is on a stable dose of metformin (≥1500 mg/day, for ≥12 weeks) without 
insulin and with A1C ≥6.5% and ≤10.0%.
OR
(b) Patient is on stable doses of metformin (≥1500 mg/day, for ≥12 weeks) and 
insulin (of any type, variance in dose to be ≤15% of total daily dose for ≥12 
weeks prior to Screening Visit/ Visit 1) with an A1C≥7.0% and ≤10%.
i.
Patients on stable doses of metformin ± insulin ≥1000 and <1500 mg/day for 
≥12 weeks can participate if there is documentation that they cannot tolerate 
higher doses of metformin.  
ii.
Patients on metformin ± insulin doses <1500 mg/day can have their 
metformin doses uptitrated to ≥1500 mg/day, and be eligible to participate 
after their dose remains stable for ≥12 weeks, if they meet all other eligibility 
criteria.
iii.
At screening, patients on insulin doses that are not stable can have the insulin 
doses adjusted and be eligible to participate after their dose remains stable for 
≥12 weeks, if they meet all other eligibility criteria. 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.  
iv.
Patients currently being treated with an AHA (other than insulin) in addition 
to metformin cannot be included in the study after wash-off.    
4. Patient is between 10 and 17 years of age (inclusive) on 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
 
 
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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 (eg, calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception. Adequate 
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 2 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.  Patients with an illiterate 
parent/guardian may be included if, in the opinion of the investigator, patient safety 
will not be compromised.  Please see Section 3.2.3.11.1 for details.  The 
parent/guardian and patient may also provide consent/assent for samples for Future 
Biomedical Research.  However, the patient may participate in the main trial without 
participating in Future Biomedical Research.
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 (ie, available for telephone calls, study visits and administration of study 
medication as needed).
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 pill count.
2.3
PATIENT EXCLUSION CRITERIA
All laboratory measurements (to determine eligibility) must be performed by the central 
laboratory after an overnight fast ≥10 hours in duration. A patient with screening 
values/findings outside ranges described in the protocol may, at the discretion of the 
investigator, have one repeat determination performed.  If the repeat value satisfies the 
criterion, the patient may continue in the screening process.  Only the specific out-of-
range value/finding should be repeated (not the entire panel).
 
 
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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
1. Patient has known type 1 diabetes mellitus or documented evidence of positive 
diabetes auto-antibodies (if performed when patient was diagnosed with diabetes).
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 
another 
antihyperglycemic agent.
Specific Treatments
4. Patient has previously taken a DPP-4 inhibitor (such as sitagliptin, vildagliptin, 
alogliptin, saxagliptin, or linagliptin) 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. Patient has initiated chronic treatment with a medication known to cause:
a.
weight gain within 30 days of Visit 1
OR
b. weight loss (such as orlistat) within 8 weeks of Visit 1
OR
c.
increase in blood glucose within 8 weeks of Visit 1
Note (a):  Patients on a weight loss program who are not in the maintenance 
phase, or who have undergone bariatric surgery within 12 months prior to signing 
the informed consent, will be excluded.
Note (b):  Patients who have been treated with an anti-psychotic agent within the 
past 12 weeks will be excluded.
 
 
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6. Patient is currently participating, or has participated, in a study in which the patient
received an investigational compound or used an investigational device within the 
prior 12 weeks of signing the informed consent or is not willing to refrain from 
participating in another study. 
Note:  a patient who has participated in a non-interventional or placebo study may be 
enrolled.  
7. 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.
8. Patient has undergone a surgical procedure within  4 weeks prior to signing informed 
consent or has major surgery planned during the study.
Note:  A patient who has undergone minor surgery within the prior 4 weeks and is 
fully recovered or a patient who has planned minor surgery may participate. Minor 
surgery is defined as a surgical procedure involving local anesthesia.
Concomitant Conditions or Diseases of Organs and Systems
9. Patient has a history of congenital heart disease or cardiovascular disease other than 
hypertension.
10. 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 may be 
enrolled if the patient’s blood pressure no longer meets exclusion criteria.
11. Patient has a medical history of active liver disease (other than non-alcoholic hepatic 
steatosis), including chronic active hepatitis B or C (assessed by medical history), 
primary biliary cirrhosis, or symptomatic gallbladder disease.
12. Patient has active nephropathy (ie, nephrotic syndrome or glomerulonephritis).
Note:  Patients with diabetic nephropathy will be eligible if they meet all other 
eligibility criteria.
13. Patient has chronic myopathy, mitochondrial disorder or a progressive neurological or 
neuromuscular disorder (eg, polymyositis, or multiple sclerosis).
14. Patient has human immunodeficiency virus (HIV) as assessed by medical history.
 
 
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15. Patient has a clinically important hematological disorder (such as aplastic anemia, 
thrombocytopenia, myeloproliferative or myelodysplastic syndrome).
16. Patient is currently being treated for hyperthyroidism or patient is on thyroid hormone 
therapy and has not been on a stable dose for at least 6 weeks.
Note: Patients under treatment for hypothyroidism with a normal TSH value may 
participate.
17. Patient exhibits abnormal growth patterns or is being treated with growth hormone.
18. Patient has a history of malignancy ≤5 years prior to signing informed consent, except 
for adequately treated basal cell or squamous cell skin cancer, or in situ cervical 
cancer.
Note (a):  A patient with a history of malignancy >5 years prior to signing informed 
consent should have no evidence of residual or recurrent disease
Note (b):  A patient with any history of melanoma, leukemia, lymphoma, or renal cell 
carcinoma is excluded.
19. Patient has a history of idiopathic acute pancreatitis or chronic pancreatitis.
Other Criteria
20. Patient has a known history of recreational or illicit drug use, or of alcohol abuse or 
dependence (within the past year).
21. 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.
22. Patient is pregnant or breast-feeding, or is expecting to conceive or donate eggs 
during the study, including 14 days following the last dose of study medication. 
23. Patient is unlikely to adhere to the study procedures, keep appointments, or 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.
24. 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.
 
 
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Exclusion Criteria Based on Laboratory Abnormalities
25. Patient has exclusionary laboratory values as listed in Table 2-1.
Table 2-1
Laboratory Exclusion Criteria
Parameter1
Study Limit for Exclusion
Creatinine2
Male: ≥1.4 mg/dL (≥124 μmol/L)
Female: ≥1.3 mg/dL (≥115 μmol/L)
Estimated glomerular filtration rate (GFR)2
<60 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 
1 If a screening lab is repeated, the last laboratory result should be used for to assess 
eligibility.
2 Either elevated creatinine or decreased estimated GFR, as assessed by modified
MDRD, meets the exclusion criteria.
3 Patients with elevated 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.
At Visit 2
26. Patient is unable to swallow study medication (based on witnessed dose).
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 “9”, or patient has a prolonged QTc 
interval for age.
At Visit 3/Randomization
29. Patient has symptomatic hyperglycemia, and/or ketonuria and/or positive test for 
ketonemia, requiring immediate initiation of antihyperglycemic therapy and in the 
opinion of the investigator is not considered likely to respond to diet and exercise 
intervention.
 
 
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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 pre-randomization period which meets any 
previously described study exclusion criterion or which, in the opinion of the 
investigator, exposes the patient to risk by enrolling in the study.
Note:  If a patient requires initiation of a new medication at Visit 3/Day 1, the current 
visit should be changed to an "Unscheduled Visit" and the patient should be 
rescheduled for a Visit 3/Day 1 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) >240 mg/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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2.4
STUDY DESIGN AND DURATION
2.4.1
Summary of Study Design
Figure 2-1
2.4.2
Treatment Plan
Refer to the Study Flow Chart (Section 1.7) for the procedures to be performed at each
visit.  Following initial screening and evaluation of metformin dose at Visit 1, eligible 
patients will proceed to Visit 2.  At Visit 2/Week -1, patients will undergo diet and 
exercise counseling, switch to Sponsor-supplied metformin XR at doses specified in
Table 2-2 to accommodate the available doses of metformin in MK-0431A XR, and 
initiate MK-0431A XR placebo.  Patients who enter the study on background insulin will 
continue on the same dose (of any type, variance of ≤15% of total daily dose) and 
formulation of insulin throughout the study (See Section 2.4.2.6 and 3.2.3.3 for Glycemic 
Rescue and Assessment and Management of Hypoglycemia).
 
 
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At Visit 3/Day 1, patients will be randomized in a 1:1 ratio to treatment with (1) MK-
0431A XR and metformin XR placebo or (2) metformin XR and MK-0431A XR 
placebo.  The dose of MK-0431A XR will be determined by the dose of metformin XR at 
Visit 2 (see Table 2-2). Patients will remain on a stable dose of double-blind study 
medication for the duration of the study.  Randomization will be stratified by: 1) dose of 
metformin at Visit 1, and 2) insulin use at Visit 1.
Table 2-2
Study Medication Scheme
Total Daily Dose of 
Metformin (IR or 
XR) at Visit 1
Total Daily Dose of Met XR and 
Single-Blind MK-0431A XR Placebo
to be Initiated at Visit 2
Total Daily Dose of 
Double-Blind Study Medication
to be Initiated at Visit 3
<1500 mg*
Met XR 
(metformin 1000 mg) 
• 2 tablets of Met XR 500 mg
• 2 tablets of MK-0431A XR 50/500 
mg placebo 
Once-a-day
MK-0431A XR 
(sitagliptin 100 mg; metformin 1000 mg)
• 2 tablets of  MK-0431A XR 50/500 mg
• 2 tablets of Met XR 500 mg placebo
Once-a-day 
-OR-
Met XR
(metformin 1000 mg)
• 2 tablets of  MK-0431A XR 50/500 mg
placebo
• 2 tablets of Met XR 500 mg, 
Once-a-day
1500 mg
Met XR 
(metformin 1500 mg)
• 1 tablet of Met XR 500 mg 
• 1 tablet of Met XR 1000 mg
• 1 tablet of MK-0431A XR 50/500 
mg  placebo 
• 1 tablet of  MK-0431A XR 50/1000 
mg placebo 
Once-a-day
MK-0431A XR 
(sitagliptin 100 mg; metformin 1500 mg)
• 1 tablet of MK-0431A XR 50/500 mg 
• 1 tablet of MK-0431A XR 50/1000 mg 
• 1 tablet of Met XR 500 mg placebo
• 1 tablet of Met XR 1000 mg placebo
Once-a-day
-OR-
Met XR 
(metformin 1500 mg)
• 1 tablet of MK-0431A XR 50/500 mg 
placebo 
• 1 tablet of MK-0431A XR 50/1000 mg 
placebo
• 1 tablet of Met XR 500 mg
• 1 tablet of Met XR 1000 mg 
Once-a-day
 
 
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Total Daily Dose of 
Metformin (IR or 
XR) at Visit 1
Total Daily Dose of Met XR and 
Single-Blind MK-0431A XR Placebo
to be Initiated at Visit 2
Total Daily Dose of 
Double-Blind Study Medication
to be Initiated at Visit 3
>1500 mg
Met XR 
(metformin 2000 mg)
• 2 tablets of Met XR 1000 mg
• 2 tablets of MK-0431A XR 50/1000 
mg placebo 
Once-a-day
MK-0431A XR 
(sitagliptin 100 mg; metformin 2000 mg)
• 2 tablets of  MK-0431A XR 50/1000 mg 
• 2 tablets of Met XR 1000 mg placebo
Once-a-day
-OR-
Met XR 
(metformin 2000 mg)
• 2 tablets of MK-0431A XR 50/1000 mg 
placebo
• 2 tablets of Met XR 1000 mg 
Once-a-day
* Patients on stable doses of metformin ≥1000 and <1500 mg/day for ≥12 weeks can participate if there is 
documentation that they cannot tolerate higher doses of metformin.
During Phase A, those patients meeting the thresholds for rescue therapy will either 
uptitrate their background insulin or initiate insulin glargine.  Beginning at Visit 6/Week 
20 (end of Phase A, beginning of Phase B) or at any visit thereafter, patients who have 
not been rescued in Phase A will either uptitrate their background insulin or initiate 
insulin glargine if their FFSG is >130 mg/dL (7.2 mmol/L) and their FS A1C is >7.5% at 
the visit.  The insulin dosing will be at the discretion of the investigator (based on locally 
accepted, national, or international guidelines for the use of insulin).  Please refer to 
Sections 2.4.2.5 and 2.4.2.6 for more information.
Throughout the study, glycemic endpoints (measured in the central laboratory) will 
remain masked to the patient and investigator.  However, in order for the investigator to 
perform an evaluation for possible glycemic rescue with insulin in Phase A or 
discontinuation from the study, the central laboratory will report to the investigator in an 
unmasked manner any FPG laboratory value meeting rescue or discontinuation criteria 
(refer to Sections 2.4.2.6 and 2.4.2.7).  
Note:  The patient and family will be instructed to monitor for ketonuria/ketonemia and 
check fingerstick blood sugars frequently and to contact the site immediately if the 
patient experiences an acute intercurrent illness (eg, fever >101°F [38.5°C] and/or 
vomiting or abdominal pain) at any time during the study. For patients not on baseline 
insulin therapy, insulin therapy may be initiated during an 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 (ie <14 days) 
use 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.
 
 
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2.4.2.1
Study Visits General Information
Fasting Prior to Scheduled Visits
Patients should be counseled to fast (ie, no food,  no drink except water, no double-blind 
study medication, but non-antihyperglycemic non-study medications should be taken as 
prescribed) for at least 10 hours prior to study Visit 1, Visit 3, Visit 6, Visit 9, Rescue,
and Discontinuation. The Investigator should manage insulin doses appropriately for 
patients on insulin to prevent/ minimize the risk of hypoglycemia while fasting.
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 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.  Clinic Visit 4, Visit 5, Visit 7, and Visit 8 may
be performed by a qualified health professional at the patient’s home/location other than 
the site if approved by the country and local IRB/EC. These visits should be performed 
according to the guidelines that may exist at the participating institution, and should be 
consistent with the investigators 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 clinic Visits 1, 3, 6, 9, Rescue,
and, Discontinuation. 

The requirement not to take any blinded study medication at home the morning of the 
clinic visit (except at Visit 2).
Note:  Non-study medications that are not antihyperglycemic medications should be 
taken as directed by the prescribing physician.

The requirement to bring study medication, blood glucose meter, hypoglycemia 
assessment tool(s), and any collected SMBG information to the clinic visit.
 
 
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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 
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 (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 on a stable dose of metformin IR or XR (for ≥12 weeks prior to Visit 1)
without insulin and have a Visit 1 A1C of ≥6.5% and ≤10.0% and who meet all other 
enrollment criteria will be eligible to switch from their pre-study dose of metformin to 
Sponsor-supplied metformin XR at doses specified in Table 2-2 above (Section 2.4.2), 
and enter the single-blind placebo run-in period. 
Patients on stable doses of metformin and insulin (for ≥12 weeks prior to Visit 1) and 
have a Visit 1 A1C of ≥7% and ≤10% (see inclusion criteria #2) and who meet all other 
enrollment criteria will switch to Sponsor-supplied metformin XR (Table 2-2), while 
continuing on their background insulin and enter the single blind run-in period.
The first doses of metformin XR and single-blind placebo (MK-0431A XR placebo) 
should be taken as witnessed doses in the clinic after completion of all Visit 2 study 
procedures.  Patients will then take metformin XR and single-blind placebo as directed 
for one week prior to randomization. It is essential that all procedures be performed 
before the patient takes the witnessed dose for the visit. 
The hypoglycemia assessment tool(s) will be dispensed at Visit 2.  Eligible patients will 
have 1) diet/exercise counseling; 2) training in self-monitoring of blood glucose (SMBG) 
at home 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.
 
 
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2.4.2.4
Visit 3/Randomization Visit to Visit 6/Week 20:  Phase A Double-Blind 
Treatment Period
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.
At Visit 3/Day 1, patients will be randomized to receive:

two tablets of MK-0431A XR (50/500 mg x 2; 50/500 mg and 50/1000 mg; or 
50/1000 mg x 2) and two tablets of metformin XR placebo (matching the 
metformin dose in MK-0431A XR), administered once daily with a meal, 
preferably in the evening 
OR  

two tablets of metformin XR (500 mg x 2; 500 mg and 1000 mg; or 1000 mg x 2) 
and two tablets of MK-0431A XR placebo (matching the metformin XR dose), 
administered once daily with a meal, preferably in the evening.  
The first dose of double-blind study medication will be taken as a witnessed dose in 
the clinic after completion of all procedures for the study visit.  It is essential that all
procedures be performed before the patient takes the witnessed dose for the visit. The 
dose of MK-0431A XR will be determined by the dose of metformin XR at Visit 2 (see 
Table 2-2).  Patients will then take double-blind study medications as directed for the 
duration of the study.  Patients who meet protocol-specified glycemic rescue thresholds 
will either uptitrate their background insulin if they are on background insulin, or initiate
insulin glargine if they are not on background insulin as described in Section 2.4.2.6.
2.4.2.5
Visit 6/Week 20 through Visit 9/Week 54:  Phase B Double-blind
Treatment Period
Patients in both the MK-0431A XR group and the MK-0431A XR placebo group (also 
receiving metformin XR) will continue on their double-blind study medication.  Those 
patients who are not on background insulin will initiate insulin glargine if their FFSG 
>130 mg/dL (7.2 mmol/L) and their FS A1C >7.5%.  Those patients who have entered 
the study on background insulin will up-titrate their insulin dose if their FFSG is >130 
mg/dL (7.2 mmol/L) and their FS A1C is >7.5%. Any change in insulin dose >15% of 
the screening dose will be considered as rescue if it is sustained for ≥14 days. The insulin
dosing will be at the discretion of the investigator (based on accepted, local, national or 
international guidelines for the use of insulin).  Patients who refuse to uptitrate their 
background insulin or initiate insulin glargine (or for whom it is considered 
inappropriate) when glycemic rescue thresholds are met will be discontinued from the 
study.
The first dose of Phase B double-blind study medication will be taken as a witnessed 
dose in the clinic after completion of all procedures for the study visit. It is essential 
 
 
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that all procedures be performed before the patient takes the witnessed dose for the 
visit. 
2.4.2.6
Glycemic Rescue – Phase A
After randomization, patients meeting protocol-specified glycemic rescue thresholds will 
be eligible for initiation of glycemic rescue therapy in Phase A (Table 2-3).  When 
thresholds for rescue are met, patients who are not on background insulin will initiate 
insulin glargine and those patients who have entered the study on background insulin will 
uptitrate their background insulin dose.  Any change in insulin dose >15% of the 
screening dose will be considered as rescue if it is sustained for ≥14 days. The insulin
dosing will be at the discretion of the investigator (based on accepted, local, national or 
international guidelines for use of insulin).  Patients who refuse to uptitrate their 
background insulin or initiate insulin glargine (or for whom it is considered 
inappropriate) when rescue thresholds are met will be discontinued from the study.
Note: Patients requiring transient (ie <14 days) use of insulin or an increase in 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.  
The patient and parent/guardian will be (1) informed of the FFSG values that meet the 
threshold corresponding to the patient’s duration in the study (eg, a patient has 3 
consecutive FFSG >240 mg/dL [13.33 mmol/L] between Day 1 and Week 4) and 
(2) instructed to call the site if the patient has 3 consecutive days of FFSG values that 
exceed the specified thresholds.  Patients and parents should be counseled that if one 
FFSG value is above the threshold for rescue, the FFSG value has to be checked the 
following morning.  If the FFSG value is above the threshold for rescue on the second 
day, the fasting glucose has to be checked on the third day as well, and the site must be 
called if all three values are above the thresholds 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 2-3) at each TC (telephone contact) and 
clinic visit.  For reference, site personnel will also record the rescue threshold level in the 
fingerstick glucose log book provided to the patient.  
When the patient calls the site with FFSG values that exceed the rescue thresholds for 3 
consecutive days, the site should schedule a clinic visit (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 by the local and central laboratory.  The 
value from the local laboratory can be used to assess the need for rescue (and the value 
from the central laboratory will be reported in the database). The patient will be rescued 
(by uptitration of background insulin or by initiation of insulin glargine) if the FPG is 
greater than the threshold specified in Table 2-3.    
Insulin (background and rescue) will be sourced locally and administered subcutaneously 
based on instructions provided by the investigator (based on accepted local, national or 
international guidelines for the use of insulin).  Note that for patients who are on or 
initiate basal insulin, prandial insulin can be added at the Investigator's discretion after at 
 
 
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least 6 weeks of treatment.  The choice, dose, and titration of prandial insulin will be the 
Investigator's responsibility.  Patients who refuse to uptitrate their background insulin or 
initiate insulin glargine (or for whom it is considered inappropriate) when glycemic 
rescue thresholds are met will be discontinued from the study medication (see section 
2.4.2.7).  Note that patients who are not compliant with study medication should be re-
trained on compliance with medication and diet/exercise.  The patient should be 
contacted a week later to assess if the FFSG values continue to meet rescue criteria and 
follow rescue procedures.
Table 2-3
Glycemic Rescue Criteria for Phase A
Time in Study
FFSG Thresholds 1
FPG Thresholds 2
             Day 1 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 12
>200 mg/dL (11.11 mmol/L)
>200 mg/dL (11.11 mmol/L)
After Week 12 through Week 20
>180 mg/dL (10.00 mmol/L)
>180 mg/dL (10.00 mmol/L)
1 The initial FFSG values would trigger repeat FFSG measurements.  An FPG measurement will be 
triggered if 3 consecutive FFSG values meet criteria, and rescue will be initiated if the FPG is above 
threshold.   
2  Perform confirmatory FPG if first AM fasting fingerstick glucose (FFSG) value is greater than the 
defined threshold on 3 consecutive days (after assessing for study medication compliance).
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 glargine for patients not on insulin 
treatment at screening, or should consider up-titrating insulin therapy for those patients 
on insulin treatment at screening.
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 or a laboratory safety test 
abnormality. All patients will be followed up until resolution (ie, return to normal or 
patient’s baseline, or diagnosis determined, or course of abnormalities established) for 
any laboratory safety test abnormality resulting in discontinuation.
 
 
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2.4.2.7.1
The Reason for Protocol-Specified Discontinuation From the Study is 
Listed Below
a) Informed consent withdrawn or patient requests discontinuation from study.
2.4.2.7.2
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 3.2.3.16.2 for follow up of these patients. Initiation of open-label AHA 
will not be considered as prohibited medication in these patients.
a) Hyperglycemia:  Patients will be discontinued from the study if they meet the 
criteria outlined below.  

In Phase A, patients meeting glycemic rescue criteria for whom: 1) the addition of 
open-label insulin glargine is refused by the patient or deemed clinically 
inappropriate by the investigator, or 2) up-titration of open-label insulin (for 
patients on background insulin or for those who have initiated insulin glargine at 
rescue) is refused by the patient or deemed clinically inappropriate by the 
investigator. 

In Phase B, patients meeting glycemic intensification criteria for whom: 1) the 
addition of open-label insulin glargine is refused by the patient or deemed 
clinically inappropriate by the investigator, or 2) up-titration of open-label insulin 
(for patients on background insulin or for those who have initiated insulin
glargine at rescue) is refused by the patient or deemed clinically inappropriate by 
the investigator. 
b) 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).
Note (a):  Patients who are on open-label insulin (background or rescue therapy) and 
meet these criteria can have their insulin dose reduced or interrupted at the 
Investigator’s discretion and may continue in the study.  Patients who continue to 
have hypoglycemia even after insulin is interrupted should discontinue study 
medication.
Note (b):  Prior to discontinuation, the investigator should check that the patient’s 
glucose meter and test strips are functioning accurately and that the test procedure is 
being correctly performed by the patient.
 
 
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c) Elevation 
in 
ALT 
(alanine 
aminotransferase) 
and/or 
AST 
(aspartate 
aminotransferase) ≥3-times the ULN (upper limit of normal) as specified in 
Appendix 6.4.
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 (for age and sex) (see Event of Clinical Interest (ECI) 
Guidance for Potential DILI (Drug-Induced Liver Injury) in Clinical Trials guidance 
document). 
d) Serum creatinine concentrations consistently ≥1.5 mg/dL (132.6 μmol/L) in males 
and ≥1.4 mg/dL (123.8 μmol/L) in females 
OR  
eGFR <60 mL/min/1.73 m2.
Note (a):  If serum creatinine value meets the gender-specific serum creatinine 
discontinuation criteria, regardless of the patient’s eGFR, the patient must be 
discontinued.
Note (b):  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).
e) Requirement for one of the excluded medications listed in Section 3.2.1.
f)
Pregnancy
Note:  A positive urine pregnancy test requires immediate interruption of study 
medication until serum βHCG 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.
g) 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.
h) 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 3.2.3.19.  Please refer to Section 3.2.3.16.2 on 
how to manage patients who discontinue study medication but who do not withdraw 
consent. 
 
 
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2.4.2.8
Mandatory 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 study medication) to query for 
SAEs.  If any SAE requires a supplemental procedure, this should be performed as 
medically necessary.  See Section 3.2.3.16 for details.
2.4.3
Beginning and End of Study Definition
The study begins when the first patient signs the ICF. End of Study for P289 will be 
declared when the last patient in both P289 and P170 (base and extension) 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 patients is 
randomized, any patient with an outstanding status will be declared as ‘lost to follow up’. 
2.5
LIST OF EFFICACY/PHARMACOKINETIC/IMMUNOGENICITY, ETC., 
MEASUREMENTS
Efficacy measurements include laboratory assessments of A1C, FPG, lipid panel, and 
measures of beta cell function (proinsulin/insulin ratio).
2.6
LIST OF SAFETY MEASUREMENTS
Safety assessments will include collection of adverse events, clinical evaluation (physical 
examination, vital signs, body weight, BMI, assessment of growth and development), and 
laboratory 
safety 
assessments 
(blood 
chemistry, 
hematology 
and 
urine 
microalbumin/creatinine ratio and urinalysis).
2.7
STATISTICAL ANALYSIS PLAN SUMMARY
Key elements of the statistical analysis plan are summarized below; the comprehensive 
plan is provided in Section 3.5 of the protocol details.
All efficacy and safety endpoints at Week 20 will be analyzed by pooling Phase A data 
from MK-0431A XR P289 with Week 0 to Week 20 data from MK-0431A P170 (base 
study).  All endpoints at Week 54 will be analyzed by pooling data from P289 (Phases A 
and B) with data from MK-0431A P170 (base and extension studies).  Selected efficacy 
(A1C and FPG) and safety endpoints will be summarized based on data from P289 alone
by treatment group.
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 2-4.
The primary efficacy hypothesis will be evaluated in the pooled population from this 
study and MK-0431A P170 by comparing the addition of sitagliptin relative to placebo to 
metformin IR/XR on change from baseline in A1C at Week 20 using a constrained 
longitudinal data analysis (cLDA) method proposed by Liang and Zeger [62]. The model 
 
 
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will include terms for treatment, time, baseline metformin dose (<1500 mg, 1500 mg, or 
>1500 mg), study (MK-0431A P170 and MK-0431A XR P289), baseline BMI percentile, 
insulin use at screening (yes/no), and interactions of time by metformin dose, time by 
study, and time by treatment unless the model fails to converge, with a restriction of the 
same baseline mean across treatment groups. To ensure model convergence, the term for 
insulin use at screening will be removed from the model if necessary. An unstructured 
covariance matrix will be used to model the correlation among repeated measurements. If 
the total analysis sample size from 2 treatments of both studies at Week 54 is small (ie, 
less than 50), then the terms for the stratification factors may be removed from the model 
in the order of the insulin use at screening followed by baseline metformin dose if 
necessary. An assessment of the poolability of the data will be performed prior to the 
pooling (described in Section 3.5.5.1).
Table 2-4
Summary of Analysis Strategy for Key Efficacy Endpoints
Endpoint
Statistical 
Method
Analysis 
Population
Missing Data Approach
Change from Baseline in A1C
at Week 20
cLDA
Full Analysis Set
Model-based
2.7.2
Safety Analyses
Safety analyses will be performed in the All-Patients-as-Treated (APaT) population.
Safety and tolerability will be assessed following a tiered approach by clinical review of 
all relevant parameters including adverse events, predefined limits of change (PDLCs), 
laboratory tests, and vital signs. For safety endpoints designated as Tier 1 [percentages of 
patients with symptomatic adverse events of hypoglycemia, and selected gastrointestinal 
(GI) events (ie, nausea, vomiting, abdominal pain or discomfort, and diarrhea)], p-values 
and 95% CIs for between-treatment differences will be provided using the Miettinen and 
Nurminen (M&N) method [63], stratified by baseline metformin dose, and study (MK-
0431A XR P289 and MK-0431A P170).
2.7.3
Power and Sample Size
The sample size for this study is expected to be at least 90 patients, but no more than 110 
patients, and the sample size for P170 (base) is expected to be at least 120 patients, but no 
more than 140 patients.  Power calculations are based on the minimum number of 
expected patients from both studies.
Approximately 105 patients (pooling patients from both MK-0431A P170 and MK-
0431A XR P289) will be randomized to each of the treatment groups (sitagliptin and 
placebo). A sample size of 105 patients per treatment will provide an effective sample 
size of 92 patients per treatment 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 92 patients per treatment will provide 86% power to detect a between-group difference 
 
 
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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 0.35%.
2.7.4
Interim Analysis
No interim analyses are planned.
 
 
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3. PROTOCOL DETAILS
3.1
RATIONALE
3.1.1
Background and Rationale for this Study
The incidence and prevalence of T2DM in the pediatric population is increasing 
worldwide [1 to 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 to 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 to 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 in the pediatric population is associated with the development of microvascular 
complications, particularly nephropathy [36 to 39], as well as the presence of several 
cardiovascular risk factors that increase the likelihood of early macrovascular 
complications in this population [3; 39 to 42].  As in adults, blood glucose levels likely 
influence the development and progression of both the microvascular and possibly 
macrovascular complications of T2DM [36; 43].  Therefore, given the substantial lifelong 
cumulative exposure to hyperglycemia that is inevitable for this population, the
availability of effective therapy for the treatment of T2DM in pediatric patients is critical.
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 to 47].  Metformin, a biguanide, lowers glucose concentrations by 
decreasing hepatic glucose output and increasing insulin sensitivity in liver and muscle.  
Although initially effective in lowering A1C [48], studies suggest that 35-50% of 
pediatric patients need an additional agent within a year of diagnosis [49; 50].  Since the 
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; 51; 52], it is likely that an 
agent, or combination of agents, that targets each of these key defects will be necessary to 
be added-on to metformin to maintain glycemic control and delay progression of T2DM 
[53].
Sitagliptin is an orally active, selective dipeptidyl peptidase-IV (DPP-4) inhibitor that 
increases the levels of active incretin hormones, including glucagon-like peptide-1 (GLP-
1) and glucose-dependent insulinotropic polypeptide (GIP), resulting in enhanced 
glucose-dependent insulin secretion and suppressed glucagon release [54].
The complementary mechanisms of action through which sitagliptin and metformin lower 
glucose concentrations suggest that the use of sitagliptin in combination with metformin 
 
 
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in pediatric patients with T2DM who have inadequate glycemic control on metformin 
will improve glycemic control in these patients.
This study is therefore designed to assess the safety and efficacy of MK-0431A XR 
(fixed-dose combination tablet of sitagliptin and extended-release metformin) relative to 
metformin XR for the treatment of T2DM in youths failing metformin therapy (alone or 
in combination with insulin). 
Data from adult studies suggest that the safety and efficacy of metformin IR is similar to 
that of metformin XR.  The safety and efficacy of metformin IR is similar in adults and 
children.  It is anticipated that the safety and efficacy of metformin XR will be similar to 
metformin IR in the pediatric population.  Therefore, it is reasonable to expect that the 
safety and efficacy of the addition of sitagliptin to on-going therapy with extended-
release metformin (administered as MK-0431A XR [JANUMET XR] in MK-0431A XR 
P289) is likely to be similar to that of the addition of sitagliptin to on-going therapy with 
immediate-release metformin (administered as MK-0431A [JANUMET] in MK-0431A 
P170).  Therefore, the data at Week 20 from MK-0431A XR P289 (Phase A) and MK-
0431A P170 (base study) will be combined for the primary analyses, with a combined 
sample size for both studies to be approximately 210 patients (120 patients from MK-
0431A P170 and 90 patients from MK-0431A XR P289).  
In addition, to provide longer term safety data, a 34-week extension to MK-0431A P170 
(the current pediatric study to assess the safety and efficacy of MK-0431A [JANUMET]), 
which is a 20-week study (referred to as MK-0431A P170 base study) will be 
implemented.  Data from patients who consent to participate in the extension study for 
MK-0431A P170 (data from the base and extension studies) will be combined with data 
from MK-0431A XR P289 (Phases A+B) to provide data over 54 weeks.  It is anticipated 
that approximately 50 patients will be exposed to MK-0431A (JANUMET) or MK-
0431A XR (JANUMET XR) for 54 weeks.
3.1.2
Rationale for Efficacy Endpoints
Hemoglobin A1c (A1C)
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.  Fasting plasma glucose will also be followed at each visit to 
characterize the time course of glucose control.
3.1.3
Rationale for Selection of Study Population
This is a study designed to assess the safety and efficacy of the fixed-dose combination of 
sitagliptin and extended-release metformin (MK-0431A XR) in youths with T2DM with 
inadequate glycemic control on a stable dose of metformin therapy (alone or in 
combination with insulin).   Since T2DM is not prevalent in children less than 10 years of 
age, youths 10 to 17 years of age (inclusive) with T2DM will be enrolled in this study.
 
 
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Pediatric patients 10-17 years of age with T2DM and inadequate glycemic control on 
metformin monotherapy are an optimal population to assess the safety and efficacy 
profile of the addition of a new agent in this group of patients. However, a significant 
proportion of pediatric patients 10-17 years of age with T2DM on metformin are being 
treated with insulin in addition, and despite being on insulin, have inadequate glycemic 
control [53, 55-57]. These patients are likely to be part of the patient population that will 
be treated with sitagliptin when it is approved for use in pediatric patients. The safety 
and efficacy of the addition of sitagliptin to patients with inadequate glycemic control on 
metformin and insulin has already been established in adults [58], and a similar profile is 
expected in pediatric patients 10-17 years of age. Therefore, including them in this 
clinical trial will make the clinical trial population representative of the target population, 
and will allow the results to be generalizable to a wide range of potential patients who 
could benefit from therapy with sitagliptin or sitagliptin-containing fixed-dose 
combination products.  A stable daily dose of insulin for the purposes of this trial will be 
defined by a variation in the total daily dose of insulin ≤15%; for instance, a patient on a 
total daily dose of 35 U of insulin can have a variation in their daily dose from 
approximately 30 U to 40 U of insulin, a variance that is not uncommon in these 
significantly obese and insulin resistant patients.
3.1.4
Rationale for Dose Regimen 
Sitagliptin
The sitagliptin dose for this study is based on data from MK-0431 P081 (A single-dose 
study to assess the pharmacokinetics, safety, and tolerability of sitagliptin in youths 10-17 
years old [inclusive] with T2DM). This study evaluated single oral 50-, 100-, and 200-mg 
doses of sitagliptin in pediatric patients 10-17 years old (inclusive) with T2DM, and 
compared the pharmacokinetics of sitagliptin in this population with that in adult patients 
with diabetes (MK-0431 P005).  The findings are described below.
Sitagliptin Pharmacokinetics (PK) and Dose Selection in Pediatric Patients:
Single oral doses of 50-, 100-, and 200-mg sitagliptin were administered in the fasted 
state, and were absorbed with a Tmax of ~3 hrs. Consistent with what is observed in 
adults, within the 50 to 200 mg dose range, sitagliptin AUC0-∞increased in a dose-
proportional manner, whereas sitagliptin Cmax increased in a modestly greater than dose-
proportional manner and C24hr increased in a modestly less than dose proportional manner 
in pediatric patients 10-17 years old (inclusive) with T2DM. Pooled across all available 
doses, pediatric patients 10-17 years old (inclusive) with T2DM had an approximately 
18% lower AUC0-∞as compared to adult patients with T2DM (historical data from MK-
0431 P005).  This observed difference in AUC0-∞was contained within the prespecified 
bounds for similarity between adults and pediatric patients 10-17 years old (inclusive) 
with T2DM, and was therefore not considered clinically meaningful. At the sitagliptin 
200 mg dose, plasma C24hr levels were ~26% lower in pediatric patients 10-17 years old 
(inclusive) with T2DM than in adults, whereas Cmax was similar in both populations.  The 
observed mean weighted average inhibition (WAI) of plasma DPP-4 activity over 24 
hours following single oral doses of sitagliptin in pediatric patients with T2DM was 
 
 
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significantly different from that observed after placebo.  The differences of DPP-4 WAI 
relative to placebo following administration of sitagliptin 50-, 100-, and 200-mg were 
approximately 67.2%, 73.8%, and 81.2%, respectively in pediatric patients with T2DM, 
and were ~10% lower than those observed in healthy adults at these doses in MK-0431 
P001/002 (80.4%, 82.9%, and 91.3%, respectively).  Day 1 trough (ie 24-hours postdose) 
DPP-4 inhibition percentages in pediatric patients with T2DM were also lower than those 
in healthy adults, with observed inhibitions of 54.0%, 62.8%, and 75.8% in pediatric 
patients 10-17 years old (inclusive) with T2DM compared to ~65%, ~75% and ~85% in 
healthy adult patients for the 50-, 100-, and 200-mg doses, respectively.  The PK/PD 
relationship between sitagliptin plasma concentration and DPP-4 inhibition was similar 
between pediatric patients 10-17 years old (inclusive) and adult patients with T2DM.  
The relationship can be described by an Imax model, with an IC50 value for pediatric 
patients 10-17 years old (inclusive) of ~25.4 nM being near identical to the observed IC50
value for adults with T2DM (25.7 nM).  The differences in the extent of DPP-4 inhibition 
between pediatric patients 10-17 years old (inclusive) and adults with T2DM can 
therefore be attributed to the small differences in plasma sitagliptin concentrations 
between these populations.  The magnitude of this difference is not expected to translate 
to a clinically meaningful difference in glycemic efficacy, and should not require higher 
doses of sitagliptin in pediatric patients (10-17 years old) compared to adults with T2DM. 
Therefore, a sitagliptin dose of 100 mg/day will be used in this study (administered as 
fixed-dose combination tablets of 50 mg of sitagliptin and extended-release metformin 
[500 mg or 1000 mg] to give a total daily dose of 100 mg of sitagliptin when 
administered once daily).
Metformin
Metformin PK and Dose in Pediatric Patients: 
Publicly available information indicates that after administration of a single oral 
metformin 500 mg tablet with food, geometric mean metformin Cmax and AUC differed 
less than 5% between pediatric patients (12-16 years of age) with T2DM and gender- and 
weight-matched healthy adults (20-45 years of age), all with normal renal function, 
resulting in the same doses recommended for pediatric and adult patients with T2DM 
(Glucophage U.S. product circular).  Furthermore, in adult patients, the PK of metformin 
administered twice daily as an immediate-release formulation is similar to the PK of an 
equal dose of extended-release formulation administered once daily (Glucophage XR U.S. 
product circular).  While there are no data regarding the use of metformin XR in pediatric 
patients with T2DM, the observed similarity in the PK and PD (pharmacodynamics) of 
metformin (immediate-release formulation) in pediatric and adult patients with T2DM 
suggests that pediatric and adult dosing for metformin XR will be also be similar.
Patients will enter the study on maximally tolerated doses of metformin (immediate- or 
extended-release formulations).  The maximum daily dose of metformin, if tolerated, will 
be 2000 mg.  Patients receiving less than 1000 mg of metformin a day will be excluded 
from the study.
 
 
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At Visit 2/Week -1, patients will be switched from their pre-study dose of metformin to 
Sponsor-supplied metformin XR (Table 2-2).  Patients whose daily dose of metformin is 
<1500 mg will be switched to 1000 mg of metformin XR daily.  Patients whose daily 
dose of metformin is 1500 mg will be switched to (or maintained on) 1500 mg of 
metformin XR daily.  Patients whose daily dose of metformin is >1500 mg will be 
switched to 2000 mg of metformin XR daily.
Fixed-dose Combination of Sitagliptin and Extended-Release Metformin (MK-
0431A XR)
At Visit 3/Day 1, patients will be randomized to either 1) the fixed-dose combination of 
sitagliptin/extended-release metformin (MK-0431A XR) and metformin XR placebo or
2) to metformin XR and MK-0431A XR placebo.  Patients will continue on the same 
daily dose of metformin XR initiated at Visit 2/Week -1, whether they are randomized to 
MK-0431A XR and metformin XR placebo or to metformin XR and MK-0431A XR 
placebo (see Table 2-2).
A Phase I trial, MK-0431A XR P296, to assess the PK and swallowability of the FDC of 
sitagliptin and extended-release metformin has completed. No changes to this protocol 
were required based on the results from study P296. 
Insulin
Insulin is approved for use in pediatric patients with T2DM and inadequate glycemic 
control on metformin therapy.  Use of basal insulin is associated with less hypoglycemia 
in patients with T2DM compared to intermediate-acting insulin [57].  Insulin glargine, a 
basal insulin, is widely used in pediatric patients, and is therefore used as the agent for 
glycemic rescue therapy in Phase A for patients not on background insulin (See Section 
2.4.2.6 for glycemic rescue thresholds).  The procedure and dose for initiation of insulin 
glargine, and for uptitration of background insulin will be at the investigator's discretion, 
based on local, national, or international guidelines.  
At Visit 6/Week 20 (beginning Phase B), or at subsequent clinic visits,  based on a single 
measurement of FS A1C and FFSG (See Section 2.4.2.5 for details) patients on 
background insulin will uptitrate their insulin, and patients not on background insulin will 
initiate insulin glargine.  In adults, an A1C value of 7.0% corresponds with an FPG of 
approximately 130 mg/dL (7.2 mmol/L) [59, 60].  A threshold of a single measurement 
of FFSG of >130 mg/dL (7.2 mmol/L) with a concomitant FS A1C measurement of 
>7.5%, was chosen to be conservative (ie, to reduce the risk of hypoglycemia) in this 
pediatric population, given the possible differences between the measurement of A1C via 
a fingerstick or at the central laboratory, and between the measurement of FFSG 
(capillary glucose measurements) and FPG.  The procedure and dose for initiation, 
uptitration and continued use of insulin will be at the investigator's discretion, based on 
local, national, or international guidelines.  
 
 
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NOTE:  After at least 6 weeks of treatment with a basal insulin, prandial insulin can be 
added at the Investigator's discretion.  The choice, dose, and titration of prandial insulin 
will be the Investigator's responsibility. 
3.1.5
Rationale for Placebo Use
The placebo control group is an essential arm in this trial, as it supports the evaluation of 
the safety and efficacy of sitagliptin in pediatric patients 10 to 17 years of age (inclusive) 
with T2DM and inadequate glycemic control on the maximally tolerated dose of 
metformin therapy (alone or in combination with insulin).    
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 glucose levels in another treatment group, would not accurately 
characterize the glucose-lowering efficacy of the addition of sitagliptin to ongoing 
metformin therapy in this population.  Non-placebo controlled, active-comparator studies 
provide important information, but the efficacy profile of the addition of an agent is best 
characterized by comparison to the addition of placebo, especially in the first trial of the 
FDC, MK-0431A XR, in the pediatric population (MK-0431A XR P289).  In addition, at 
the present time, the only antihyperglycemic agent approved for use in pediatric patients 
with T2DM who have inadequate glycemic control on metformin monotherapy is insulin.  
Therefore, it will not be feasible to conduct a blinded active-controlled study to evaluate 
the safety and efficacy of MK-0431A XR.  The placebo-control group in this trial will 
therefore support the blinded evaluation of the safety and efficacy of MK-0431A XR in 
this pediatric population with T2DM and inadequate glycemic control on the maximally 
tolerated dose of metformin   
The main concern with the use of a placebo arm is the possibility of exposure to 
prolonged periods of hyperglycemia, which will be handled in the following manner in 
this study.  Patients will be counseled using specially-designed material that is unique for 
pediatric patients with T2DM, and unlike in real-life clinical situations, will be seen in 
clinic and contacted by telephone very frequently.  They will also monitor their 
fingerstick glucose and initiate glycemic rescue therapy at progressively lower glucose 
thresholds during the course of the study that will ensure that patients will not be exposed 
to hyperglycemia for prolonged periods of time.  Rescue criteria included in this study 
(see Section 2.4.2.6) are more stringent than the criteria recommended for use in studies 
of adult patients with T2DM [61].
3.1.6
Future Biomedical Research
Merck will conduct Future Biomedical Research on blood, serum and plasma 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 
 
 
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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 6.5:  Collection and 
Management of Specimens for Future Biomedical Research.
3.2
STUDY PROCEDURES
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 regimen 
and dose of thyroid medication for at least 6 weeks prior to Visit 1 and/or a stable dose of 
lipid-lowering and anti-hypertensive medications for at least 4 weeks prior to Visit 1.
Note:  Medications to treat hyperthyroidism are prohibited.
Antihyperglycemic Medications
Double-blind study medication, open-label insulin (background or rescue therapy), and 
insulin glargine are the only AHA (anti-hyperglycemic agent) medications permitted in 
the study.  Patients who discontinue study medication may be treated with 
antihyperglycemic medication as considered clinically appropriate.
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 the 
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.
 
 
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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 (ie, 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 
pediatric patients 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.
3.2.3
Procedures
3.2.3.1
Monitoring of Glycemic Control
Self-Monitored Blood Glucose (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.  During both the pre-randomization and double-blind treatment periods, patients 
will be instructed to monitor fingerstick glucose (1) once daily (at least 2 measurements 
before breakfast, each week, 2) whenever they have symptoms of hypoglycemia or (2) 
during an intercurrent illness.  For patients on insulin (as background therapy at 
randomization or as a rescue medication during the study), the investigator will counsel 
the patient and parent/guardian on the recommended frequency of home glucose 
monitoring based on locally accepted clinical practice guidelines.
 
 
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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 FFSG values that meet glycemic rescue criteria (refer to Section 2.4.2.6) after 
randomization.
3.2.3.2
Monitoring for Ketones
At Visit 2/Week -1, patients will be supplied with screening strips to assess 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 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.  Regardless of blood glucose 
levels, if urine ketones are "moderate” or “large” (as indicated on the dipstick), or blood 
ketones are “positive”, 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 (eg, 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.
The patient and parent/guardian will be instructed to complete the 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 (ie, 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 (a):  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”.
 
 
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Note (b):  the hypoglycemia assessment tool(s) 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 (ie, 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 episode of symptomatic hypoglycemia must be reported as an adverse 
event on the AE 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).
Patients on Background Insulin Therapy
Patients on insulin should be counselled 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. Further management of insulin doses will be at the investigator’s 
discretion.
 
 
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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 
on 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, or in place of, the urine pregnancy test.  A positive urine 
pregnancy test requires immediate interruption of study medication until serum β-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.
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 6.6
 
 
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3.2.3.6
Laboratory Monitoring
Patients should be fasting for at least 10 hours before Visits 1, 3, 6, 9, Rescue, and
Discontinuation. Fasting is not required prior to other visits. 
All laboratory tests outlined in the Study Flow Chart (eg, FPG, A1C, CBC, chemistry 
panel, lipid panel, TSH, etc.) will be performed by the central laboratory (with the 
exception of the site fingerstick A1C, site and patient fingerstick glucose determinations, 
and site dipstick urinalysis).
Glycemic endpoints (measured at the central laboratory) will be masked during the 
double-blind treatment period.  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 meeting rescue and/or discontinuation criteria (refer to 
Sections 2.4.2.6 and 2.4.2.7).
Laboratory test results for chemistry (eg, 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 Sections 2.3 and 2.4.2.7).
At or after Visit 3/Day 1, ALT and AST elevations greater than or equal to 3-times the 
upper limit of normal (ULN) will be flagged by the Central Laboratory and patients will 
be retested, according to Appendix 6.4.
3.2.3.7
ECG Procedures
ECGs performed at Visit 2/Week -1, Visit 6/Week 20,
Visit 9/Week 54,
Discontinuation Visit (if applicable), and Rescue Visit (if applicable) will be read 
locally, and will not be sent to a central ECG reading laboratory.
3.2.3.8
Assessment of Swallowing Ability
The patient’s ability to swallow study medication will be assessed by collecting data from 
the patient using The Swallowing Ability Questionnaire and from the individual 
administering the witnessed dose using The Site Assessment of Swallowability 
Questionnaire. 
The Swallowing Ability Questionnaire is a sponsor developed measure to be completed 
by the patient. The Swallowing Ability Questionnaire will be administered to the patients
at Visit 2/Week -1, Visit 3/Day 1, Visit 4/Week 6, Visit 5/Week 12, Visit 6/Week 20, 
Visit 7/Week 28, Visit 8/Week 40, Visit 9/Week 54, Discontinuation Visit (if 
applicable), and Rescue Visit (if applicable). 
The Site Assessment of Swallowability Questionnaire is a Sponsor-developed set of 
questions to be completed by the individual at the site administering the witnessed doses. 
This form captures the site personnel’s assessment of the patient’s ability to swallow the 
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after the witnessed dose. The Site Assessment of Swallowability Questionnaire will be
completed after the witnessed dose is administered at Visit 2/Week -1, Visit 3/Day 1, 
and Visit 6/Week 20. 
3.2.3.9
Tanner Staging
Tanner Staging will be performed in order to assess the physical measurements of sexual 
development. Tanner Staging will be performed at Visit 3/Day 1, Visit 6/Week 20, Visit 
9/Week 54, Discontinuation Visit (if applicable), or Rescue Visit (if applicable).  Refer 
to Appendix 6.11 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.
3.2.3.10 Collect Substance Use Information
The use of tobacco (pack years) and alcohol should be collected in the eCRFs.
3.2.3.11 Informed Consent
The investigator must obtain documented consent from each potential patient prior to 
participating in a clinical trial or Future Biomedical Research.
3.2.3.11.1 General Informed Consent
Consent must be documented by the patient’s dated signature or by the patient’s legally 
acceptable representative’s dated signature on a consent form 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.  
A copy of the signed and dated consent form should be given to the patient before 
participation in the trial.
The initial informed consent form, any subsequent revised written informed consent form 
and any written information provided to the patient must receive the IRB/ERC’s 
approval/favorable opinion in advance of use.  The patient or his/her legally acceptable 
representative should be informed in a timely manner if new information becomes 
available that may be relevant to the patient’s willingness to continue participation in the 
trial.  The communication of this information will be provided and documented via a 
revised consent form or addendum to the original consent form that captures the patient’s 
dated signature or by the patient’s legally acceptable representative’s dated signature.
Specifics about a trial and the trial population will be added to the consent form template 
at the protocol level.  
 
 
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The informed consent will adhere to IRB/ERC requirements, applicable laws and 
regulations and Sponsor requirements.
3.2.3.11.1.1 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. 
3.2.3.11.1.2 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.
3.2.3.11.1.3 Future Biomedical Research
The following specimens are to be obtained as part of Future Biomedical Research:

Blood for genomics use 

Serum and plasma for future use
3.2.3.12 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.  
3.2.3.13 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.
3.2.3.14 Stratification
Randomization at Visit 3 will be stratified by the patients’ dose of metformin and insulin 
use at Visit 1 into the following 6 strata: (1) <1500 mg, and insulin user; (2) 1500 mg, 
and insulin user; (3) >1500 mg, and insulin user; (4) <1500 mg, and non-insulin user; (5) 
1500 mg, and non-insulin user; (6) >1500 mg, and non-insulin user.
3.2.3.15 Randomization/Allocation
A single patient cannot be assigned more than 1 randomization number.
 
 
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3.2.3.16 Poststudy Follow-Up
3.2.3.16.1 Poststudy 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 SAEs that occurred after the administration of the last dose of study 
medication.  The date of the telephone contact should be recorded and any SAEs that 
have occurred should be recorded in the Adverse Events eCRF.
If any SAE requires supplemental procedures, they should be performed as medically 
necessary and recorded in the Procedures eCRF.
3.2.3.16.2 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 SAEs that occurred after the administration of the last dose of 
study medication.
After this 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), and collection of adverse events.  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 (ie, not at Week 20 or Week 54), up until the 
patient has reached the Week 54 visit (ie, the visit that is approximately 54 weeks 
from randomization Visit 3/Day 1). The purpose of these telephone contacts will 
be to assess for SAEs 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.
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, 
 
 
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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. 
The date of the telephone contact should be recorded and any SAE information and A1C 
values that have been obtained should be recorded in the eCRFs.  

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.
3.2.3.17 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 medication, but 
should continue to be monitored in the study.
Additionally, the investigator must go into the IVRS system and perform the unblinding
in the IVRS system to update drug disposition.  In the event that the emergency 
 
 
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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.
3.2.3.18 Interruption/Discontinuation/Withdrawal from Study Medication
Since patients will be receiving treatment with metformin, if a patient 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 Janumet XR or 
metformin labels).  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 (eg, 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 the patient 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.
3.2.3.18.1 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 (eg, 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.
3.2.3.19 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 9/ Week 54.  Refer to the Study Flow Chart, Section 1.7, for 
details.
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 3.2.3.16.2).
3.2.3.20 Collect Substance Use Information
Information regarding the use of tobacco (pack years) and alcohol should be collected.
3.3
EFFICACY/PHARMACOKINETIC/IMMUNOGENICITY, ETC. 
MEASUREMENTS
3.3.1
Clinical and Laboratory Measurements for Efficacy
Efficacy measurements include laboratory assessment of: A1C, FPG, lipid parameters, 
and fasting insulin and proinsulin.
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.
 
 
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3.4
SAFETY MEASUREMENTS
3.4.1
Clinical and Laboratory Measurements for Safety

Collection and assessment of adverse events, physical examination, TS, 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 instrument (the hypoglycemia assessment tools) will be provided to the 
patient to collect hypoglycemia information.

Laboratory safety studies will consist of blood chemistry (including ALT, AST, 
creatine phosphokinase [CPK], total bilirubin, and alkaline phosphatase), 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 6.7.
3.4.1.1
Assessment of Swallowability of MK-0431A XR tablets
Swallowability of MK-0431A XR will be assessed throughout the course of the study 
starting at Visit 2/Week -1 (placebo run-in).

At Visit 2/Week -1, swallowability of study medication tablets will be assessed 
using the Swallowing Ability Questionnaire administered to the patient and by the 
site personnel’s assessment of swallowability of the witnessed dose using the Site 
Assessment of Swallowability Questionnaire as well as collection of adverse 
events related to swallowing the witnessed dose. 

At Visit 3/Day 1, swallowability of double-blind study medication will be 
assessed using the Swallowing Ability Questionnaire administered to the patient 
and by the site personnel’s assessment of swallowability of the witnessed dose 
based on using the Site Assessment of Swallowability Questionnaire as well as 
collection of adverse events related to swallowing the witnessed dose.

At subsequent study visits, specified in the Study Flow Chart (Section 1.7), 
swallowability of double-blind study medication will be assessed using the 
Swallowing Ability Questionnaire administered to the patient and the collection 
of adverse events related to swallowing the tablets. 
 
 
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3.4.2
Data Monitoring Committee 
3.4.2.1
Executive Oversight Committee
The Executive Oversight Committee (EOC) consists of members of the Sponsor's Senior 
Management.  The EOC will receive and decide upon any recommendations made by the 
external Data Monitoring Committee (eDMC) regarding the trial.
3.4.2.2
Data Monitoring Committee
To supplement the routine trial monitoring outlined in this protocol, an eDMC will 
monitor the interim safety data from this trial.  The voting members of the committee are 
external to the Sponsor.  The members of the eDMC must not be involved with the trial 
in any other way (eg, they cannot be trial investigators) and must have no competing 
interests that could affect their roles with respect to the trial.  The eDMC 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 eDMC will make recommendations to the EOC regarding steps to ensure both 
patient safety and the continued ethical integrity of the trial.  Also, the eDMC will review 
interim trial results, consider the overall risk and benefit to trial participants and 
recommend to the EOC if the trial should continue in accordance with the protocol.
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 eDMC reports, minutes, and recommendations will be described in a 
separate charter that is reviewed and approved by the eDMC.  The eDMC will monitor 
the trial at an appropriate frequency, as described in the detailed eDMC charter. The 
eDMC 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 subject 
administered a pharmaceutical product and which does not 
necessarily have to have a causal relationship with this treatment. An adverse event can 
therefore be any 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 
 
 
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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 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:
1. Administration of MK-0431A XR/matching placebo tablets that would result in more 
than or equal to 200 mg of sitagliptin per day for more than 1 day.
2. Administration of MK-0431A XR/matching placebo tablets that would result in more 
than 200 mg of sitagliptin per day.
3. Administration of MK-0431A XR/matching placebo or metformin XR/matching 
placebo tablets that would result in more than 3000 mg of metformin per day.
For recommended management of acute overdose for MK-0431A XR, 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.
 
 
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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).
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;
 
 
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●
Results in persistent or significant disability/incapacity;
●
Results in or prolongs an existing inpatient hospitalization;
●
Is a congenital anomaly/birth defect;
●
Is an other important medical event.
Note: In addition to the above criteria, adverse events meeting either of the below 
criteria, although not serious per ICH definition, are reportable to the Sponsor in the same 
timeframe as SAEs to meet certain local requirements. Therefore, these events are 
considered serious by the Sponsor for collection purposes.
●
Is a cancer;
●
Is associated with an overdose.
Refer to Table 3-1 for additional details regarding each of the above criteria.
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 Nonserious 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 
 
 
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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.*
*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 
(eg, 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).
 
 
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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, in the view of the investigator, at immediate risk of death from the experience 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 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)
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 experience when, based upon 
appropriate medical judgment, the event may jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes listed previously (designated above 
by a †).
Duration
Record the start and stop dates of the adverse event. If less than 1 day, indicate the appropriate length of time and units
Action taken 
Did the adverse event cause the 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 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 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, 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 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.  (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 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.
3.5
STATISTICAL ANALYSIS PLAN (SAP)
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, along with an explanation as to 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. No separate SAP will be issued for this study.
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 will be conducted as a double-blind study under in-house 
blinding procedures. 
After all patients remaining in the study have completed Week 54 (or discontinued prior 
to Week 54) of Phase B of this study and the MK-0431A P170 extension study, and 
medical and scientific reviews of the data have been completed, the analysis will be 
conducted and a CSR will be created to summarize the results of this study. The results of 
the pooled P289 and P170 (base and extension) studies will be summarized in a separate 
report.
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 for within- and/or between-treatment 
differences are listed below.  
The baseline value will be defined as the Visit 3/Day 1 (randomization) measurement.  If 
this measurement is not available, the last available pre-treatment value will be used as 
the baseline value.  If no pre-treatment measurement is available, the baseline value will 
be treated as missing.  The primary time point of the study is Week 20. 
The analysis for efficacy and safety endpoints at Week 20 in Phase A will be performed 
by pooling data from MK-0431A XR P289 and MK-0431A P170.  Data from Phases 
A+B of P289 will be pooled with data from the base and extension (Weeks 0-54) studies 
of MK-0431A P170.  
 
 
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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 (unless otherwise stated) in the report that will 
be written after the study is complete.  Week 20 is the primary time point for efficacy 
analysis. 
Parameters that are derived from more than 1 measurement, such as non-HDL-C, will be 
calculated based on the measurements taken on the same visit.
Day range definitions for the efficacy endpoints are provided in Appendix 6.8.
Table 3-2
Efficacy Endpoints
Endpoint Accessing Primary Hypothesis
Change from baseline in A1C at Week 20
Secondary Endpoints (assessed at Weeks 20 and 54 or as indicated)
Change from baseline in A1C at Week 54
Proportion of patients meeting A1C goal (<7.0%, <6.5%) at Week 20 and Week 54 
Change from baseline in FPG at Week 20 and Week 54
Proportion of patients initiating glycemic rescue therapy by Week 20
Proportion of patients initiating insulin glargine at/after Week 20
Other Endpoints
Change from baseline in fasting endpoints at Week 20 and Week 54:

Insulin

Proinsulin

Proinsulin/insulin ratio

Homeostatic Model Assessment of β-cell function (HOMA-β)

Homeostatic Model Assessment of insulin resistance (HOMA-IR)
Time to initiation of glycemic rescue therapy at Week 20 and Week 54
Percent change from baseline in lipid panel at Week 20 and Week 54

Triglycerides (TG)

LDL-C

HDL-C

Non-HDL-C

Total cholesterol (TC) 
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.  
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 6.9.  These 
 
 
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criteria are based upon the laboratory normal ranges and abnormalities considered to be 
potentially clinically meaningful.
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)
NOTE:  HOMA-β and HOMA-IR will not be calculated for patients on background 
insulin because fasting insulin will not be measured in these patients.
Day range definitions for the efficacy endpoints are provided in Appendix 6.8.
3.5.4
Analysis Populations
3.5.4.1
Efficacy Analysis Populations
The Full Analysis Set (FAS) populations will serve as the primary populations for the 
analysis at Week 20 and Week 54 with pooled populations of this study and P170 
(base+extension).  
Two populations will be defined for efficacy analyses, the Week 20 Full Analysis Set 
(FAS) that will include all randomized patients who took at least one dose of study 
medication in the Week 0 to Week 20 period of P289 (ie, Phase A) or of P170 (ie, base 
study) regardless of whether they continued beyond that period of the study, and the 
Week 54 FAS that will include only those patients from each study who received at least 
one dose of study medication beyond Week 20 (ie, the Phase B of P289 and extension 
study of P170).  For analyses using the longitudinal data analysis (LDA) model, both 
FAS populations further require that those patients 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, both FAS populations further require that 
those patients have a baseline measurement. 
The Week 20 FAS will be considered the primary efficacy analysis population. The 
Phase A+B analyses will also be performed using the Week 54 FAS population as a
secondary analysis.
The time-to-insulin initiation analysis will include all randomized patients. 
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.  
Details on the approach to handling missing data are provided in Section 3.5.5, Statistical 
Methods.
 
 
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3.5.4.2
Safety Analysis Populations
Two populations will be defined for safety analyses, the Week 20 All Patients as Treated 
(APaT) population consisting of all randomized patients who took at least one dose of 
study medication in the Week 0 to Week 20 period of P289 (ie, Phase A) or of P170 (ie, 
base study) regardless of whether they continued beyond that period of the study, and the 
Week 54 APaT that will include only those patients from each study who received at 
least one dose of study medication beyond Week 20 (ie, Phase B of P289 and extension 
study of P170).  
Patients will be included in 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 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 α=0.05 level (2-sided).
Analyses will be performed for Phase A (Week 0 to Week 20) and Phases A+B (Week 0
to Week 54). Data from Phase A of P289 will be pooled with data from MK-0431A P170 
(base study), and Phases A+B from P289 will be pooled with data from MK-0431A P170 
(base and extension studies).  Supportive efficacy and safety analyses will also be 
provided by summary statistics by treatment group for selected efficacy endpoints (FPG, 
A1C) and safety endpoints for P289 alone. Data on swallowability will be presented 
without pooling because these data are being collected only in P289. 
3.5.5.1
Statistical Methods for Efficacy Analyses
This section describes the statistical methods that address the primary, secondary, and 
exploratory objectives.  
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 
 
 
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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 (MK-0431A and MK-0431A XR versus metformin 
IR/XR)
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 (MK-0431A and MK-0431A XR versus 
metformin IR/XR)
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.
20-Week Pooled Data (Phase A from P289 and MK-0431A P170 Base Study)
Primary Endpoint:  TE Estimand
To address the primary hypothesis using the TE estimand, the mean change from baseline 
in A1C produced by MK-0431A and MK-0431A XR at Week 20 will be compared to 
that of metformin IR/XR using the least-squares (LS) means of the MK-0431A IR/XR 
and metformin IR/XR treatment groups as estimated via a longitudinal data analysis 
(LDA) method. The model will include terms for treatment, time, baseline metformin 
dose (<1500 mg, 1500 mg, or >1500 mg), study (MK-0431A XR P289 and MK-0431A 
P170), baseline BMI percentile, insulin use at screening (yes/no), and the interactions of 
time by metformin dose, time by study, and time by treatment, unless the model fails to 
 
 
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converge.  For the Week 20 analysis, the LDA model will further assume a common 
baseline mean across treatment groups within each combination of study/baseline 
metformin dose/insulin use (which is valid due to randomization) and a different mean 
for each treatment at each of the post-baseline time points.  This LDA model is called 
constrained LDA (cLDA), proposed by Liang and Zeger [62].    To ensure model 
convergence, the term for insulin use at screening will be removed from the model if 
necessary. The response vector consists of baseline and the values observed at each post-
baseline time point.  Time is treated as a categorical variable so that no restriction is 
imposed on the trajectory of the means over time.  The 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. The poolability of two studies will be assessed in a preliminary 
cLDA model at Week 20 which includes terms for treatment, study, time, treatment by 
time interaction, and treatment by study interaction. The interaction between treatment 
and study will be tested for significance at α=0.05 level to determine the heterogeneity of 
treatment effect across studies. If p <0.05, then further analyses will be conducted to 
examine the nature of the interaction, quantitative or qualitative. Unless qualitative 
interaction is confirmed, the cLDA model for the primary hypothesis will be performed 
by pooling populations from the two studies. If the Week 20 analyses are based on the 
pooled populations, then the Week 54 analyses will be based on the pooled populations 
as well.   
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 combination of study/baseline metformin dose/insulin use.  
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 
 
 
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either the baseline or post-baseline measurements, thereby increasing efficiency. Details 
of the model specification, assumptions, and SAS implementation codes are given in 
Appendix 6.10.
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, 
baseline metformin dose, study (MK-0431A P170 and MK-0431A XR P289), and 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 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: 12 to <20 weeks; C: 6 to <12 weeks; D: 0 to 
<6 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.
 
 
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In order to perform the RD analysis, there must be at least one subject in each of the 8
reference groups (four deviation patterns two treatment groups). 
In these studies, patients were not required to return for clinic visits when discontinued 
from study medication until the implementation in September 2015 of amendments 
P170-11 (base study), and P289-07. Thus, the RD analysis may not be feasible due to 
insufficient observed Week 20 data post discontinuation of study medication. In that 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. 
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 subject’s baseline value plus a shift and standard deviation computed 
based on the root mean squared error from the ANCOVA model described above. For 
subjects 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.
Secondary Endpoints
All other continuous efficacy endpoints except triglycerides will be analyzed using the 
above cLDA model. For analyses of lipid endpoints, the response vector consists 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.
Triglycerides will be analyzed using a nonparametric method: an ANCOVA based upon 
Tukey’s normalized ranks [68] on the percent change from baseline.  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 [69] 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 Miettinen and Nurminen (M&N) method [63], an 
unconditional, asymptotic method, stratified by, study (MK-0431A XR P289 and MK-
0431A P170), insulin use at screening (yes/no), and baseline A1C (> or ≤ median). 
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at screening will be removed from the model. 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 0431170289.  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 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 [66]. 
The estimated response rates and adjusted effective sample sizes [67] 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 (CMH) 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 
in Phase A.  The proportion of patients initiating glycemic rescue therapy in Phase A in 
each treatment group will be summarized.  Plots of the Kaplan-Meier estimate of the 
distribution of the time-to-initiation of glycemic rescue therapy in Phase A will be 
provided for each treatment arm and log-rank tests, stratified by study, comparing the 
time-to-initiation distribution of sitagliptin versus placebo will be conducted.  In this 
analysis, patients will be censored at the time of discontinuation from study medication.  
Table 3-3 summarizes the analysis strategy for all efficacy endpoints in Phase A.
 
 
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Table 3-3
Analysis Strategy for Efficacy Variables in Phase A
Endpoint/Variable
Approach
Statistical Method
Analysis 
Population
Missing Data 
Approach
Endpoints Assessing Primary Hypothesis
Change from baseline in A1C 
P (TE)
cLDA
FAS
Model-based
    at Week 20
P (TP)
ANCOVA
FAS
RD/RTB
S
Summary Statistics
FAS/All Data*
Data as Observed
Other Endpoints
Change from baseline in FPG 
at Week 20
P
cLDA
FAS
Model-based
S
Summary Statistics
FAS/All Data*
Data as Observed
Proportion of patients with 
A1C at Goals (<7.0%, <6.5%) 
at Week 20
P
S
S
M&N
CMH
M&N
FAS
ASR
FAS/Subgroup‡
Multiple Imputation
“not at goal”
Multiple Imputation
Percent change from baseline 
in lipid parameters (other than 
triglycerides) at Week 20
P
cLDA
FAS
Model-based
Percent change from baseline 
in triglycerides at Week 20
P
Non-parametric method
FAS
LOCF
Change from baseline in 
Insulin, Proinsulin and 
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 Phase A
P
Kaplan-Meier
ASR
N/A
Proportion of patients initiating 
glycemic rescue therapy during 
Phase A
P
Summary
ASR
N/A
ASR = All patients randomized; P=Primary approach; RD=Retrieved dropout;  RTB=Return-to-baseline; 
S=Secondary approach; TE=Treatment effect;  TP=Treatment policy.
‡ Subgroup=patients with baseline A1C ≥7.0% (applicable to A1C goal <7.0% analysis).
* Includes data following initiation of rescue therapy as well as data collected after discontinuation of study 
medication.
54-Week Pooled Data (Phases A+B from P289 and MK-0431A P170 base and 
extension studies)
The statistical models for the analyses at Week 54 will be analogous to those in Phase A
unless noted otherwise below. No between-group comparisons will be provided for Week 
54.  
The analysis of (percent) change from baseline in continuous efficacy endpoints in the 
Week 54 FAS population using the longitudinal data analysis model will not assume a 
common mean across treatment groups at baseline. If the total analysis sample size from 
2 treatments of both studies at Week 54 is small (ie, less than 50), then the terms for the 
stratification factors may be removed from the model in the order of the insulin use at 
screening followed by baseline metformin dose if necessary.
 
 
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Analyses of the percentages of patients at the A1C goals of <7.0% and <6.5%at Week 54
will be analogous to those at Week 20. 
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.
Table 3-4 summarizes the strategy for Phases A+B efficacy analyses. 
Table 3-4
Analysis Strategy for Efficacy Variables in Phases A+B
Endpoint/Variable
Statistical Method
Analysis 
Population
Missing Data 
Approach 
Change from baseline in A1C 
at Week 54
LDA†
FAS
Model-based
Summary
FAS/All Data‡
Data as Observed
Change from baseline in FPG 
at Week 54
LDA†
FAS
Model-based
Summary
FAS/All Data‡
Data as Observed
Proportion of patients with
A1C at goals (<7.0%, <6.5%) 
at Week 54
M&N
M&N
FAS
FAS/Subgroup§
MI
MI
Percent change from baseline 
in lipid parameters (other than 
triglycerides) at Week 54
LDA†
FAS
Model-based
Percent change from baseline 
in triglycerides at Week 54
Summary
FAS
LOCF
Proportion of patients initiating 
insulin glargine 
Summary
FAS
N/A
† The analyses will be performed in the Week 54 FAS population.
‡ Includes data following initiation of rescue therapy as well as data collected after discontinuation of 
study medication.
§ Patients with baseline A1C ≥7.0% for A1C goal <7.0% analysis.
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), laboratory tests, BMI, vital signs, growth velocity and 
Tanner Staging data, and urine microalbumin/creatinine ratio, and patient reported 
outcomes.
Per the trial design, patients who discontinued study medication prior to Visit 9/Week 54
and agreed to continue follow-up and further data collection will be contacted every 8-12 
weeks up until the patient has reached 54 weeks from randomization, Visit 3/Day 1, to 
collect any SAEs that occurred after the discontinuation of the study medication.  
For the pooled populations, safety analyses will be conducted for Week 0 to Week 20
(P289 Phase A and P170 base study) and Week 0 to Week 54 (P289 Phases A+B and 
P170 base and extension studies). For P289 alone, the safety analyses will be conducted 
 
 
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for Phase A (Week 0 to Week 20) and Phases A+B (Week 0 to Week 54).  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 data from
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.
All safety endpoints, except hypoglycemia, will be summarized regardless of the 
initiation of insulin glargine. Summaries of hypoglycemia endpoints will exclude data 
measured following the initiation of insulin glargine.  
The analysis of safety results will follow a tiered approach (see Table 3-5).  The tiers 
differ with respect to the analyses that will be performed.  Safety parameters or adverse 
events of 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 (specific terms as well as system organ class terms) and PDLC in 
laboratory, vital signs 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 PDLC will belong to Tier 3.
The threshold of at least 4 events was chosen because the 95% confidence interval for the 
between-group difference in percent incidence will always include zero when treatment 
groups of equal size each have less than 4 events and thus would add little to the 
interpretation of potentially meaningful differences.  Because many 95% confidence 
intervals may be provided without adjustment for multiplicity, the confidence intervals 
should be regarded as a helpful descriptive measure to be used in review, and not a 
formal method for assessing the statistical significance of the between-group differences 
in adverse events and PDLCs.
Continuous measures such as changes from baseline in laboratory parameters and vital 
signs will be considered Tier 3 safety parameters.  Summary statistics for baseline, on-
treatment, and change from baseline values will be provided by treatment group in table 
format.  Mean change from baseline over time will be plotted with the corresponding 
standard errors.
Swallowability data collected from the Swallowing Ability Questionnaire and the Site 
Assessment of Swallowability Questionnaire will also be summarized by treatment group 
for this study alone. 
 
 
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Adverse events of symptomatic hypoglycemia and selected gastrointestinal (GI) adverse 
events (ie, nausea, vomiting, abdominal pain or discomfort [including abdominal pain, 
abdominal discomfort, stomach discomfort], diarrhea) are Tier 1 endpoints. 
In addition, the AE categories consisting of the percentage of patients with any AE, a 
drug related AE, a serious AE, an AE which is both drug-related and serious, and who 
discontinued due to an AE will be considered Tier 2 endpoints.  The p-values (Tier 1 
only) and 95% confidence intervals (Tier 1 and Tier 2) will be provided for between-
treatment differences in the percentage of patients with events; these analyses will be 
performed using the Miettinen and Nurminen method, an unconditional, asymptotic 
method [63], stratified by baseline metformin dose, and study (MK-0431A P170 and 
MK-0431A XR P289). The CMH weighting scheme will be used for stratification factors 
in the analysis. For continuous Tier 2 safety parameters, change from baseline or percent 
change from baseline will be analyzed using the same LDA models described in Section 
3.5.5.1. Only 95% confidence interval for between-group difference will be provided.
The continuous endpoints of waist circumference and BMI will be considered Tier 2 
safety parameters.  Changes from baseline in laboratory parameters, vital signs and urine 
parameters that are not prespecified as Tier-1 or Tier-2 endpoints will be considered 
Tier 3 safety parameters.  Summary statistics for baseline, on-treatment, and change from 
baseline values will be provided in table format.  Mean change from baseline over time 
will be plotted with the corresponding standard errors for endpoints designed to be 
collected at multiple time points post randomization.
Table 3-5 summarizes the analysis strategy for safety endpoints.  
 
 
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Table 3-5
Analysis Strategy for Safety Parameters
Tier
Safety Endpoint
p-Value
95% CI for Treatment
Comparison
Descriptive 
Statistics
Tier 1
Any AE of symptomatic hypoglycemia
X
X
X
Selected (GI) events (diarrhea, nausea, abdominal 
pain/discomfort, 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, and waist circumference
X
X
Tier 3
All endpoints listed after Tier 2 (above) that have 
incidence <4 patients in all treatment groups
X
Additional hypoglycemia adverse event endpoints
X
Change from baseline results (laboratory measurements 
and vital signs, urine microalbumin/creatinine ratio)
X
Swallowing Ability Questionnaire (patient)
X
Site Assessment of Swallowability Questionnaire
X
Growth velocity and Tanner Staging
X
† 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 a background 
insulin and for patients not on a background of insulin at screening.
The Tier 1 analysis for hypoglycemia will include the numbers and percentages of 
patients experiencing one or more adverse event of symptomatic hypoglycemia, 
regardless of fingerstick 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 fingerstick glucose 
value: 

Adverse events of hypoglycemia (symptomatic or asymptomatic)

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:
 
 
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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 (ie, 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 (ie, 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 (ie, 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 and Demographics
Summaries will be provided based on the pooled data from both studies, MK-0431A XR 
P289 and MK-0431A P170, as well as on P289 alone. 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), 
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 or Other), ethnicity (Hispanic/Latino or not)

Baseline A1C, and distribution of A1C at baseline (A1C levels <8%, ≥8% and <9%, 
≥9%)

Baseline FPG

Metformin dose level at Visit 1 (<1500 mg, 1500 mg, >1500 mg)

Time since diagnosis of diabetes mellitus (> or ≤1 year)

Baseline substance use (tobacco/alcohol)

Insulin use at screening (yes/no)
3.5.6
Multiplicity
There is a single efficacy hypothesis for one primary endpoint, change from baseline in
A1C at Week 20, consisting of a comparison of 2 treatments.  Therefore, no multiplicity 
adjustment is necessary to control the overall Type I error at 0.05 (2-sided) for efficacy 
hypotheses.
3.5.7
Sample Size and Power Calculations
3.5.7.1
Sample Size and Power for Efficacy Analyses
The sample size for this study is expected to be at least 90 patients, but no more than 110 
patients, and the sample size for P170 base is expected to be at least 120 patients, but no 
more than 140 patients.  Power calculations are based on the minimum number of 
expected patients from both studies.
 
 
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Approximately 105 patients (pooling patients from MK-0431A XR P289 and MK-0431A 
P170) will be randomized to each of the treatment groups (MK-0431A and MK-0431A 
XR versus metformin IR/XR).   A sample size of 105 patients per treatment group will be 
equivalent to an effective sample size of approximately 92 per treatment 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 92 per treatment will provide 86% (96%) power 
to detect a between-group difference of 0.5% (0.6%) 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 0.35%. These calculations were based upon the following assumptions:

Cumulative attrition rates at Weeks 6, 12, and 20 are 0.10, 0.15, and 0.20, 
respectively 

A conditional correlation matrix at Weeks 6, 12, and 20 is 










1
93
.0
74
.0
93
.0
1
87
.0
74
.0
87
.0
1
The correlation matrix assumptions above are based on data from MK-0431 P036.
Table 3-6 shows the power for succeeding in the test of the primary hypothesis of the 
combined studies, for two treatment differences (0.5% and 0.6%) and standard deviations 
of 1.1 of change from baseline of A1C, using α=0.05 (two-sided) with t-statistics.  
Previously observed between-group differences (sitagliptin minus placebo) in change 
from baseline in A1C in adults for metformin add-on studies range from -0.51 to -1.02% 
after 18 to 24 weeks of treatment.  The observed treatment differences in adults for 
metformin add-on studies with the similar A1C entry criteria as the current study ranges 
from -0.51 to -0.65%.  Therefore, the power calculations are provided at treatment 
difference 0.5% or 0.6%.  The observed standard deviation in adults for metformin add-
on studies with the similar A1C entry criteria ranges from 0.65 to 1.09%.  Unpublished 
internal analyses 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 3-6
Power for Superiority in Change from Baseline in A1C (%)
92 Evaluable Patients Per Group and α = 0.05 (two-sided)
Difference (%) 
Standard Deviation (%) 
Power (%) 
0.6 
1.1 
96% 
0.5
1.1
86%
It is anticipated that approximately 50 patients will be exposed to MK-0431A XR (from 
MK-0431A XR P289, Phase A+B) or MK-0431A (from MK-0431A P170 base and 
extension studies) for 54 weeks.
 
 
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3.5.7.2
Sample Size and Power for Safety Analyses
If no adverse events are observed in a treatment group from pooling data of MK-0431A
XR P289 and MK-0431A P170 in which 105 patients are enrolled in the treatment group, 
the upper bound of the 95% confidence interval for the within-group incidence rate is 
3.4 %.
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 by pooling MK-0431A XR P289 and MK-0431A P170 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

Metformin dose level at Visit 1:  <1500 mg, 1500 mg, or >1500 mg

Baseline BMI percentile: ≥ or <median

Time since diagnosis of diabetes at baseline: > or ≤ 1 year
The consistency of the treatment effect will be assessed in the context of a repeated 
measures ANCOVA (RMANCOVA) method, which is a generalization of the standard 
ANCOVA to accommodate repeated measurements.  The RMANCOVA model will 
adjust for baseline value for A1C, baseline metformin dose (<1500 mg, 1500 mg, or 
>1500 mg), subgroup, study, insulin use at screening (yes/no), and treatment-by-
subgroup interaction for all subgroups listed above except the background insulin 
therapy.
For the analysis of background insulin therapy, the term of insulin use at 
screening (yes/no) will be removed from the RMANCOVA model. However, for the 
analysis of other subgroups, the term for insulin use at screening will be eliminated if 
necessary due to sparse cells. In the analysis 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 
 
 
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will not be performed. The treatment effect across trial centers will be summarized for 
A1C at Week 20 with descriptive statistics.
Results from the subgroup analyses should be reviewed cautiously.  Because sample sizes 
within subgroups will be smaller than the overall study sample size, estimation may not 
be precise and 95% CIs will usually be wide in the subgroup analyses.
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. Analyses of efficacy data from Phase A will not be conducted until 
the final database (including data through Week 54) is unblinded.
3.5.10 Compliance (Medication Adherence)
The computation of compliance will be based on the study medication case report form
from P289 alone and the pooled population from MK-0431A XR P289 and MK-0431A
P170. A day within the Double-blind Treatment Period will be considered a compliant 
day if the patient reports taking the required number of tablets encompassing both the 
assigned treatment(s) and any matching placebo tablets defined as follows:
For P289 alone:
1) MK-0431A XR or matching placebo: 2 tablets
2) Metformin XR or matching placebo: 2 tablets
For the pooled population:
1) MK-0431A (IR or XR) or matching placebo: 2 tablets
2) Metformin (IR or XR) or matching placebo: 2 tablets
If the study medication eCRF indicates general compliance problems with any double-
blinded therapy, the patient will be considered non-compliant for that day regardless of 
the number of tablets for the assigned treatment(s) and any matching placebo reported.
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. The “Number of 
Days in the Study” is the total number of days from Day 1 to the day of study completion 
or study discontinuation.
 
 
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For each patient, the compliance rate, based on time until study medication 
discontinuation, and the adherence rate, based on time until study discontinuation, will be 
calculated, using the following formula
Compliance rate (%) =
Number of Compliant Days
× 100
Number of Days in the Double-blind Treatment Period
Adherence rate (%) =
Number of Compliant Days
×
100.
Number of Days in the Study
Summary statistics will be provided on percent compliance and percent adherence by
treatment group.
3.5.11 Extent of Exposure
The extent of exposure to study treatment will be evaluated by summary statistics (N, 
mean, median, standard deviation and range) and frequencies for the "Number of Days on 
Therapy" by treatment group (sitagliptin and placebo) from the pooled studies MK-
0431A XR P289 and MK-0431A P170, and from P289 alone.
3.6
LABELING, PACKAGING, STORAGE, DISPENSING, AND RETURN OF 
CLINICAL SUPPLIES
3.6.1
Patients and Replacement Information
Clinical supplies will be packaged to support randomization of up to approximately 110
patients.  Randomized patients who discontinue study medication will not be replaced.
Clinical supplies will be packaged according to a component schedule generated by the 
SPONSOR.
3.6.2
Product Descriptions
Investigational materials will be provided by the SPONSOR as summarized in
Table 3-7.
 
 
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Table 3-7
Product Descriptions
Product Name & Potency
Dosage Form
Comments
MRT1 MK-0431A 50 mg / 500 mg
Tablet
Protect from moisture
MRT MK-0431A 50 mg / 500 mg Placebo
Tablet
Protect from moisture
MRT MK-0431A 50 mg / 1000 mg
Tablet
Protect from moisture
MRT MK-0431A 50 mg / 1000 mg Placebo
Tablet
Protect from moisture
Metformin XR 1000 mg
Tablet
N/A
Metformin XR 1000 mg Placebo
Tablet
N/A
Metformin XR 500 mg 
Tablet
N/A
Metformin XR 500 mg Placebo
Tablet
N/A
1Modified release tablet
All placebos will be created by Merck Sharp & Dohme Corp., a subsidiary of Merck & 
Co., Inc., in the image of the active product.
Other clinical supplies, such as open-label insulin and insulin glargine will be supplied by 
the investigator or by the site as needed. The investigator or designee will record the lot 
number, expiration date, and drug dispensed.
3.6.3
Primary Packaging and Labeling Information
Supplies will be packaged in HDPE bottles as described in Table 3-8 below.
Table 3-8
Packaging of Clinical Supplies
Interval ID/ 
Container ID
Product Name & Potency
Fill 
Count
Dosing Instructions
A
MK-0431A 50 mg/ 500 mg Placebo
28
Once daily with a meal, preferably 
in the evening.
B
MK-0431A 50 mg / 1000 mg Placebo
28
Once daily with a meal, preferably 
in the evening
C
Metformin XR 500 mg
28
Once daily with a meal, preferably 
in the evening
D
Metformin XR 1000 mg
28
Once daily with a meal, preferably 
in the evening
E
MK-0431A 50 mg / 500 mg or Placebo
35
Once daily  with a meal, preferably 
in the evening
F
MK-0431A 50 mg / 1000 mg or Placebo
35
Once daily  with a meal, preferably 
in the evening
G
Metformin XR 1000 mg or Placebo
35
Once daily  with a meal, preferably 
in the evening
H
Metformin XR 500 mg or Placebo
35
Once daily  with a meal, preferably 
in the evening
 
 
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Container label text may include the following:

Packaging Control #/ Packaging Lot ID #

Space for baseline #

Randomization  # or Component ID #

Space for Randomization #

Fill Count & Dosage Form

Container ID

Interval ID

Re-evaluation date

Dosing Instructions

Storage Conditions

Compound ID - Protocol #

Country regulatory requirements

SPONSOR address (If applicable)

Translation Key (If applicable)
3.6.4
Clinical Supplies Disclosure
IVRS studies
The IVRS should be used in order to unblind patients and to unmask drug identity. The 
SPONSOR will not provide disclosure envelope with the clinical supplies. Drug 
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.  Prior to 
unblinding, the investigator will attempt to contact the clinical monitor. Any unblinding 
that occurs at the site must be documented.
3.6.5
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 specified in this 
protocol or in the product label attached to the protocol. Documentation of temperature 
monitoring should be maintained.
3.6.6
Standard Policies / Return of Clinical Supplies
Investigational clinical supplies must be received by a designated person at the study site, 
handled and stored safely and properly, and kept in a secured location to which only the 
investigator and designated assistants have access. Clinical supplies are to be dispensed 
only in accordance with the protocol. The investigator is responsible for keeping accurate 
records of the clinical supplies received from the SPONSOR, the amount dispensed to 
and returned by the patients, and the amount remaining at the conclusion of the study. In 
accordance with Good Pharmacy Practices, gloves should always be worn by study 
personnel if directly handling tablets or capsules that are returned (ie, when counting 
returns). The CRA should be contacted with any questions concerning investigational 
products where special or protective handling is indicated. At the end of the study, all 
clinical supplies including partial and empty containers must be returned as indicated on 
the Contact Information page(s). 
 
 
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U.S. sites should follow instructions for the Clinical Supplies Return Form and contact 
your SPONSOR representative for review of shipment and form before shipping.
For sites outside of the United States, the local country SPONSOR personnel will provide 
appropriate documentation that needs to be completed for drug accountability.
3.6.7
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 advice:
“You have participated in a study conducted by Merck Sharp & Dohme Corp., a 
subsidiary of Merck & Co., Inc. This is to advise you that you were among those who 
received a look-alike tablet created by Merck Sharp & Dohme Corp., a subsidiary of 
Merck & Co., Inc., to resemble the drug GLUCOPHAGE XR (Metformin XR) as much 
as possible. You did not receive the active drug GLUCOPHAGE XR (Metformin XR) as 
manufactured by Merck KGaA and its Subsidiaries”.
3.7
DATA MANAGEMENT
Information regarding Data Management procedures for this protocol will be provided by 
the SPONSOR.
3.8
BIOLOGICAL SPECIMENS
Information regarding biological specimens for this protocol will be provided by the 
SPONSOR.
 
 
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4. ADMINISTRATIVE AND REGULATORY DETAILS
4.1
CONFIDENTIALITY
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.
4.2
COMPLIANCE WITH LAW, AUDIT, AND DEBARMENT
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, 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.
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.
 
 
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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 (eg, thorough understanding of clinical trial methods, 
appropriate enrollment of patient cohort, timely achievement of study milestones, 
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.
4.3
COMPLIANCE WITH FINANCIAL DISCLOSURE REQUIREMENTS
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 
 
 
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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.
4.4
QUALITY CONTROL AND QUALITY ASSURANCE
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.
4.5
COMPLIANCE WITH INFORMATION PROGRAM ON CLINICAL 
TRIALS 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.
4.6
PUBLICATIONS
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 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 
 
 
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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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5. LIST OF REFERENCES
1. Rapaport R, Silverstein JH, Garzarella L, Rosenbloom AL. Type 1 and type 2 
diabetes mellitus in childhood in the United States: practice patterns by pediatric 
endocrinologists. J Pediatr Endocrinol Metab 2004;17:871-7.
2. Pinhas-Hamiel O, Dolan LM, Daniels SR, Standiford D, Khoury PR, Zeitler P. 
Increased incidence of non-insulin-dependent diabetes mellitus among adolescents. J 
Pediatr 1996;128(5, Part 1):608-15.
3. Fagot-Campagna A, Pettitt DJ, Engelgau MM, Burrows NR, Geiss LS, Valdez R, et 
al. Type 2 diabetes among north American children and adolescents:  an 
epidemiologic review and a public health perspective. J Pediatr 2000;136(5):664-72.
4. Pavkov ME, Hanson RL, Knowler WC, Bennett PH, Krakoff J, Nelson RG. Changing 
patterns of type 2 diabetes incidence among Pima Indians. Diabetes Care 2007; 
30(7):1758-63.
5. Dabelea D, Hanson RL, Bennett PH, Roumain J, Knowler WC, Pettitt DJ. Increasing 
prevalence of type II diabetes in American Indian children. Diabetologia 1998; 
41:904-10.
6. Moore KR, Harwell TS, McDowall JM, Helgerson SD, Gohdes D. Three-year 
prevalence and incidence of diabetes among American Indian youth in Montana and 
Wyoming, 1999 to 2001. J Pediatr 2003;143:368-71.
7. SEARCH for Diabetes in Youth Study Group. The burden of diabetes mellitus among 
US youth: prevalence estimates from the search for diabetes in youth study. Pediatrics 
2006;118(4):1510-8.
8. SEARCH. Incidence of diabetes in youth in the United States. JAMA 2007;297:2716-
24.
9. Lobstein T, Jackson-Leach R. Estimated burden of paediatric obesity and co-
morbidities in Europe. Part 2: numbers of children with indicators of obesity-related 
disease. Int J Pediatric Obesity 2006;1:33-41.
10. Pinhas-Hamiel O, Zeitler P. The global spread of type 2 diabetes mellitus in children 
and adolescents. J Pediatr 2005;146(5):693-700.
11. Haines L, Wan KC, Lynn R, Barrett TG, Shield JPH. Rising incidence of type 2 
diabetes in children in the U.K. Diabetes Care 2007;30:1097-101.
12. Bell RA, Mayer-Davis EJ, Beyer JW, D'Agostino RB Jr, Lawrence JM, Linder B, et 
al. Diabetes in Non-Hispanic White youth - Prevalence, incidence, and clinical 
characteristics: the SEARCH for diabetes in youth study. Diabetes Care 2009; 
32(Suppl 2):S102-S111.
 
 
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13. Dabelea D, DeGroat J, Sorrelman C, Glass M, Percy CA, Avery C, et al. Diabetes in 
Navajo youth prevalence, incidence, and clinical characteristics: the SEARCH for 
diabetes in youth study. Diabetes Care 2009;32(Suppl 2):S141-S147.
14. Invitti C, Guzzaloni G, Gilardini L, Morabito F, Viberti G. Prevalence and 
concomitants of glucose intolerance in European obese children and adolescents. 
Diabetes Care 2003;26(1):118-24.
15. Lawrence JM, Mayer-Davis EJ, Reynolds K, Beyer J, Pettitt DJ, D'Agostino RBJr, et 
al. Diabetes in Hispanic American youth prevalence, incidence, demographics, and 
clinical characteristics: the SEARCH for diabetes in youth study. Diabetes Care 
2009;32(Suppl 2):S123-S132.
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 youth study. Diabetes Care 2009;32(Suppl 2):S133-S140.
17. Mayer-Davis EJ, Beyer JW, Bell RA, Dabelea D, D'Agostino RB Jr, Imperatore G, et 
al. 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.
18. Open database: Supplemental Tables. Diabetes Care. c2009. 2009.
19. Reinehr T, Andler W, Kapellen T, Kiess W, Richter-Unruh A, Schönau E, et al. 
Clinical 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.
26. Arslanian SA, Lewy VD, Danadian K. Glucose intolerance in obese adolescents with 
polycystic ovary syndrome:  roles of insulin resistance and risk of cardiovascular 
disease. J Clin Endocrinol Metab 2001;86(1):66-71.
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.
28. Dabelea D, Pettitt DJ, Hanson RL, Imperatore G, Bennett PH, Knowler WC. Birth 
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: beta-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 Clin Endocrinol Metab 2006;91(2):401-4.
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 2005; 
54:1735-43.
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.
36. Bogdanovic R. Diabetic nephropathy in children and adolescents. Pediatr Nephorol 
2008;23:507-25.
37. Krakoff J, Lindsay RS, Looker HC, Nelson RG, Hanson RL, Knowler WC. Incidence 
of Retinopathy and nephropathy in youth-onset compared with adult-onset type 2 
diabetes. Diabetes Care 2003;26(1):76-81.
 
 
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38. Pavkov ME, Bennett PH, Knowler WC, Krakoff J, Sievers ML, Nelson RG. Effect of 
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.
40. Petitti DB, Imperatore G, Palla SL, Daniels SR, Dolan LM, Kershnar AK, et al. 
Serum lipids and glucose control. Arch Pediatr Adolesc Med 2007;161:159-65.
41. Sanders BH, Lubsch LM, West DS. Prevalence and treatment of metabolic syndrome 
in adolescents with type 2 diabetes. Ann Phamacother 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.
43. DCCT/EDIC Study Research Group. Intensive diabetes treatment and cardiovascular 
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 
Reviews 2005;3(1):33-9.
45. Pinhas-Hamiel O, Zeitler P. Clinical presentation and treatment of type 2 diabetes in 
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. Pediatrics 2004;114(1):259-63.
47. Canadian Diabetes Association. Type 2 diabetes in children and adolescents. Clin 
Pract Guidelines 2003:S91-S93.
48. Jones KL, Arslanian S, Peterokova VA, Park JS, Tomlinson MJ. Effect of metformin 
in pediatric patients with type 2 diabetes. Diabetes Care 2002;25:89-94.
49. Kadmon, PM, Gruppuso PA.  Glycemic control with metformin or insulin in 
adolescents with type 2 diabetes mellitus.  J Pediatr Endocrinol Metab 2004;17:1185-
1193
50. Farrah SE, Wals KT, Friedman IB, Pisacano MA, DiMartino-Nardi J.  Prevalence of 
retinopathy and microalbuminuria in pediatric type 2 diabetes mellitus. J Pediatr 
Endocrinol Metab 2006;19:937-942
 
 
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51. 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 2003;362: 
951-7.
52. Yeckel CW, Taksali SE, Dziura J, Weiss R, Burgert TS, Sherwin RS, et al. The 
normal glucose tolerance continuum in obese youth:  evidence for impairment in 
β-cell function independent of insulin resistance. J Clin Endocrinol Metab 2005; 
90(2):747-54.
53. Zuhri-Yafi M, Brosnan PG, Hardin DS. Treatment of type 2 diabetes mellitus in 
children and adolescents. J Pediatr Endocrinol Metab 2002;15(Suppl 1):541-6.
54. Baggio LL, Drucker DJ. Biology of incretins: GLP-1 and GIP. Gastroenterol 
2007;132:2131-57.
55. Silverstein JH, Rosenbloom AL. Treatment of type 2 diabetes mellitus in children and 
adolescents. J Pediatr Endocrinol Metab 2000;13:1403-9.
56. Kaufman FR. Type 2 diabetes mellitus in children and youth: a new epidemic*. J 
Pediatr Endocrinol Metab 2002;15:737-44.
57. Klingensmith G, Connor CG, Ruedy K, Beck RW, Kollman C, Haro H, et al.  
Presentation of youth with type 2 diabetes in the pediatric diabetes consortium.  
Pediatric Diabetes 2016;17:266-273
58. Ramachandran A, Riddle MC, Kabali C, Gerstein HC on behalf of the ORIGIN 
investigators. Relationship between A1C and fasting plasma glucose in dysglycemic 
or type 2 diabetes.  An analysis of baseline data from the ORIGIN trial. 2012;35:749-
753.
59. Rosenstock J, Dailey G, Massi-Benedetti M, Fritsche A, Lin Z, Salzman A. Reduced 
hypoglycemia with insulin glargine. A meta-analysis comparing insulin glargine with 
human NPH in type 2 diabetes.  Diabetes Care 2005;28:950-55.
60. van'T Riet E, Alssema M, Rijkelijkhuizen JM, Kostense PJ, Nijpels G, Dekker JM.  
Relationship between A1C and glucose levels in the general Danish population.  The 
new Hoorn study.  Diabetes Care;2010:33:61-66.
61. Hodges JL, Lehmann EL. The efficiency of some nonparametric competitors of the 
ttest. Ann Math Statist 1956;27:324-35.
 
 
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62. 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;85:660-667.
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 treatment of high blood pressure in children and adolescents.  Pediatr 
2004;114(2):555-76.
 
 
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6. APPENDICES
6.1
BMI-FOR-AGE CHARTS
Sites should follow their approved country-specific BMI-for-age percentile charts, if 
available (eg, sites within the United States will refer to the Centers for Disease Control 
charts).  If an approved BMI-for-age percentile chart is not available, refer to the World 
Health Organization charts shown in Figures 1 and 2 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.

The body mass index-for-age percentile will be at the intersection of the child’s age 
and BMI measurement.
 
 
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Figure 1
BMI-for-Age—Girls, 5 to 19 Years (Percentiles)
2007 WHO Reference
Ref: [62]
 
 
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Figure 2
BMI-for-Age—Boys, 5 to 19 Years (Percentiles)
2007 WHO Reference
Ref: [62]
 
 
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6.2
BLOOD PRESSURE TABLE FOR GENDER/AGE/HEIGHT FOR BOYS 
AGE 10-17
Years 
of Age
Blood 
Pressure
Systolic Blood Pressure by Percentile of Height 
(mmHg)
Diastolic Blood Pressure by Percentile of Height 
(mmHg)
(Years) 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; otherwise, these guidelines should be used. 
Ref: [63]
 
 
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6.3
BLOOD PRESSURE TABLE BY GENDER/AGE/HEIGHT FOR GIRLS 
AGE 10-17
Years of 
Age
Blood 
Pressure
Systolic Blood Pressure by Percentile of Height 
(mmHg)
Diastolic Blood Pressure by Percentile of Height 
(mmHg)
(Years)
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; otherwise, these guidelines should be used. 
Ref: [63]
 
 
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6.4
STANDARD OPERATING PROCEDURES FOR LIVER ENZYME 
ELEVATIONS
Every increase in ALT, and/or AST, above the limits described in the protocol is defined 
as clinically significant (ie, 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 (see Section 3.4.6.2).  Alkaline 
phosphatase reference ranges for age and sex are listed below.
Alkaline Phosphatase Reference Ranges by Age and Sex 1
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).
 
 
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A. Patients should return to the center within 3 days for the following: (history can 
be obtained over the phone in the interim)
1. Obtain further information.
2. Careful questioning of recent alcohol consumption, including a recent change in 
pattern of alcohol use.
3. Search for drug-related causes of hepatitis and liver injuries (acetaminophen; 
amiodarone; aspirin; chlorpromazine; dantrolene; erythromycin; halothane; 
isoniazid; methyldopa; nitrofurantoin; oxyphenisatin; perhexiline maleate; 
phenytoin; propylthiouracil; rifampin; sulfonamides; tetracyclines) or other new 
medications.
4. Search for alternative medical causes such as cholelithiasis, recent alcohol 
consumption, history of intercurrent illness (eg, 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.
 
 
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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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6.5
COLLECTION AND MANAGEMENT OF SPECIMENS FOR FUTURE 
BIOMEDICAL RESEARCH 
6.5.1
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.
6.5.2
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.
6.5.3
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 (ie, 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 (eg, DNA or RNA extraction, etc.) following the Merck 
approved policies and procedures for specimen handling and preparation.
 
 
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6.5.4
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 (ie, 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 (eg, EMEA, FDA), whereby this information would be directly 
transferred to the health authority.
 
 
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6.5.5
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 (eg, 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.
6.5.6
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 (eg, 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. 
6.5.7
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.
6.5.8
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 subject 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 (eg, 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.
6.5.9
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 (eg, 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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6.5.10 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.
6.5.11 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 (ie, 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.
6.5.12 Self-Reported Ethnicity
Patients who participate in future biomedical research will be asked to provide self-
reported ethnicity.  Patients who do not wish to provide this data may still participate in 
future biomedical research.
6.5.13 Questions
Any questions related to the future biomedical research should be e-mailed directly to 
clinical.specimen.management@merck.com.
 
 
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6.6
BLOOD PRESSURE AND ANTHROPOMETRIC MEASUREMENTS
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 to 
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 (to the nearest 0.2 kg) will be measured after voiding.  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 weight to study sites that do not have 
one. The scale must be calibrated according to the manufacturer’s instructions at 
set-up and when it is transferred or moved.  Additional calibrations 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 (eg, 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 when mounting it to the wall, and according to 
the manufacturer’s instructions thereafter.  
Waist Circumference
The tape measure used should be 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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6.7
LABORATORY EVALUATIONS
Fasting plasma glucose (FPG) test (Visits 1, 3, 6, 9, Rescue, and Discontinuation)
Whole blood hemoglobin A1c (A1C) test (Visits 1, 3, 4, 5, 6, 7, 8, 9, Rescue, and 
Discontinuation)
Note:  Do not collect A1C at Rescue or Discontinuation Visits if the visit occurs before 
Visit 4/Week 6.
Fasting insulin and proinsulin tests (Visits 3, 6, Rescue, and Discontinuation)
Do not collect samples for fasting serum insulin and proinsulin on patients on insulin
(background, rescue [Phase A] or glycemic therapy [Phase B]).
Fasting serum C-peptide test (Visit 1)
Only obtained for patients with a diagnosis of T2DM < 2 years.
(In South Africa and India, C-peptide will be measured in all patients.)
Diabetes Autoantibody Panel (Only for India--Visit 1)
Glutamic acid decarboxylase 65- kDa autoantibody (GAD65-Ab)
Insulinoma-associated protein-2 autoantibody (IA2 Ab)
Lipid Analyses (Visits 1, 3, 6, 9, Rescue, and Discontinuation)
Total cholesterol
Triglycerides (TG)
HDL cholesterol
LDL cholesterol-calculated
Non-HDL cholesterol – calculated
Hematology (Visits 1, 3, 5, 6, 7, 9, Rescue, 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, 6, 7, 9, Rescue, and Discontinuation)
Serum sodium test
Serum potassium test
Serum chloride test
Serum bicarbonate test
Serum calcium test
 
 
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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, 4, 5, 6, 7, 8, 9, Rescue, and Discontinuation)
performed for all females at the investigator’s site
Serum beta-human chorionic gonadotropin (β-hCG) test in all randomized patients with a 
positive urine pregnancy test.
Dipstick Urinalysis (Visits 1, 3, 6, 9, Rescue, 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 urinalysis should not be performed if the patient is menstruating.
Urine microalbumin/creatinine ratio (Visits 3, 6, 9, Rescue, and Discontinuation)
This urine sample 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.
Thyroid Function Test (Visit 1)
Serum thyroid-stimulating hormone (TSH) test
Future Biomedical Research (FBR) Samples (Visits 3, 6, 9, Rescue, and 
Discontinuation)
Serum (SST) and Plasma (EDTA) Samples 
Blood (DNA) for FBR (Visit 3 only)
 
 
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6.8
MAPPING OF RELATIVE DAY RANGES TO WEEKS
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 (eg, AEs and 
PDLCs), all results will be included without mapping to individual time points.
Required Phase
Relative Day Range
Week
Day Relative to Start of Trial†
Baseline/Treatment
Day ≤1
0
A
2≤ Day ≤63
6
A
64≤ Day ≤112
12
A
Day 113
20
Day Relative to Start of Phase B‡ (Visit 6)
B
Day ≤98
28
B
99≤ Day ≤189
40
B
Day 190
54
† Start of Phase A is defined as first dose of Phase A study medication for all treated patients and the randomized 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 6 day for patients who entered 
Phase B off study medication.
The following rules 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, and insulin-related parameters.
Required Phase
Relative Day Range
Week
Day Relative to Start of Trial†
Baseline/Treatment
Day ≤1
0
A
Day 70
20
Day Relative to Start of Phase B‡ (Visit 6)
B
Day >119
54
† Start of Phase A is defined as first dose of Phase A study medication for all treated patients and the randomized 
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 6 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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6.9
PREDEFINED LIMITS OF CHANGE (PDLC)
The following predefined limits of change will be assessed in the statistical analysis, as 
described in Section 3.5.
Categories Assessed for Each 
Criterion
Laboratory Test
Predefined Limits of Change† 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
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.
ALT = alanine aminotransferase, AST = aspartate aminotransferase, BUN = blood urea nitrogen, LLN = Lower limit of normal; 
ULN = Upper limit of normal; WBC = white blood cell.
 
 
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6.10 CONSTRAINED LONGITUDINAL DATA ANALYSIS (CLDA) METHOD 
(WITH ADJUSTMENT FOR BASELINE VALUES) – TECHNICAL 
DETAILS FOR MODEL SPECIFICATION, ASSUMPTIONS, AND SAS 
IMPLEMENTATION CODES
Model
Let Yijt be the response for patient i, with treatment assignment j, at time t. The marginal 
mean responses of the cLDA model can be formulated as
,0
    
,
)
(
0
0


t
Y
E
ij

and
.
,...,
2,1
      
,1,0
     
,
)
(
0
T
t
j
Y
E
jt
ijt






The mean response γ0 at t=0 is constrained to be the same for both treatment groups due 
to randomization. The effect γjt denotes the change from baseline for treatment j at time t. 
The cLDA model assumes that baseline and post-baseline values have a joint multivariate 
normal distribution. An unstructured covariance matrix can be specified in the mixed 
model to account for within patient correlation at times t≥0 (including baseline).
The treatment difference for the mean change from baseline at time point t, 
T
t
,...,
2
,1

is defined as:
t
t
t
0
1





.
At each time point t, 
T
t
,...,
2
,1

, the mean change from baseline (LSMEANS) for test 
drug and control are 
t1
and 
t0
, respectively, as defined in the cLDA model above.
This longitudinal model provides valid statistical inference in the presence of possible 
missing data if the missing data mechanism is ignorable (or more specifically, missing at 
random [MAR] or missing completely at random [MCAR]). This missing data 
mechanism requires that the probability of a data point being missing does not depend on 
the missing data after adjusting for the observed data.
The LDA model assumes that the mechanism for any missing data is missingness at 
random (MAR), which means that missingness is caused by data that have already been 
observed, rather than by data that have not been observed. Any missingness that is caused 
by treatment is MAR, because treatment is an observed variable. Missingness that is the 
result of hyperglycemia-related discontinuation is also MAR, because it depends only on 
observed glycemic measurements. Other potential reasons for discontinuation include 
laboratory safety measurements outside acceptable limits, clinical or laboratory adverse 
events, relocation, withdrawal of consent, and violation of the protocol. Missingness due 
to some of those reasons (such as relocation) is likely to be completely at random (a 
 
 
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special case of MAR), and for the other reasons is likely to be MAR. It is not expected 
that non-MAR mechanisms will account for a substantial amount of missing data.
Model Convergence
If the unstructured covariance model fails to converge with the default algorithm, then 
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.
SAS Code
SAS code for fitting the full likelihood cLDA model is provided below.
********************************************************************;
** data step necessary prior to running SAS PROC MIXED;
********************************************************************;
DATA long; SET long;
ARRAY T{4} t0-t3; * time indicator variables;
ARRAY TT{8} tt0-tt7; * time by treatment indicator variables;
** define week times treatment indicator variables;
DO i = 1 to 4;
DO j = 1 to 2;
T{i} = (time=(i-1));
TT{i+4*(j-1)} = T{i}*(trt=j);
END;
END;
DROP i j;
RUN;
********************************************************************;
** fitting the cLDA model using SAS PROC MIXED;
********************************************************************;
PROC MIXED DATA=long;
CLASS subjid dosestrat typestrat time;  ** subj is the subject id number **;
MODEL y=dosestrat  typestrat time dosestrat*time typestrat*time tt5 tt6 tt7;
REPEATED time / SUBJECT=subjid TYPE=UN;
ESTIMATE 'MK-431A  vs. metformin ' tt7;
ODS OUTPUT Estimates=outm1;
RUN;
 
 
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6.11 TANNER STAGING
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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6.12 List of Prior Amendments
Amendment 01 dated 10Oct2012, Country-specific Brazil.
Amendment 02 dated 10Oct2012, Country-specific Brazil.
Amendment 03 dated 24Jun2013, Country-specific, South Africa.
Amendment 04 dated 09Apr2014, Global.
Amendment 05 dated 12Jan2015, Global.
Amendment 06 dated 04Feb2015, Country-specific, Saudi Arabia.
Amendment 07 dated 31Aug2015, Global.
Amendment 08 dated 20Oct2015, Country-specific, Saudi Arabia.
Amendment 09 – Not released.
 
 
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7. ATTACHMENTS
Merck 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
8.1
SPONSOR’S REPRESENTATIVE
TYPED NAME
SIGNATURE
DATE
8.2
INVESTIGATOR
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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