Clinical trial NCT02492763
Conditions: Type II Diabetes Mellitus
Sponsor: Merck Sharp & Dohme LLC
Start date: 2015-07-27; Completion date: 2017-04-18
Enrollment: 176 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a multicenter randomized, double-blind, placebo- and active-controlled (liraglutide; Victoza®), parallel-group, clinical trial of MK-8521 in participants with type 2 diabetes mellitus (T2DM) with inadequate glycemic control while on a stable dose of metformin (≥1000 mg/day).

The trial will include a 1-week screening period; at least an 8-week antihyperglycemic agent (AHA) washout period, if required; a 14-week blinded therapy period (which includes single-blind run-in and double-blind therapy); and a 14-day post-treatment visit, 2 weeks after the last dose of investigational product.

The primary hypothesis of the trial is that MK-8521 provides greater reduction in hemoglobin A1C relative to placebo after 12 weeks of once-daily administration in participants with T2DM with inadequate glycemic control on metformin monotherapy.

Detailed description:

Arms: arm 1: Participants receive double-blind MK-8521 300 μg daily (QD), subcutaneously, over 12 weeks. arm 2: Participants receive double-blind MK-8521 180 μg QD, subcutaneously, over 12 weeks. arm 3: Participants receive matching double-blind placebo, QD over 12 weeks. arm 4: Participants receive open-label 1.8 mg of liraglutide, QD, subcutaneously, over 12 weeks.
Interventions: intervention 1: MK-8521 intervention 2: Placebo intervention 3: Liraglutide intervention 4: Metformin
Intervention descriptions: intervention 1: Dose strengths: 180 μg QD administered subcutaneously. A 2-step dose escalation regimen \[60 μg, 120 μg\] over the first 2 weeks is used to achieve the final dose up to 180 μg.); 300 μg QD administered subcutaneously (A 3-step dose escalation regimen \[60 μg, 120 μg, 180 μg\] over the first 3 weeks is used to achieve the final dose up to 300 μg. intervention 2: Double dummy matching placebo for the MK-8521 and placebo arms: matching placebo for MK-8521 300 μg QD administered subcutaneously; matching placebo for MK-8521 180 μg QD administered subcutaneously. A dose escalation regimen consistent with that of the MK-8521 300 μg and 180 μg arms of the study; mock escalation will be performed over the first 2 to 3 weeks. intervention 3: Dose strength: 1.8 mg QD administered subcutaneously. A 2-step dose escalation regimen (0.6 mg, 1.2 mg) over the first 2 weeks is used to achieve the final dose up to 1.8 mg. intervention 4: Metformin immediate release (IR) or metformin extended release (XR) administered ≥1000 mg QD as background therapy

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Official Protocol Title: A Phase IIa, Multicenter, Placebo- and Active-controlled, 
Randomized, Double-Blind, Clinical Trial to Evaluate the Safety 
and Efficacy of MK-8521 Compared to Placebo in Subjects with 
Type 2 Diabetes Mellitus 
NCT number: 
NCT02492763 
Document Date: 
21-Dec-2016 


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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 Investigator Trial File
Binder (or equivalent).
TITLE:
A Phase IIa, Multicenter, Placebo- and Active-controlled, Randomized, Double-Blind, 
Clinical Trial to Evaluate the Safety and Efficacy of MK-8521 Compared to Placebo in 
Subjects with Type 2 Diabetes Mellitus
IND NUMBER:  119,329
EudraCT NUMBER:  2016-002056-25


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TABLE OF CONTENTS
SUMMARY OF CHANGES................................................................................................ 10
1.0
TRIAL SUMMARY.................................................................................................. 14
2.0
TRIAL DESIGN........................................................................................................ 14
Trial Design ........................................................................................................... 14
2.1
Trial Diagram........................................................................................................ 19
2.2
3.0
OBJECTIVE(S) & HYPOTHESIS(ES).................................................................. 20
Primary Objective(s) & Hypothesis(es) .............................................................. 20
3.1
Secondary Objective(s) & Hypothesis(es)........................................................... 20
3.2
Exploratory Objectives......................................................................................... 20
3.3
4.0
BACKGROUND & RATIONALE.......................................................................... 21
Background ........................................................................................................... 21
4.1
Pharmaceutical and Therapeutic Background .................................................... 21
4.1.1
Completed Pre-clinical and Clinical Trials......................................................... 22
4.1.2
4.1.2.1
Completed Pre-clinical Trials ...................................................................... 22
4.1.2.2
Completed Clinical Trials............................................................................ 22
Information on Other Trial-Related Therapy...................................................... 26
4.1.3
Rationale................................................................................................................ 26
4.2
Rationale for the Trial and Selected Subject Population .................................... 26
4.2.1
Rationale for Dose Selection/Regimen/Modification......................................... 28
4.2.2
4.2.2.1
Starting Dose for This Trial ......................................................................... 28
Rationale for Endpoints ...................................................................................... 29
4.2.3
4.2.3.1
Efficacy Endpoints....................................................................................... 29
4.2.3.2
Safety Endpoints .......................................................................................... 30
4.2.3.3
Pharmacokinetic Endpoints ......................................................................... 31
4.2.3.4
Planned Exploratory Biomarker Research................................................... 31
4.2.3.5
Future Biomedical Research........................................................................ 31
5.0
METHODOLOGY ................................................................................................... 32
Entry Criteria........................................................................................................ 32
5.1
Diagnosis/Condition for Entry into the Trial ...................................................... 32
5.1.1
Subject Inclusion Criteria.................................................................................... 32
5.1.2


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Subject Exclusion Criteria .................................................................................. 34
5.1.3
Trial Treatment(s) ................................................................................................ 40
5.2
Dose Selection/Modification .............................................................................. 41
5.2.1
5.2.1.1
Dose Selection (Preparation) ....................................................................... 41
5.2.1.2
Dose Escalation of Investigational Product ................................................. 42
Timing of Dose Administration .......................................................................... 43
5.2.2
Trial Blinding/Masking....................................................................................... 44
5.2.3
Randomization or Treatment Allocation............................................................ 44
5.3
Stratification.......................................................................................................... 44
5.4
Concomitant Medications/Vaccinations (Allowed & Prohibited).................... 44
5.5
Rescue Medications & Supportive Care............................................................. 46
5.6
Diet/Activity/Other Considerations..................................................................... 47
5.7
Diet...................................................................................................................... 47
5.7.1
5.7.2. Alcohol, Caffeine and Tobacco .......................................................................... 47
Activity ............................................................................................................... 47
5.7.3
Subject Withdrawal/Discontinuation Criteria................................................... 47
5.8
Subject Withdrawal/Discontinuation from Treatment Criteria ...................... 48
5.9
Monitoring Subjects Who Discontinue Investigational Product (Blinded or 
5.9.1
Open-Label) ........................................................................................................ 52
Subject Replacement Strategy............................................................................. 52
5.10
Beginning and End of the Trial ........................................................................... 52
5.11
Clinical Criteria for Early Trial Termination ................................................... 53
5.12
6.0
TRIAL FLOW CHART ........................................................................................... 54
7.0
TRIAL PROCEDURES ........................................................................................... 61
Trial Procedures ................................................................................................... 61
7.1
Administrative Procedures.................................................................................. 61
7.1.1
7.1.1.1
Informed Consent......................................................................................... 61
7.1.1.1.1
General Informed Consent.................................................................... 61
7.1.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research................................................................................................ 61
7.1.1.2
Inclusion/Exclusion Criteria ........................................................................ 62
7.1.1.3
Subject Identification Card .......................................................................... 62


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7.1.1.4
Medical History ........................................................................................... 62
7.1.1.5
Prior and Concomitant Medications Review ............................................... 62
7.1.1.5.1
Prior Medications.................................................................................. 62
7.1.1.5.2
Concomitant Medications..................................................................... 62
7.1.1.6
Assignment of Screening Number............................................................... 62
7.1.1.7
Assignment of Randomization Number....................................................... 62
7.1.1.8
Trial Compliance (Medication/Diet/Activity/Other) ................................... 63
7.1.1.8.1
Diet and Exercise Counseling and Monitoring..................................... 63
7.1.1.8.2
Dispense Hypoglycemia Assessment Log and Instruct on 
Hypoglycemia Symptoms and Management ........................................ 63
7.1.1.8.3
Dispense Glucose Meter and SMBG Instructions ................................ 64
7.1.1.8.4
Witnessed Dosing ................................................................................. 64
7.1.1.8.5
Dispense Single-Blind Placebo Run-in Investigational Product .......... 64
7.1.1.8.6
Dispense Double-Blind/Open-Label Investigational Product .............. 64
7.1.1.8.7
Medication Compliance Monitoring..................................................... 65
Clinical Procedures/Assessments........................................................................ 66
7.1.2
7.1.2.1
Vital Signs (Sitting Blood Pressure and Heart Rate) ................................... 66
7.1.2.2
Postural (Orthostatic) Blood Pressure and Heart Rate................................. 67
7.1.2.3
Body Weight ................................................................................................ 67
7.1.2.4
Height........................................................................................................... 68
7.1.2.5
Physical Examination................................................................................... 68
7.1.2.6
Electrocardiogram (12-lead ECG) ............................................................... 68
7.1.2.7
Fasting Fingerstick Glucose (FFSG) ........................................................... 69
7.1.2.8
Review of SMBG Measurements and Hypoglycemia Assessment Log 
(HAL)........................................................................................................... 69
7.1.2.9
Assess Subject for Discontinuation Based on Central Laboratory FPG ...... 69
7.1.2.10 Adverse Event Monitoring........................................................................... 69
7.1.2.10.1 Hyperglycemia...................................................................................... 69
7.1.2.10.2 Hypoglycemia....................................................................................... 69
Reporting Events of Hypoglycemia ............................................. 69
7.1.2.10.2.1
Laboratory Procedures/Assessments .................................................................. 70
7.1.3
7.1.3.1
Laboratory Safety and Efficacy Evaluations ............................................... 70
7.1.3.2
Pharmacokinetic/Pharmacodynamic Evaluations ........................................ 71


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7.1.3.3
Future Biomedical Research........................................................................ 71
Other Procedures................................................................................................. 72
7.1.4
7.1.4.1
Withdrawal/Discontinuation........................................................................ 72
7.1.4.1.1
Withdrawal From Future Biomedical Research ................................... 72
7.1.4.2
Blinding/Unblinding .................................................................................... 72
7.1.4.3
Calibration of Critical Equipment................................................................ 73
Visit Requirements.............................................................................................. 73
7.1.5
7.1.5.1
Fasting Prior to Scheduled Visits................................................................. 73
7.1.5.2
Scheduling Visits ......................................................................................... 73
7.1.5.3
Subject Contacts........................................................................................... 74
7.1.5.3.1
Adverse Event and Study Medication Compliance Telephone 
Contacts ................................................................................................ 74
7.1.5.3.2
Visit Reminders .................................................................................... 74
7.1.5.3.3
Safety Follow-up Telephone Contacts.................................................. 75
7.1.5.4
Screening Visits ........................................................................................... 75
7.1.5.4.1
Visit 1/Screening................................................................................... 75
7.1.5.4.2
Visit 1A/Washout ................................................................................. 75
7.1.5.4.3
Run-in (Visit 2/Week-2)....................................................................... 76
7.1.5.5
Treatment Period (Visit 3 through Visit 10) ................................................ 76
7.1.5.5.1
Randomization (Visit 3/Day 1)............................................................. 76
7.1.5.5.2
Week 1 through Week 12: Treatment Period ....................................... 77
7.1.5.6
Follow-up Day 14: Post Treatment Visit ..................................................... 77
7.1.5.7
Follow-up for Subjects Who Discontinue Investigational Product ............. 77
Assessing and Recording Adverse Events .......................................................... 77
7.2
Definition of an Overdose for This Protocol and Reporting of Overdose to 
7.2.1
the Sponsor.......................................................................................................... 78
Reporting of Pregnancy and Lactation to the Sponsor ....................................... 78
7.2.2
Immediate Reporting of Adverse Events to the Sponsor.................................... 79
7.2.3
7.2.3.1
Serious Adverse Events ............................................................................... 79
7.2.3.2
Events of Clinical Interest............................................................................ 80
Evaluating Adverse Events ................................................................................. 80
7.2.4
Sponsor Responsibility for Reporting Adverse Events ...................................... 83
7.2.5
TRIAL GOVERNANCE AND OVERSIGHT ................................................... 83
7.3


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Executive Oversight Committee ......................................................................... 83
7.3.1
Data Monitoring Committee ............................................................................... 83
7.3.2
8.0
STATISTICAL ANALYSIS PLAN ........................................................................ 83
Statistical Analysis Plan Summary ..................................................................... 83
8.1
Efficacy Analysis ................................................................................................ 83
8.1.1
Safety Analysis ................................................................................................... 84
8.1.2
Power and Sample Size....................................................................................... 84
8.1.3
Interim Analysis.................................................................................................. 84
8.1.4
Statistical Analysis Plan ....................................................................................... 85
8.2
Responsibility for Analyses/In-House Blinding ................................................. 85
8.2.1
Hypotheses.......................................................................................................... 86
8.2.2
Analysis Endpoints ............................................................................................. 86
8.2.3
8.2.3.1
Efficacy Endpoints....................................................................................... 86
8.2.3.2
Safety Endpoints .......................................................................................... 87
8.2.3.3
Pharmacokinetics Endpoints........................................................................ 87
Analysis Populations........................................................................................... 87
8.2.4
8.2.4.1
Efficacy Analysis Populations ..................................................................... 87
8.2.4.2
Safety Analysis Populations ........................................................................ 88
Statistical Methods.............................................................................................. 89
8.2.5
8.2.5.1
Efficacy Analyses ........................................................................................ 89
8.2.5.2
Safety Analyses............................................................................................ 91
8.2.5.3
Summaries of Baseline Characteristics, Demographics, and Other 
Analyses....................................................................................................... 94
Multiplicity ......................................................................................................... 94
8.2.6
Sample Size and Power Calculations.................................................................. 95
8.2.7
Subgroup Analyses ............................................................................................. 96
8.2.8
Interim Analyses ................................................................................................. 96
8.2.9
8.2.9.1
Triggered Safety Review for Discontinuation Due to HR........................... 96
8.2.9.2
Planned Efficacy and Safety Review........................................................... 96
Compliance (Medication Adherence) ................................................................. 98
8.2.10
9.0
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES ................................................................................................................. 98


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Investigational Product ........................................................................................ 98
9.1
Packaging and Labeling Information ................................................................. 99
9.2
Clinical Supplies Disclosure................................................................................. 99
9.3
Storage and Handling Requirements.................................................................. 99
9.4
Returns and Reconciliation................................................................................ 100
9.5
Standard Policies................................................................................................. 100
9.6
10.0
ADMINISTRATIVE AND REGULATORY DETAILS..................................... 100
Confidentiality..................................................................................................... 100
10.1
Confidentiality of Data ..................................................................................... 100
10.1.1
Confidentiality of Subject Records ................................................................... 100
10.1.2
Confidentiality of Investigator Information...................................................... 101
10.1.3
Confidentiality of IRB/IEC Information........................................................... 101
10.1.4
Compliance with Financial Disclosure Requirements..................................... 101
10.2
Compliance with Law, Audit and Debarment ................................................. 102
10.3
Compliance with Trial Registration and Results Posting Requirements ...... 103
10.4
Quality Management System............................................................................. 104
10.5
Data Management............................................................................................... 104
10.6
Publications ......................................................................................................... 104
10.7
11.0
LIST OF REFERENCES....................................................................................... 106
12.0
APPENDICES......................................................................................................... 109
Merck Code of Conduct for Clinical Trials...................................................... 109
12.1
Collection and Management of Specimens for Future Biomedical 
12.2
Research............................................................................................................... 111
Understanding the Intent, Scope and Public Health Benefits of 
12.3
Exploratory Biomarker Research: A Guide for IRBs/IECs and 
Investigational Site Staff .................................................................................... 117
Mapping of Relative Day Ranges to Weeks...................................................... 128
12.4
13.0
SIGNATURES......................................................................................................... 129
Sponsor's Representative ................................................................................... 129
13.1
Investigator.......................................................................................................... 129
13.2


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LIST OF TABLES
Table 1  Pre-Randomization Management ............................................................................. 16
Table 2  MK-8521 Clinical Program Overview ..................................................................... 23
Table 3  Laboratory Exclusion Criteria .................................................................................. 37
Table 4  Visit 2/Week -2 Laboratory Exclusion Criteria........................................................ 39
Table 5  Trial Treatment ......................................................................................................... 40
Table 6  Dose Escalation for Subjects Randomized to MK-8521 or Placebo ........................ 43
Table 7  Glycemic Thresholds For Discontinuation............................................................... 49
Table 8  Suggested Liraglutide Dispensing Guidance............................................................ 65
Table 9  Laboratory Tests ....................................................................................................... 70
Table 10  Evaluating Adverse Events..................................................................................... 81
Table 11  Summary of Analysis Strategy for Key Efficacy Endpoints .................................. 84
Table 12  Analysis Strategy for Efficacy Endpoints............................................................... 90
Table 13  Analysis Strategy for Safety Endpoints.................................................................. 92
Table 14  Summary of Planned Efficacy and Safety Interim Analysis Strategy.................... 98
Table 15  Product Descriptions............................................................................................... 99


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LIST OF FIGURES
          
Figure 1  Trial Design............................................................................................................. 19


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SUMMARY OF CHANGES
PRIMARY REASON(S) FOR THIS AMENDMENT:
Section Number (s)
Section Title(s)
Description of Change (s)
Rationale
2.1
Trial Design
Added details regarding the planned 
interim analysis.
Provided clarity and details 
regarding the aspects of interim 
analyses to be performed.

Re-evaluation of
sample 
size  

Guidelines 
for
potential 
termination of the study

Differentiation of the safety 
triggered review from the 
planned interim analyses
4.2.3.1
Efficacy Endpoints
Removed text regarding
the interim 
analysis.
5.12
Clinical Criteria for Early Trial 
Termination
Updated text to reflect changes based on 
the planned interim analysis.
7.3.2
Data Monitoring Committee
Added details regarding
the planned 
interim analysis.
8.1.4
Interim Analysis
Added a planned interim analysis to 
potentially increase the sample size or 
terminate the study for futility.  
8.2.1
Responsibility for Analyses/In-
House Blinding
Added 
additional 
detail 
regarding 
approach to unblinding for the planned 
interim analysis
8.2.9.1
Safety Review for 
Discontinuation Due to HR
Section title was changed to Triggered 
Safety Review for Discontinuation Due to 
HR. 
8.2.9.2
Efficacy and Safety Review for 
Planning Future Studies
Section title was changed to Planned 
Efficacy and Safety Review.
Text was modified to explain the planned 
interim analyses and possible actions 
including study termination or increase  
sample size.


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ADDITIONAL CHANGE(S) FOR THIS AMENDMENT:
Section 
Number (s)
Section Title (s)
Description of Change (s)
Rationale
2.2 
Trial Diagram
Trial diagram was corrected to indicate
A1C requirement of 7.5-10.5% at V2.
Corrected 
typographical 
error.
Trial 
diagram 
incorrectly 
indicated 
A1C 
requirement of 7.5-10.5% at V3.
5.5
Concomitant 
Medication 
(Allowed & Prohibited)
Removed text stating
that subjects 
continue to take their own supply of 
metformin as prescribed by their primary 
care physician while they are in the trial.
Prescriptions for metformin may be 
written by primary care physician or study 
investigator.
5.1.3
5.5
Subject Exclusion Criteria
Concomitant 
Medications/Vaccinations 
(Allowed and Prohibited)
Added Note indicating that systemic
and ophthalmic beta blockers are 
prohibited.
Added additional examples of beta 
blocker
or 
medications 
with 
sympathomimetic activity.
Provides clarity on exclusion criterion and 
prohibited medication use.
6.0
Trial Flow Chart
• Updated footnote b to include body 
weight, chemistry and hematology as 
required procedures at the 14-Day Post 
Treatment Follow-Up Visit.
• Added footnote bb to indicate when to 
obtain and send to central laboratory PK 
samples for MK8521 or Liraglutide
• 
Corrected 
inconsistencies 
between 
protocol sections.
• Clarified that if a subject is randomized 
to Liraglutide (open label), only the PK 
samples 
for 
Liraglutide 
should 
be 
obtained and sent to the central laboratory 
(and PK samples for MK-8521 should not 
be obtained). Conversely, if a subject is 
randomized to MK-8521/placebo only PK 
samples for MK-8521 should be obtained 
and sent to the central laboratory (and PK 
samples for Liraglutide should not be 
obtained).


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Section 
Number (s)
Section Title (s)
Description of Change (s)
Rationale
7.1.2.1
Vitals Signs (Sitting Blood 
Pressure and Heart Rate)
Removed text referring to recording last 
set of BP and HR measurements in 
source.
All BP and HR measurements should be 
recorded in source.  
7.1.3.2
Pharmacokinetic/Pharmacod
ynamic Evaluations
Added text indicating when to obtain and 
send to central laboratory PK samples for 
MK8521 or Liraglutide
Clarified that if a subject is randomized to 
Liraglutide (open label), only the PK 
samples 
for 
Liraglutide 
should 
be 
obtained and sent to the central laboratory
(and PK samples for MK-8521 should not 
be obtained). Conversely, if a subject is 
randomized to MK-8521/placebo only PK 
samples for MK-8521 should be obtained 
and sent to the central laboratory (and PK 
samples for Liraglutide should not be 
obtained).
8.2.4.1
Efficacy Analysis Population
Expanded 
PP 
drug 
compliance 
violation to exclude subjects who have 
high likelihood of poor compliance 
based on PK data and to exclude all 
subjects from sites with a high degree 
of non-compliance based on PK data.
Clarified 
that 
the 
PP 
exclusion 
regarding inability to tolerate MK-
8521 applies only to the 300 µg group
Added modified FAS population.
Utilize PK data to assess compliance
Clarification
Permit 
assessment 
of 
efficacy 
excluding data from sites with high 
degree of non-compliance as assessed 
by PK


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Section 
Number (s)
Section Title (s)
Description of Change (s)
Rationale
8.2.4.2
Safety analysis populations
Added modified ASaT population.

To permit safety analysis excluding 
data from sites with high degree of 
non-compliance as assessed by PK
8.2.5.1
Efficacy Analyses
Change and percent change from 
baseline 
in 
triglycerides 
will 
be 
analyzed using a robust regression 
approach.
The primary (A1C) and key secondary 
endpoints (FPG and body weight) will 
also be analyzed using an ANCOVA 
model in the PP population.

Added modified FAS population for 
analysis
Because change and percent change in 
triglycerides typically has a skewed 
distribution, the cLDA model which is 
based 
on 
the 
symmetric 
normal 
distribution may not be appropriate.
ANCOVA model is more appropriate 
than cLDA for PP population.

Rationale provided above (Section 
8.2.4.1)
8.2.5.2
Safety Analyses
Added modified ASaT population
Rationale provided above (Section 
8.2.4.2)
8.2.6
Multiplicity
Modified text related to type 1 error 
control related to the interim analysis 
described in Section 8.1.4.
Clarification


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1.0 TRIAL SUMMARY
Abbreviated Title
MK-8521 Phase IIa Trial in Subjects with Type 2 Diabetes Mellitus
Trial Phase
IIa
Clinical Indication
Treatment of type 2 diabetes mellitus in patients with inadequate 
glycemic control with metformin monotherapy
Trial Type
Interventional
Type of control
Placebo and Active
Route of administration
Subcutaneous
Trial Blinding
Double-blind
Treatment Groups
MK-8521 300 µg (dose to be gradually escalated over the first 3
weeks up to 300 µg), or MK-8521 180 µg (dose to be gradually 
escalated over the first 2 weeks up to 180 µg), or Placebo to MK-8521
(mock escalation over the first 2-3 weeks), or open-label liraglutide 
(dose to be gradually escalated over the first 2 weeks up to 1.8 mg) for 
12 weeks.
Number of trial subjects
Approximately 160 subjects will be enrolled.
Estimated duration of trial
The sponsor estimates that the trial will require approximately 20
months from the time the first subject signs the informed consent until 
the last subject’s last study-related phone call or visit.
Duration of Participation
Each subject will participate in the trial for up to approximately 25 
weeks from the time the subject signs the Informed Consent Form 
(ICF) through the final contact.  This will include a 1-week screening 
period (Visit 1 to Visit 1A or Visit 2); an 8-week antihyperglycemic 
agent (AHA) washout period (Visit 1A to Visit 2) if required; a 2-
week single-blind placebo run-in period (Visit 2 to Visit 3); a 12-week
treatment period (Visit 3 to Visit 10) and a post-treatment visit 2 
weeks after the last dose of investigational product.
2.0 TRIAL DESIGN
Trial Design
2.1
This is a multicenter randomized, double-blind, placebo- and active-controlled (liraglutide; 
Victoza®), parallel-group, clinical trial of MK-8521 in subjects with T2DM on a stable dose 
of metformin (≥1000 mg/day).
This trial will be conducted in conformance with Good 
Clinical Practices (GCP).
The duration of the trial will be up to 25 weeks (with up to 12 clinic visits) for each subject.
This will include a 1-week screening period (Visit 1 to Visit 1A or Visit 2); if required, an
antihyperglycemic agent (AHA) washout period of at least 8 weeks (Visit 1A to Visit 2); a 2-
week single-blind placebo run-in period (Visit 2 to Visit 3); a 12-week placebo- and active-
controlled treatment period (Visit 3 to Visit 10); and a 14-day post-treatment visit 2 weeks
after the last dose of investigational product.
Approximately 160 subjects ≥21 and ≤65 years of age with T2DM, diagnosed in accordance 
with American Diabetes Association guidelines with inadequate glycemic control 
(hemoglobin A1c [A1C] ≥7.5% and ≤10.5% [≥58 mmol/mol and ≤91 mmol/mol]) while on a 
stable dose of metformin monotherapy ≥1000 mg/day and who meet all enrollment criteria 
Randomization Ratio
1:1:1:1


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will be randomized.  Subjects will continue on their stable dose of metformin throughout the 
trial including the 14-day post-treatment visit.
Management of Subjects Prior to Randomization
Pre-randomization management of subjects is summarized in Table 1 below.  At Visit 
1/Screening, subjects who meet criteria for one of the two groups presented in Table 1, based 
on their anti-hyperglycemic agent (AHA) status and A1C, and also meet other study 
eligibility criteria detailed in Section 5.0, will be eligible for enrollment.  
Management between Visit 1/screening and Visit 2/initiation of placebo run-in will differ 
depending on AHA status at screening as follows:
• Subjects on metformin monotherapy at screening will proceed to Visit 2/Week -2, at 
which time they will receive diet and exercise counseling and enter a 2 week placebo 
run-in period.  If they continue to meet eligibility criteria, randomization will occur at 
Visit 3/Day 1.
• Subjects on dual AHA therapy (metformin plus a second permissible AHA) will proceed 
to Visit 1A, at which time they will receive diet and exercise counseling and initiate 
washout of the non-metformin agent.  The washout period will be at least 8 weeks, after 
which they will proceed to Visit 2/Week -2 and enter a 2 week placebo run-in period.  If 
they continue to meet eligibility criteria, randomization will occur at Visit 3/Day 1.  
Eligibility for continued study participation will be assessed at Visits 1, 2, and 3 
(Randomization/Day 1) based on the criteria detailed in Section 5.1.  For subjects for whom 
Visit 2 occurs more than 2 weeks after Visit 1 (including all subjects undergoing washout), 
this includes the requirement, that A1C at Visit 2 be ≥7.5% and ≤10.5% (≥58 mmol/mol and 
≤91 mmol/mol) and that required laboratory results (see Flow Chart, Section 6.0) are 
consistent with enrollment criteria.  
Note: If Visit 2 occurs ≤2 weeks after Visit 1, then repeat A1C and screening laboratories 
should not be conducted.  
The placebo run-in may be initiated at Visit 2/Week -2 while laboratory data, including A1C, 
are pending, but randomization may not occur until all eligibility criteria are confirmed.  If a 
subject has initiated the placebo run-in but screen fails due to A1C or other laboratory data 
collected at Visit 2, they should be contacted and told to discontinue the placebo run-in.
For subjects who meet enrollment criteria at Visit 1 except for elevated triglycerides (TG) 
and/or elevated blood pressure, the investigator may initiate or adjust lipid-lowering and/or 
blood pressure medication and permit the subject to proceed with pre-randomization 
activities.  Note the following for these subjects:
• All modification of lipid-lowering and/or blood pressure medication must occur prior to 
Visit 2/Week -2 (with unscheduled visits, as needed).
• Lipid-lowering and/or blood pressure medications must be at a stable dose for at least 4 
weeks prior to Visit 3/randomization.  The screening period (Visit 1 to Visit 2) should be 
extended as necessary to meet this requirement.


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• Subjects for whom lipid-lowering medication is initiated or modified to address elevated 
TG must meet TG eligibility criteria at Visit 2 to proceed to randomization.  All subjects 
must meet blood pressure eligibility criteria at Visit 3/randomization to proceed with 
randomization.
Placebo Run-In
At Visit 2/Week -2, eligible subjects will enter the 2-week, single-blind, placebo run-in 
period.  All subjects (including those subjects who will eventually be randomized to open-
label liraglutide) will be dispensed 2 vials/day single-blind investigational product (referred 
to as Vial A and Vial B (MK-8521 180 g and MK-8521 300 g matching placebos,
respectively) and instructed to take one injection (0.1 mL) per day from each vial at 
approximately the same time of day in the morning during the 2-week single-blind placebo 
period prior to randomization.  Subjects should be reminded to withhold single-blind 
investigational product on the day of Visit 3/ Day 1.  Note: Subjects who miss more than one 
daily dose (i.e., 2 injections on the same day or 2 single injections on separate days) of the 
placebo run-in medication are ineligible for randomization.
Subjects meeting eligibility for randomization through Visit 3/Day 1, based on the criteria 
detailed in Section 5.1, will be eligible to enter the double-blind treatment period.
Table 1  Pre-Randomization Management
Regimen at Visit 1/
Screening
Visit 1/Screening A1C 
Entry Criterion
Subject Management during the Pre-
Randomization Period
On
metformin 
monotherapy (≥1000 
mg/day)
for 
≥12 
weeks
A1C ≥7.5% and ≤10.5% (≥58 
mmol/mol and ≤91 mmol/mol)

Continue metformin at Visit 1 dose 
throughout the trial.

Proceed 
to Visit 2/Week -2 and 
initiate placebo run-in as appropriate

Randomize at Visit 3 if subject 
continues to be eligible.
On dual therapy of
metformin 
(≥1000 
mg/day for ≥4 weeks) 
and a second AHA1  
A1C ≥7.0% and ≤10.0% (≥53 
mmol/mol and ≤86 mmol/mol)

Continue metformin at Visit 1 dose 
throughout the trial.

Discontinue treatment with other
AHA at Visit 1A/Washout

Proceed to Visit 2/Week -2 after an
AHA washout of ≥8 weeks.  Initiate 
placebo run-in as appropriate

Randomize at Visit 3 if subject 
continues to be eligible2
1Allowable AHAs prior to screening (Visit 1): DPP-4 inhibitors, α-glucosidase inhibitors, sulfonylureas and glinides. 
2Randomization requirements include Visit 2 A1C ≥7.5% and ≤10.5% (≥58 mmol/mol and ≤91 mmol/mol) 
Management of Randomized Subjects
At Visit 3/Day 1, subjects who meet enrollment criteria will enter the 12-week treatment 
period.  Subjects will be randomized in a 1:1:1:1 ratio to 1 of 4 treatment groups: (1) MK-
8521 300 µg once-daily (QD), (2) MK-8521 180 µg QD, (3) MK-8521 placebo QD, (4) 
open-label liraglutide 1.8 mg QD.  All treatments will be administered with subcutaneous 
injection. Subjects are to remain on their stable dose of metformin (≥1000 mg/day) while 
receiving investigational product (blinded or open-label) during the treatment period.


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Subjects randomized to either MK-8521 180 µg or 300 µg or placebo will have a 2 and 3
step dose escalation regimen, respectively, to achieve the planned study dose (see Table 6, 
Section 5.2.1.2).  Subjects randomized to liraglutide will have a 2 step dose escalation 
regimen to achieve the planned study dose.
A double-dummy approach will be used in the trial because the volume of MK-8521 
administered differs between the 180 µg and 300 µg dose arms.  With the double-dummy 
approach, subjects randomized to MK-8521 or MK-8521 placebo will administer 2 injections 
each day: 1 injection from Vial C containing active MK-8521 180g dose or placebo and 1 
injection from Vial D containing MK-8521 300 g or placebo.  Subjects randomized to the 
MK-8521 180 g group will also receive placebo for MK-8521 300g; subjects randomized 
to the MK-8521 300g group will also receive placebo for MK-8521 180 g; subjects 
randomized to placebo will receive placebo for both MK-8521 300g and MK-8521 180 g.  
Subjects randomized to liraglutide will receive only open-label liraglutide for the duration of 
the trial.
MK-8521 or MK-8521 Placebo Dosing
For subjects randomized to the MK-8521 300 µg treatment group, Vial C will contain 
placebo and Vial D will contain active MK-8521.  The starting dose in the MK-8521 300 
µg treatment group will be 60 µg (0.1 mL from each vial) from Visit 3/Day 1 through Day 
6.  The dose will then be escalated to 120 µg (0.2 mL from each vial) from Visit 4/Week 1 
through Day 13, to 180 µg (0.3 mL from each vial) from Visit 5/Week 2 through Day 20, 
and to the final dose of 300 µg (0.3 mL from Vial C and 0.5 mL from Vial D) from Visit 
6/Week 3 for the remainder of the 12 weeks (approximately 63 days).
For subjects randomized to the MK-8521 180 µg treatment group, Vial C will contain 
active MK-8521 and Vial D will contain placebo.  The starting dose in the MK-8521 180
µg treatment group will be 60 µg (0.1 mL from each vial) from Visit 3/Day 1 through Day 
6.  The dose will then be escalated to 120 µg (0.2 mL from each vial) from Visit 4/Week 1 
through Day 13, and to the final dose of 180 µg (0.3 mL from each vial) from Visit 5/Week 
2 through Day 20. In order to maintain blinding with the MK-8521 300 µg treatment group 
(see above), the dose from Vial C will remain at 0.3 mL/day and the dose Vial D will 
increase to 0.5 mL/day from Visit 6/Week 3 for the remainder of the 12 weeks 
(approximately 63 days).
In order to maintain blinding with the MK-8521 treatment arms, subjects randomized to 
placebo will receive a dose escalation regimen consistent with that for MK-8521 300 µg 
and 180 µg treatment groups (see above).  For subjects randomized to the Placebo
treatment group, both Vial C and Vial D will contain placebo.  The starting dose in the 
Placebo treatment group will be 0.1 mL from each vial from Visit 3/Day 1 through Day 6.  
The dose will then be escalated to 0.2 mL from each vial from Visit 4/Week 1 through Day 
13, to 0.3 mL from each vial from Visit 5/Week 2 through Day 20, and to the final dose of 
0.3 mL from Vial C and 0.5 mL from Vial D from Visit 6/Week 3 for the remainder of the 
12 weeks (approximately 63 days).
Subjects who cannot tolerate 0.5 mL/day from Vial D may continue in the trial on 0.3 
mL/day (180 g/day for subjects randomized to active MK-8521) from each vial (refer to 
Section 5.2.1.2 for further details).


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Liraglutide Dosing
Subjects randomized to the liraglutide 1.8 mg treatment group will start at a dose of 
liraglutide 0.6 mg from Visit 3/Day 1 through Day 6, 1.2 mg from Visit 4/Week 1 through
Day 13 and 1.8 mg from Visit 5/Week 2 for the remainder of the 12 weeks (approximately
70 days).
Subjects who cannot tolerate the 1.8 mg/day dose of liraglutide may continue in the trial on 
the 1.2 mg/day dose.
Subjects who are discontinued from investigational product (blinded or open-label) for any 
reason other than withdrawal of consent will be followed by telephone contacts for the 
duration of the trial according to the Trial Flow Chart - Section 6.0.  The purpose of the 
telephone contacts will be to assess for SAEs.  All subjects will perform a post-treatment 
visit 14 days after the last dose of investigational product. The purpose of the 14-day post 
treatment visit will be to assess for safety/efficacy parameters.
Interim analysis
An interim analysis will be performed when at least 50% of subjects have completed the 
Week 12 Visit or discontinued prior to the Week 12 Visit and will include an assessment of 
both efficacy endpoints (including A1C and weight loss) and safety endpoints (including 
AEs and change from baseline in heart rate).  One of the goals of this interim analysis will 
be to determine whether the study has sufficient potential to demonstrate the necessary 
efficacy and safety profile to justify continued development of MK-8521.  If so, the study 
will continue to completion.  If not, the study will be terminated.  An additional goal of the 
interim analysis is sample size re-estimation.   The results of this interim analysis will be 
reviewed by the Sponsor standing internal Data Monitoring Committee (siDMC). The 
approach to the interim analysis is described in more detail in Section 8.2.9. 
This trial is designed to evaluate the safety and tolerability of the addition of treatment with 
MK-8521 to the regimen of adult subjects with T2DM and inadequate glycemic control on 
diet, exercise and metformin monotherapy.  It is also designed to evaluate the effect of MK-
8521 on glycemic control and body weight following a 12-week dosing period as compared 
to placebo and with reference to liraglutide.  
Please note, throughout this protocol, “Sponsor” refers to “Sponsor or its delegate” and 
“Subsidiary” refers to “Subsidiary or designee”.
Specific procedures to be performed during the trial, as well as their prescribed times and 
associated visit windows, are outlined in the Trial Flow Chart - Section 6.0. Details of each 
procedure are provided in Section 7.0 – Trial Procedures.


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Trial Diagram
2.2
The trial design is depicted in Figure 1.
1Allowable AHAs at Screening (Visit 1) are: DPP-4 inhibitors, α-glucosidase inhibitors, sulfonylureas and 
glinides.
2If lipid-lowering or blood pressure medication requires initiation or adjustment, adjustments should be made 
prior to Visit 2/Week -2 (with unscheduled visits, as needed).  The screening period (Visit 1 to Visit 2) should
be extended so that subjects are on a stable regimen for at least 4 weeks prior to Visit 3/Day 1.  Subjects 
requiring AHA washout can have adjustments made concurrently with AHA washout.
3Visit 1A/Washout is required if a subject requires AHA washout.  If necessary, adjustment or initiation of 
lipid-lowering or blood pressure medication can also be performed at the visit.
4Subjects who complete Visit 10 or those who discontinue early will have the Follow-up Visit 14 days after the 
last dose of investigational product.
Figure 1  Trial Design


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3.0 OBJECTIVE(S) & HYPOTHESIS(ES)
Primary Objective(s) & Hypothesis(es)
3.1
In subjects with T2DM with inadequate glycemic control on metformin monotherapy, after 
12 weeks of once-daily administration:
1. Objective:  To assess the A1C-lowering efficacy of the addition of MK-8521 relative 
to placebo.
Hypothesis: 300µg/day or both doses of MK-8521 provide greater reduction in A1C 
relative to placebo.
2. Objective:  To evaluate safety and tolerability of MK-8521.
Secondary Objective(s) & Hypothesis(es)
3.2
In subjects with T2DM with inadequate glycemic control on metformin monotherapy, after 
12 weeks of once-daily administration of MK-8521, to assess the effect relative to placebo 
on:
1. Body weight
Hypothesis: 300µg/day or both doses of MK-8521 reduce body weight relative to 
placebo.
2. Fasting plasma glucose
Hypothesis: 300µg/day or both doses of MK-8521 provide greater reduction in FPG
relative to placebo.
3. Fasting lipids (including LDL-cholesterol level, HDL-cholesterol level, triglyceride 
level).
4. Systolic and diastolic blood pressure
In subjects with T2DM with inadequate glycemic control on metformin monotherapy, 
after 12 weeks of once-daily administration of MK-8521, to estimate the effect 
relative to liraglutide on:
5. Glycemic measures (A1C and FPG)
6. Body weight
7. Fasting lipids (including LDL-cholesterol level, HDL-cholesterol level, triglyceride 
level).
8.
Systolic and diastolic blood pressure
Exploratory Objectives
3.3
1. Objective: To explore the relationship between genetic variation and response to the 
treatment(s) administered.  Variation across the human genome will be analyzed for 
association with clinical data collected in this study.


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4.0 BACKGROUND & RATIONALE
Background
4.1
Refer to the Investigator’s Brochure (IB) for detailed background information on MK-8521.
Pharmaceutical and Therapeutic Background
4.1.1
There has been an increase in the global prevalence of T2DM largely attributed to rising rates 
of excess body weight and obesity.  Approximately 85% of patients with T2DM are obese or 
overweight, a key factor underlying the development and maintenance of insulin resistance
and pancreatic β cell failure [1, 2].  Pharmacological agents that lower glucose while also 
lowering body weight represent a major advantage in the treatment of diabetes.
Among new therapies for T2DM, peptidyl mimetics of the gut-derived incretin hormone
glucagon-like peptide 1 (GLP-1) stimulate insulin biosynthesis and secretion in a glucose-
dependent manner and cause modest weight loss. Several of these agents are currently 
approved for the treatment of patients with T2DM (including exenatide [Byetta™and
Bydureon™]) and liraglutide [Victoza™]) [3].
Glucagon acutely increases hepatic glucose production and subsequently raises blood glucose 
levels.  However, emerging evidence suggests that glucagon receptor (GCGR) activation 
may also mediate a post prandial satiety signal [4] and with chronic stimulation may result in 
weight loss [5].  In preclinical murine models, combined tonic activation of both the GLP-1 
receptor (GLP-1R) and the GCGR resulted in anti-hyperglycemic activity with significant 
weight loss (superior to incretin action) [6].  Likewise, in healthy overweight/obese 
volunteers, co-administration of GLP-1 during glucagon infusion resulted in increased 
energy expenditure without hyperglycemia (of note, administration of glucagon alone 
caused a rise in blood glucose and GLP-1 alone did not cause any change in energy 
expenditure) [7].
Oxyntomodulin (OXM), an endogenous gut-derived peptide agonist of both the GLP-1R and 
the GCGR, has been suggested to reduce food intake and body weight, increase energy 
expenditure, improve glucose metabolism and promote weight loss in both rodents and 
overweight and obese humans [8-9].  In a study by Wynne et.al, 26 participants with a BMI 
of 25 - 40 kg/m2 self-administered saline or OXM subcutaneously for 4 weeks in a
randomized, double-blind, parallel-group protocol. Body weight was reduced by 2.3 ± 0.4 kg 
in the treatment group over the study period compared with 0.5 ±0.5 kg in the control group 
(P =0.011) [8].  Energy intake by the active treatment group was significantly reduced by 170 
± 37 kcal (25 ± 5%) at the initial study meal (P >0.001) and by 250 ± 63 kcal (35 ± 9%) at 
the final study meal (P = 0.002).  In a subsequent study by Wynne et.al, fifteen healthy 
overweight and obese men and women (age: 23–49 years, BMI: 25.1–39.0 kg/m2) self-
administered subcutaneous OXM or placebo, three times daily for four days.  Energy 
expenditure was measured by indirect calorimetry and combined heart rate (HR) and 
movement monitoring.  OXM did not alter resting energy expenditure but increased activity-
related energy expenditure by 143±109 kcal/day or 26.2±9.9% (P=0.022), total energy 
expenditure by 9.4±4.8% (P=0.045) and physical activity level by 9.5±4.6% (P=0.049). A 
reduction in body weight of 0.5±0.2% was observed during the OXM administration period 
(P=0.023) [9].


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MK-8521 is an acylated peptide that has agonist effects at both GLP-1R and GCGR, and 
hence can be considered a dual receptor agonist.  By augmenting both weight loss and 
exerting a glucose-lowering effect, dual agonism may provide a more effective strategy than 
GLP-1 only targeted peptides. The program hypothesis is that the activation of these two 
receptors by MK-8521 should lead to an additive effect on body weight loss (greater than 
that observed with GLP-1R agonists) and a glucose lowering effect similar to that observed 
with GLP-1R agonists. Dual activation of the GLP-1R and the GCGR is anticipated to lead 
to glucose lowering via several mechanisms:

A rapid acting mechanism via augmentation of insulin secretion and inhibition of 
gastric emptying by GLP-1R agonism (possibly further stimulated by GCGR 
agonism [10,11]).

A slower mechanism via complementary induction of body weight loss by GLP-
1R and GCGR agonism.
This is the fourth clinical study with MK-8521, and the second in which MK-8521 will be 
administered to subjects with T2DM.
The objective of this trial is to evaluate the safety/tolerability and efficacy (focusing on 
change in A1C and body weight vs. placebo, using liraglutide as a reference) of MK-8521 
administered to a cohort of T2DM subjects on a stable dose of metformin in an outpatient 
setting for 12 weeks.  Two doses of MK-8521 will be evaluated and will provide a better 
understanding of the correlation between dose and safety and efficacy parameters (including 
weight loss and glycemic control).  Liraglutide is included to provide a reference arm for 
both efficacy and safety endpoints.
Completed Pre-clinical and Clinical Trials
4.1.2
4.1.2.1
Completed Pre-clinical Trials
In pre-clinical trials, MK-8521 has demonstrated robust glucose- lowering and weight loss
properties in diabetic rhesus monkeys and was evaluated in 12-week toxicology studies in 
rats and rhesus monkeys to support further clinical testing. Pharmacology and toxicology 
data are reviewed in detail in the IB.
4.1.2.2
Completed Clinical Trials
As of November 2014, MK-8521 has been evaluated in three clinical trials (P001, P002 & 
P003).  See the IB and Table 2 for MK-8521 clinical program overview.


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Table 2  MK-8521 Clinical Program Overview
Activity
Protocol
Pop
N
MK-8521 
Dose 
Range 
(µg/day)
Comparato
r
Dosing 
Duration 
(Days)
Setting
Single Dose
Single 
rising 
dose
P001 
(eCTA) 
and P002
Lean 
healthy 
volunteers
32
Up to 300
µg/day
Placebo
Single
dose
Domiciled
Graded 
glucose 
infusion
P001 and 
P002
Lean 
healthy 
volunteers
22
35 µg/day
-125
µg/day
Placebo
Single
dose
Domiciled
Multiple Dose
Multiple 
rising 
dose
P002
Lean 
healthy 
volunteers,
Obese
healthy 
volunteers
(1 panel)
MK-8521 :6/ 
panel
placebo: 2/
panel
Up to 150
µg/day
Placebo
10-14
Domiciled 
Ph1B 
inT2DM
P003 Part 
I
Obese 
T2DM on 
metformin
MK-8521: 8
Liraglutide:8
Placebo: 8
Up to 120
µg/day
Placebo, 
liraglutide 
1.8 mg
14
Domiciled
P003 Part 
II
Obese      
T2DM on 
metformin
MK-8521: 18
Liraglutide: 
12
Placebo: 6
Titration 
64 µg/day
– 300
µg/day
over 29 
days
Placebo
Liraglutid
e titrated 
to 1.8
mg/day
29
Domiciled
A total of approximately 86 healthy male subjects have enrolled and approximately 70
healthy male subjects have been exposed to subcutaneous MK-8521 as a single dose ranging 
from 2- 300 µg and multiple daily doses for up to 14 days ranging from 50 to 150 µg/day. A 
total of approximately 79 male and female T2DM and 16 male and female non-diabetic 
obese /overweight subjects have been enrolled and approximately 48 of these subjects have 
been exposed to subcutaneous MK-8521 as multiple doses for up to 29 days at doses ranging 
from 34-300 µg. MK-8521 has been generally well tolerated up to 29 days of dosing, and 
robustly lowered glucose in subjects with T2DM (P003).  Potential safety issues that have 
manifested in clinical testing to date include GI intolerance and HR increases.  Both appear 
to be generally consistent with effects reported for other agents in the GLP-1R agonist class.
Clinical Pharmacokinetics (PK)
MK-8521 PK properties have been generally consistent across the tested dose range, over 
time, and between populations with the exception of the apparent impact of BMI as noted 
below.  MK-8521 is slowly absorbed post single subcutaneous administration at doses 
ranging from 2 – 300 μg, with a median Tmax of ~ 10-14 hr, and eliminated after Tmax in a 
mono-exponential manner, with an apparent terminal half-life (t1/2) of ~13-15 hr. Preliminary 
multiple dose PK data show that steady state (SS) appears to be achieved within 4-5 days of 
MK-8521 following multiple daily administrations in subjects with T2DM with accumulation 


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ratios of approximately 2 fold.  Plasma exposures of MK-8521 appeared to increase 
approximately dose-proportionally from 64-300 μg.
The observed Tmax and the apparent 
terminal T1/2 following multiple QD doses were in line with the results from Day 1 and in 
single doses.
General PK properties (Tmax, T1/2, peak: trough ratio, accumulation ratio) in obese individuals 
with and without T2DM were generally consistent with those seen in lean individuals.  
However, MK-8521 exposures in obese diabetic and non-DM subjects tested in P002 and 
P003 were lower than those observed in the lean individuals tested in P001 and P002.  Obese 
individuals appear to have slower absorption and higher volumes of distribution that lead to 
an observed lower Day 1 exposure and a higher accumulation to steady state.  In addition, the 
slower absorption in obese individuals causes a lower peak to trough ratio and overall flatter 
steady state concentration profile. In general, MK-8521 exposure decreased with increasing 
BMI.  This is generally consistent with the inverse relationship between weight and exposure 
reported for liraglutide [12].  This could result from the effect of BMI on the volume of 
distribution and slower absorption rate.  The impact of BMI on volume of distribution 
(higher in obese subjects) also increases the observed clearance.  It is also possible that 
adiposity results in a slower and decreased SC absorption.  Preliminary population PK 
analysis indicates that BMI is a significant covariate impacting MK-8521 exposure, with 
increasing BMI being associated with reduced exposure.
Clinical Efficacy
In overweight-obese subjects with T2DM on metformin monotherapy (P003), MK-8521 
doses equal to or higher than 120 µg/day over 2-4 weeks of treatment were associated with 
near maximal glycemic effects and were similar to doses equal to or higher than 1.2 mg 
liraglutide. However, due to the relatively short duration of the study and the prolonged 
titration period long term glycemic efficacy could not be assessed.  MK-8521 appeared to 
lower LDL, HDL, and triglycerides relative to both placebo and liraglutide.
Due to small sample size and short duration at the maximal dose of 300µg/day, no 
meaningful assessment of the effect of MK-8521 on body weight could be conducted in any 
of the completed clinical trials. Weight loss was observed during 4 weeks of treatment with 
MK-8521 (during dose escalation in P003 Part II) however, the study design did not support 
a rigorous assessment of weight effects.
Clinical Safety
As of November 2014, single and multiple SC doses of MK-8521 have been administered to 
a total of approximately 118 subjects, with doses from 2-300 μg as single doses and 34-300 
μg as multiple doses for up to 29 days.  The majority of reported adverse experiences (AEs) 
have been mild to moderate in intensity.  The most commonly reported AEs have been 
headache, dizziness, loss of appetite and gastrointestinal AEs of nausea, vomiting, diarrhea
and abdominal pain/discomfort.  No clinically significant glycemic abnormalities (hypo or 
hyperglycemia) have been reported.
Potential safety issues that have manifested in clinical testing to date include GI intolerance 
and HR increases.  Both appear to be generally consistent with effects reported for other 
agents in the GLP-1R agonist class [12,13,14].  GI intolerance has manifested as adverse 
events (AEs) including nausea, vomiting, and abdominal pain, and was dose limiting with 


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single and multiple doses in lean healthy individuals.  GI AEs have been encountered in 
subjects with T2DM, though tolerability has been generally good through the top dose tested 
in P003 (300µg/day).  This is likely attributed to the lower exposures achieved in the obese 
population studied in P003, and the more extended dose escalation strategy permitting
acclimation to GI effects of GLP-1R agonism.
The HR increases observed with MK-8521 have generally increased with dose.  At the top 
tested dose in T2DM patients in P003 (300µg/day) a small, non-statistically significant 
higher HR (24-hour weighted mean average) was observed with MK-8521 relative to 
liraglutide 1.8 mg [2.46 (-1.42, 6.34) beats per minute vs. liraglutide and 9.61 (4.42, 14.81)
beats per minute vs. placebo].
Greater HR increases have occurred in individuals, and 
several subjects in P001, 002 and 003 have been discontinued for meeting protocol pre-
specified HR discontinuation criteria.
Two subjects have experienced serious adverse events (SAEs) in MK-8521 clinical studies.  
Both of these occurred in subjects with T2DM in P003:

One subject with
pre-existing seizure disorder (not reported on screening) 
experienced a seizure and supraventricular tachycardia (SVT) 2 days after early 
discontinuation from the study medication.  The subject was randomized to MK-8521 
and was discontinued on Day 2 (after dosing of 64 µg MK-8521), due to detection of 
a 15 minute episode of SVT on protocol-routine telemetry monitoring.  Both the 
seizure and SVT were considered by the study investigator to be not related to study 
drug.  

One subject with a prior medical history of asthma and episodes of palpitation (not 
reported on screening) developed an SAE of pre-syncopal episode, SVT with a HR of
140-150 bpm and asthma exacerbation on the 21st day of treatment with MK-8521, 
two days after dose escalating from 180 µg/day to 240 µg/day. The subject was 
hemodynamically stable during the event.  The SVT resolved with return to normal 
sinus rhythm after the subject was transferred to an area hospital.  The SAE was rated 
as related to study drug by the investigator.
Cases of pancreatitis have been reported in patients taking GLP-1R selective agonists [13,14]
though causality is not definitively established.  No subject in MK-8521 clinical studies as of 
November 2014 has developed a clinical picture consistent with pancreatitis.  Transient, 
asymptomatic increases in lipase were observed in several subjects in the three Phase I 
clinical trials:

In P001, mild elevations (<2-fold ULN) in serum lipase were observed in 3 subjects 
after dosing at the  72 μg dose of MK-8521 level though there were no associated 
symptoms suggestive of pancreatitis.  Subjects remained asymptomatic at subsequent 
follow up.  Repeat lipase levels did go to near or within normal range.

In P002, six subjects receiving MK-8521 at multiple doses ranging from 72 μg to 150 
μg had an increase in lipase of <2.5 x ULN (maximum 713 IU/L; ULN=300 IU/L) 
between days 8 and 14 of dosing.  None of these subjects had a clinical picture 
consistent with pancreatitis and 5 of 6 subjects levels did return to below the ULN 
approximately 3 to 14 days later.


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
In P003, 7 subjects, had asymptomatic lipase elevations to >3-fold the laboratory 
upper limit of normal. Lipase elevations >3-fold the laboratory upper limit of normal 
were observed in 3 subjects on MK-8521, 3 subjects on placebo or pre-dose and 1 
subject on liraglutide. No clear association between MK-8521 dose or duration of 
drug administration and lipase elevations was observed. In 2 subjects on MK-8521,
lipase increased and decreased to within normal limits despite continued dosing.
Anti-drug antibody (ADA) formation may occur and result in ADAs cross reacting with 
endogenous peptides (GLP-1, glucagon, OXM), though the potential for ADAs to present a 
significant safety issue is unclear.  One individual treated with MK-8521 (in P002) has 
developed treatment-emergent MK-8521-binding ADAs that were transient.  These ADAs 
were found to be neutralizing in a cell based assay assessing MK-8521 activation of the 
glucagon receptor, and negative in a cell based assay assessing MK-8521 activation of the 
GLP-1 receptor.
In light of the glucose dependence of the GLP-1R glucose-lowering mechanism, the risk of 
hypoglycemia with GLP-1R agonist treatment is considered low in individuals not 
concurrently taking anti hyperglycemic agents
with hypoglycemic potential (i.e., 
sulfonylureas, insulin).  The risk is anticipated to be similarly low with MK-8521.  
Consistent with this, clinically significant hypoglycemia has not been detected in either 
healthy subjects or T2DM patients in clinical testing to date.
Other than the specific observations summarized above, there have been no important 
abnormalities noted in vital sign parameters, routine blood and urine chemistry, hematology,
glucometer measurements, ECG or physical exams.
As of November 2014, MK-8521 is not being evaluated in ongoing clinical trials.
Information on Other Trial-Related Therapy
4.1.3
Metformin is a biguanide that is widely considered to be a first line drug for the treatment of 
T2DM. Subjects who are on a stable dose of metformin (≥1000mg/day) for ≥12 weeks are 
eligible to participate in this trial.  Subjects will remain on their stable dose of metformin 
throughout the trial including the 14-day post-treatment visit.
Liraglutide is a glucagon-like peptide-1 receptor agonist that is DPP-4 resistant, and which 
has been shown to improve glycemic control in patients with T2DM [15-20]. At the present 
time, liraglutide is indicated for use as second-line therapy in both the United States (refer to 
the liraglutide package insert in Section 7) and the European Union [21].
Rationale
4.2
Rationale for the Trial and Selected Subject Population
4.2.1
Details regarding specific benefits and risks for subjects participating in this clinical trial may 
be found in the accompanying Investigators Brochure (IB) and Informed Consent documents.
Subjects in clinical trials generally cannot expect to receive direct benefit from 
treatment/vaccination during participation, as clinical trials are designed to provide 
information about the safety and effectiveness of an investigational medicine.


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The current protocol is expected to extend the experience with MK-8521, observe safety 
parameters and to assess the effect of multiple daily doses of MK-8521 on change from 
baseline in A1C and body weight after 12 weeks in subjects with T2DM. In particular, the 
current trial will allow for a direct comparison of the effects of MK-8521 and liraglutide on 
safety, tolerability as well as efficacy measured as changes in A1C and body weight.
Approximately 160 subjects with T2DM will receive MK-8521 300 g QD, MK-8521
180 g QD, placebo QD or open-label liraglutide QD for 12 weeks.  Safety data and the 
effect of MK-8521 on A1C and body weight will be assessed at 12 weeks.  The rationale for 
this approach is to examine the safety, and efficacy of MK-8521 in a larger cohort of subjects 
with baseline characteristics that resemble the target population for this compound, in an
outpatient setting.  The rationale for the duration of the study is to allow for sufficient time 
for glycemic efficacy to reflect changes in A1C and for significant changes in body weight to 
occur.
Randomization of subjects will be stratified based on baseline A1C, BMI and AHA washout 
status as these factors may affect the magnitude of response to therapy. Any imbalance of 
these characteristics between treatment arms may confound the actual treatment effect.
The rationale for including liraglutide is to provide a reference arm to better understand the 
efficacy observed with MK-8521 on glycemic and body weight endpoints, and on safety and 
tolerability (e.g., HR and GI tolerability).  As previously noted, liraglutide therapy is 
associated with improved glycemic control, body weight loss, GI adverse events, and a 2-4 
bpm increase in HR (the increase in HR was reported in Phase 3 trials and measured at 
trough levels).  Data obtained from the liraglutide arm may help to provide information on 
the profile of a dual agonist of GLP-1 and GCGR (MK-8521) vs. activation of the GLP-1 
receptor alone (liraglutide).  Potential effects on safety parameters and weight loss that may 
be obtained by activation of GCGR in the context of GLP-1 activation may be highlighted by 
the direct comparison to the liraglutide treated cohort. 
Since liraglutide is currently available only as a single use pen injector, treatment with 
liraglutide cannot be easily blinded in the context of a clinical trial.  Liraglutide will therefore 
be dispensed as an open-label medication.  Although blinded comparisons may be most 
robust, including liraglutide will still provide a useful benchmark to support the assessment 
of the safety and efficacy of MK-8521.  This conclusion is supported by the observation that 
many of the Phase 3 liraglutide active-comparator studies were conducted as open-label, with 
no notable difference in the safety or efficacy profile relative to double-blind studies.  It is 
also important to note that there is some variability of weight loss (and A1C-lowering) 
responses with liraglutide across trials—especially over the initial 3 months.  This would 
make cross study comparisons of MK-8521 with liraglutide non-robust.  Nonetheless, results 
obtained in the liraglutide arm will be interpreted in light of previously published liraglutide 
data, and with consideration of the non-blinded comparison. The primary and key secondary 
endpoints will focus on the comparison of MK-8521 with placebo.
To minimize confounding effects of other AHAs on assessment of safety parameters, body 
weight and glycemic control, only subjects on a stable dose of metformin (either at 
screening, or after an AHA run-in wash-off period, for subjects entering on metformin and 
another AHA) will be allowed to be randomized in this trial.  Since this trial is the first trial


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of MK-8521 conducted in subjects with T2DM in an outpatient setting, only subjects 21 to 
the age of 65 (inclusive) and without a history of cardiovascular disease will be allowed to 
participate.
A more detailed description of the study design and population is reviewed in Sections 2.1 
and 2.2 of this protocol.
Rationale for Dose Selection/Regimen/Modification
4.2.2
The selection of doses and regimens to be administered in this study is based on safety and 
pharmacodynamic measures obtained in P001 and P002 in healthy subjects and P003 in 
subjects with T2DM and obese healthy subjects and known characteristics of GLP-1 
agonists. 
The two doses of MK-8521 studied (180 µg and 300 µg) will offer better 
understanding of any potential dose response relationship with regards to safety (increase in 
HR and GI intolerance) and efficacy (glucose reduction and weight loss) endpoints.
In P003, administration of 300 µg MK-8521 resulted in an exposure of 66.5 nMhr in subjects 
with T2DM. Treatment of subjects with T2DM with 300 µg/ day MK-8521 was associated 
with a placebo-adjusted mean increases in HR TWA0-24hr of ~ 8.3 bpm and a liraglutide 1.8 
mg–adjusted mean increase in HR TWA0-24hr of ~2.46 bpm.  GI AEs occurred in 15/18 
(83.3%) subjects with T2DM exposed to MK-8521 in Part 2 of P003 and were generally 
mild. No clear relation between dose and GI AEs was identified and no discontinuations 
from study medication due to GI AEs occurred with MK-8521.
Glucose lowering was 
similar between 300 µg MK-8521 and 1.8 mg liraglutide. The LS mean change in 24hr 
WMG with 300 µg MK-8521 was -53.4 mg/dL vs. -59.7 mg/dL with liraglutide, and the 
change in FPG was -52 mg/dl for both liraglutide 1.8 mg and MK-8521 300 µg. In P003, 
doses equal to or higher than 120µg MK-8521 and 1.2 mg liraglutide were associated with 
near maximal glycemic effects.
The rationale for having a higher dose and lower dose arms is primarily to study the dose -
response of safety and efficacy parameters of different doses of MK-8521. The lower dose 
arm of 180 µg is expected to provide sufficient enhancement of glucose-dependent insulin 
secretion to achieve notable changes in A1C. Based on modelling and data obtained in prior 
studies, this dose should be well tolerated and associated with a placebo-adjusted mean 
increases in HR TWA0-24hr of ~ 7 bpm that is expected to be similar to the change in HR with 
liraglutide 1.8 mg. Gastrointestinal intolerance (presenting as nausea, vomiting etc.) can 
occur with GLP-1 agonist therapy and may be partially mitigated by dose titration [13]. In 
keeping with this notion, a dose escalation/titration regimen will be implemented in the 
current trial.
4.2.2.1
Starting Dose for This Trial
The initial MK-8521 dosing will begin at 60 µg/day (0.1 ml/day) and will be escalated up to 
the full dose of 180 g/day (0.3 ml/day) no later than Day 21, and 300g/day (0.5 ml/day) 
no later than Day 28 (See Section 5.2.1.2 for dose escalation).


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The rationale for the dose escalation regimen is based on gastrointestinal (GI) AE data from 
Phase I studies and reports of up to 40% GI adverse events (nausea and vomiting) at GLP-1 
agonist therapy initiation [12].  As gradual dose-escalation of exenatide has been shown to 
successfully reduce the proportion of subjects experiencing dose-limiting nausea and 
vomiting, with no loss of glucoregulatory activity, a similar dose-escalation strategy will be 
employed in this trial [13].
A double-dummy approach will be used in the trial because the volume of MK-8521 
administered differs between the 180 µg and 300 µg dose arms (see Table 6 in Section 
5.2.1.2).  With the double-dummy approach, subjects randomized to MK-8521 or MK-8521 
placebo will administer 2 injections each day: 1 injection from the MK-8521 180g vial 
(Vial C) and 1 injection from the MK-8521 300 g vial (Vial D).  Subjects randomized to the 
MK-8521 180 g group will also receive placebo for MK-8521 300g.  Subjects 
randomized to the MK-8521 300g group will also receive placebo for MK-8521 180 g.  
Subjects randomized to placebo will receive placebo for both 300g and 180 g MK-8521.  
Subjects randomized to liraglutide will receive only open-label liraglutide for the duration of 
the study.
The initial liraglutide dosing will begin at 0.6 mg/day and will be escalated up to the full dose 
of 1.8 mg/day no later than Day 21.
Rationale for Endpoints
4.2.3
4.2.3.1
Efficacy Endpoints
Efficacy endpoints will be assessed after 12 weeks of daily dosing and will include change in 
glycemic parameters and change in body weight.
Glycemic efficacy endpoints will include the changes from baseline in A1C and FPG at 
Week 12.  A1C reflects average glucose concentrations over the past 3-4 months and, 
therefore, provides a useful index of the glycemic control of treatment with MK-8521 over 
that time period.  It is a standard efficacy endpoint used to assess the glycemic efficacy of 
AHAs.  A1C is a key glycemic parameter which correlates with reduction of risk of diabetic 
microvascular complications.  The measurement of FPG will provide insight into the effects 
of treatment with MK-8521 on this endpoint and characterize the earlier time course of 
glucose control in this trial.
Body weight reduction is an anticipated outcome of co-activation of GLP-1R and GCGR.  
Body weight loss may also drive A1C reduction at a modeled rate of 0.1% reduction in A1C 
for every 1 kg reduction in body weight. While the trajectory of reduction in A1C achieved 
with GLP-1R activation (as observed with liraglutide) reaches near maximal efficacy at 12 
weeks, further potential weight loss past 12 weeks with MK-8521 may lead to further 
reduction in A1C. Data regarding body weight loss collected throughout the 12 week
treatment period will be used to model further weight loss and subsequent A1C reduction up 
to 24 weeks.
Other efficacy endpoints that will be assessed include changes from baseline at Week 12 in 
fasting plasma lipid profile (including LDL-cholesterol, HDL-cholesterol and triglycerides), 
and blood pressure. These are clinically meaningful metabolic endpoints that may change 


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with body weight loss. 
Moreover, glucagon receptor activation has previously been 
implicated in several studies as causing a reduction in LDL-cholesterol.
Efficacy endpoints obtained from both MK-8521 arms will be interpreted vs. placebo and vs.
results collected in the liraglutide-treated arm.
There exist limitations of the comparisons to liraglutide, as liraglutide will be dispensed as an 
open label medication and MK-8521 as blinded.
Data may be confounded by subjective 
assessments, compliance, or other affects based upon subject and investigator knowledge of 
the assigned therapy in the liraglutide arm.  To mitigate these effects, previously published 
liraglutide data will be taken into account. 
4.2.3.2
Safety Endpoints
Safety assessment will include collection of adverse events (including reports of nausea, 
vomiting or injection site reactions), a hypoglycemia assessment log to collect information 
on each potential episode of hypoglycemia (including concurrent fingerstick glucose value) 
and physical examination including vital signs.  Incidence of adverse events of symptomatic 
hypoglycemia is defined as a Tier 1 pre-specified safety parameter.  Tier 1 pre-specified
safety parameters are parameters subject to inferential testing.
Due to a potential increase in HR as detailed in section 4.1.2, HR will be monitored at all
study visits. 
Discontinuation criteria that incorporate parameters of increase in HR 
[Tachycardia (HR >100 bpm) of any duration associated with symptoms, sustained resting 
HR >100 bpm and sustained increase from baseline in resting HR ≥30 bpm] have been 
outlined and provide boundaries of tolerance for increase in HR (see Section 5.9). Based on 
prior studies with liraglutide, it is anticipated that agonism of the GLP-1 receptor may result 
in a low rate of patients meeting the discontinuation criteria for an increase in heart rate. In 
the event of ≥5 subjects (potentially comprising over 10% of subjects in a single study arm)
discontinuing blinded investigational product (MK-8521 or matching placebo) due to 
meeting the defined criteria for discontinuation due to an increase in HR, a review of 
unblinded safety data by a Standing Internal Data Monitoring Committee (siDMC) will be 
triggered. If a clear disparity is observed between the different study arms in the allocation 
of the discontinued subjects the siDMC may decide to continue or stop the study, or stop or 
modify the study arm. For further details on the siDMC, see the siDMC charter and Section 
7.3.2.
Key endpoints for HR that will be assessed will include change from baseline at Week 12, 
events of sustained increase from baseline in resting HR ≥30 bpm from baseline, events of 
sustained increase in resting HR > 100 bpm and tachycardia (HR >100 bpm) of any duration 
associated with symptoms.
Laboratory safety studies will include blood chemistry, lipid panel, hematology, urinalysis 
and electrocardiograms (ECGs).  Refer to Section 6.0 and Section 7.1.3.1 for further details.
Though no events of pancreatitis have occurred in subjects exposed to MK-8521, 
asymptomatic and transient elevations in circulating lipase were observed in a few subjects in 
the Phase I clinical studies. In the current study, subjects will have regular monitoring of 
circulating lipase levels and symptoms suggestive of pancreatitis. A discontinuation criterion
that incorporates both elevated circulating lipase as well as relevant symptoms has been 


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outlined (see Section 5.9) and provides boundaries of tolerance for elevated circulating lipase 
levels.
GLP-1 receptor activation may result in increase in serum calcitonin. Circulating calcitonin 
levels will be monitored during the study.
As antibody-mediated immune responses to MK-8521 could occur, anti-drug antibody 
formation will be assessed through analysis of serum samples as noted in the Trial Flow
Chart (See Section 6.0).
If MK-8521-specific antibodies are confirmed to be present,
additional tests will be performed to determine if the antibodies cross react with GLP-1,
glucagon, or OXM. Additional testing will include titer assessment and assessment of the 
ability of the antibodies to neutralize the action of MK-8521 in a cell based assay.
4.2.3.3
Pharmacokinetic Endpoints
CTrough will be assessed at predefined time points throughout the trial.
4.2.3.4
Planned Exploratory Biomarker Research
Understanding the relative contribution of GLP-1R activation vs. GCGR activation to the 
observed biologic effect may shed light on the mechanism of action of MK-8521 and 
facilitate its clinical development. 
Several biomarkers including endogenous glucagon, 
ketones, FGF-21 and kisspeptin have shown differential response to GLP-1R/GCGR co-
agonism or GCGR agonism vs. GLP-1R agonism in preclinical models. In the current study,
samples for these potential biomarkers will be collected. A decision to analyze these samples 
will be based on potential for utility in light of emerging clinical efficacy and safety 
outcomes.
Understanding the effect of MK-8521 on β-cell function and insulin resistance may shed 
light on its anti-hyperglycemic mechanism of action and facilitate further clinical 
development. Using fasting measurements of insulin, glucose and C-peptide, β-cell function 
and insulin resistance may be estimated using the HOMA-β and HOMA-IR calculations, 
respectively.  In the current study, samples for insulin and C-peptide will be collected. A 
decision to analyze these samples will be based on potential for utility in light of emerging 
clinical efficacy and safety outcomes.
Understanding genetic determinants of drug response is an important endeavor during 
medical research.  This research will evaluate whether genetic variation within a clinical trial 
population correlates with response to the treatment(s) under evaluation.  If genetic variation 
is found to predict efficacy or adverse events, the data might inform optimal use of therapies 
in the patient population.  This research contributes to understanding genetic determinants of 
efficacy and safety associated with the treatments in this study.
4.2.3.5
Future Biomedical Research
The Sponsor will conduct Future Biomedical Research on specimens routinely and 
specifically 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.


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Such research is for biomarker testing to address emergent questions not described elsewhere 
in the protocol (as part of the main trial) and will only be conducted on specimens from 
appropriately consented subjects. The objective of collecting specimens for Future 
Biomedical Research is to explore and identify biomarkers that inform the scientific 
understanding of diseases and/or their therapeutic treatments. For instance, exploratory 
pharmacogenetic 
(PGt) 
studies 
may 
be 
performed 
if 
significant 
Pharmacokinetic/Pharmacodynamic (PK/PD) relationships are observed or adverse events 
are identified.  Genomic markers of disease may also be investigated.  Such retrospective 
pharmacogenetic studies will be conducted with appropriate biostatistical design and analysis 
and compared to PK/PD results or clinical outcomes. Any significant PGt relationships to 
outcome would require validation in future clinical trials. The overarching goal is to use such 
information to develop safer, more effective drugs/vaccines, and/or to ensure that subjects 
receive the correct dose of the correct drug/vaccine at the correct time.  The details of this 
Future Biomedical Research sub-trial are presented in Section 12.2 - Collection and 
Management of Specimens for Future Biomedical Research.  Additional informational 
material for institutional review boards/ethics committees (IRBs/ERCs) and investigational 
site staff is provided in Section 12.3.
5.0 METHODOLOGY
Entry Criteria
5.1
Diagnosis/Condition for Entry into the Trial
5.1.1
Male/female subjects between the ages of 21 and 65 years (inclusive) with T2DM will be 
enrolled in this trial.
Subject Inclusion Criteria
5.1.2
In order to be eligible for participation in this trial, the subject must:
At Visit 1/Screening
1. have T2DM in accordance with American Diabetes Association guidelines [25] and 
be ≥21 to ≤65 years of age (inclusive) on the day of signing the informed consent 
form (ICF).
2. Meet one of the following criteria: 

be on a stable dose of metformin monotherapy (≥1000 mg/day; metformin IR or 
metformin XR) for at least 12 weeks prior to Visit 1/Screening with a Visit 
1/Screening A1C ≥7.5 and ≤10.5% (≥58 mmol/mol and ≤91 mmol/mol).  

be on dual therapy with metformin (≥1000 mg/day: dose stable for at least 4
weeks prior to Visit 1/Screening) and a second* AHA with a Visit 1/Screening 
A1C of ≥7.0% and ≤10.0% (≥53 mmol/mol and ≤86 mmol/mol) and be willing to 
washout second AHA.
*Note:
Allowable AHAs are: DPP-4 inhibitors, α-glucosidase inhibitors, 
sulfonylureas and glinides.


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Note: A1C may be repeated once if the investigator’s assessment is that the value is 
inconsistent with prior values or inconsistent with the subject’s clinical status. The 
last laboratory draw/result should be used to assess eligibility.
3. have a body mass index (BMI) ≥23 kg/m2 and ≤40 kg/m2.
(BMI = weight (kg)/[height (m)]2.)
4. have personally signed and dated the ICF indicating that he/she has been informed of 
all pertinent aspects of the trial.
Note: the subject may also provide consent for Future Biomedical Research.  However, 
the subject may participate in the main trial without participating in Future 
Biomedical Research.
5. be willing and able to comply with scheduled visits, treatment plan, laboratory tests, 
and other study procedures.
6. Meet one of the following categories:
a) The subject is a male.
b) The subject is a female who is not of reproductive potential, defined as a female who 
either: (1) is postmenopausal (defined as at least 12 months with no menses in women 
≥45 years of age); (2) has had a hysterectomy and/or bilateral oophorectomy, bilateral 
salpingectomy, or bilateral tubal ligation/occlusion at least 6 weeks prior to screening; 
OR (3) has a congenital or acquired condition that prevents childbearing.
c) The subject is a female who is of reproductive potential and agrees to avoid becoming 
pregnant: while receiving study drug and for 14 days after the last dose of study drug 
by complying with one of the following: (1) practice abstinence† from heterosexual 
activity OR (2) use (or have her partner use) acceptable contraception during 
heterosexual activity.  Acceptable methods of contraception are‡:
Single method (one of the following is acceptable):
•
non-hormonal intrauterine device (IUD)
•
vasectomy of a female subject’s male partner
Combination method (requires use of two of the following):
•
diaphragm with spermicide (cannot be used in conjunction with cervical 
cap/spermicide)
•
cervical cap with spermicide (nulliparous women only)
•
contraceptive sponge (nulliparous women only) 
•
male condom or female condom (cannot be used together)
†Abstinence (relative to heterosexual activity) can be used as the sole method of 
contraception if it is consistently employed as the subject’s preferred and usual 
lifestyle and if considered acceptable by local regulatory agencies and 
ERCs/IRBs.  Periodic abstinence (e.g., calendar, ovulation, sympto-thermal, post-


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ovulation methods, etc.) and withdrawal are not acceptable methods of 
contraception.
‡If a contraceptive method listed above is restricted by local regulations/guidelines, 
then it does not qualify as an acceptable method of contraception for subjects 
participating at sites in this country/region.
7. have a history of stable weight for at least 6 months prior to Visit 1/Screening (as 
determined by subject report).
Note:  Weight-stable is defined as <5% change in body weight in the last 6 months.
At Visit 2/Week -2
Only for subjects for whom Visit 2/Week -2 is more than 2 weeks after Visit 1/Screening
(this will include all subjects undergoing AHA washout):
8. A1C ≥7.5% and ≤10.5% (≥58 mmol/mol and ≤91 mmol/mol).
Note:  An A1C sample should not be drawn at Visit 2/Week -2 if this occurs within 2
weeks of Visit 1/Screening.
Note:  A1C may be repeated once if the investigator’s assessment is that the value is 
inconsistent with prior values or inconsistent with the subject’s clinical status.  The 
last laboratory draw/result should be used to assess eligibility.
Subject Exclusion Criteria
5.1.3
The subject must be excluded from participating in the trial if the subject:
At Visit 1/Screening
Diabetes Diagnosis and Prior Therapy Criteria
1. has a history of type 1 diabetes mellitus or a history of ketoacidosis, or subject is 
assessed by the investigator as possibly having type 1 diabetes mellitus confirmed 
with a C-peptide <0.7 ng/mL (0.23 nmol/L).
Note: Only subjects assessed by the investigator as possibly having type 1 diabetes 
should have C-peptide measured at Visit 1/Screening.
2. has a history of other specific types of diabetes (e.g., genetic syndromes, secondary 
pancreatic diabetes, diabetes due to endocrinopathies, drug- or chemical-induced, and 
post-organ transplant).
3. Prior AHA use:

For subjects on metformin monotherapy at screening: treatment with anti-
hyperglycemic agents (AHA) other than metformin within the last 12 weeks is 
an exclusion.  However, these subjects may be re-screened after at least 12 
weeks has passed since discontinuation of the non-metformin AHA (see 
exclusion criterion #5 on restrictions for prior use of GLP-1 receptor 
agonists).


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
For subjects taking dual therapy at screening and eligible to undergo 
washout: treatment with one of the permissible AHAs (DPP-4 inhibitors, α-
glucosidase inhibitors, sulfonylureas and glinides) is not an exclusion.
4. is currently on or likely to require treatment with a prohibited medication 
(see Section 5.5 for a list of prohibited medications).
5. has been treated with any GLP-1 receptor agonist (e.g. Byetta™, Victoza™ or 
investigational agents) within the last 6 months or has had a GLP-1 receptor agonist 
discontinued due to gastrointestinal intolerance or lack of efficacy.
Note: treatment with a GLP-1 receptor agonist that was discontinued >6 months prior 
to Visit 1/screening is not an exclusion if the GLP-1 receptor agonist was 
discontinued for reasons other than gastrointestinal intolerance or lack of efficacy.
6. is taking a beta blocker or medications with sympathomimetic activity (e.g. 
pseudoephedrine, phenylpropanolamine, inhaled albuterol, methylphenidate, etc.).
Note: Systemic and ophthalmic beta blockers are prohibited.
Concomitant Disease of Organs and Systems
7. has a history of clinically significant gastrointestinal disorder (including diabetic 
gastroparesis; irritable bowel disease; recurrent episodes of nausea, vomiting, 
diarrhea and abdominal pain).
8. has a history of clinically significant and active, immunological, respiratory, 
genitourinary or major neurological (including stroke, transient ischemic attack and 
chronic seizures) abnormalities or diseases.
9. has a history of cardiovascular disease (including diabetic cardiomyopathy) or 
significant cardiac condition (including a history of myocardial infarction, stable or 
unstable angina, arterial revascularization, pathologic, symptomatic or sustained 
tachyarrhythmia [e.g. atrial fibrillation,  sustained supraventricular tachycardia, 
symptomatic non-sustained supraventricular tachycardia, ventricular tachycardia, 
ventricular fibrillation,
Wolf-Parkinson-White syndrome, congenital long QT 
syndrome, etc.]) or heart failure.
10. 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 (1) A subject with a history of malignancy >5 years prior to signing informed 
consent should have no evidence of residual or recurrent disease.
Note (2) A subject with a history of melanoma, leukemia, lymphoma, or renal 
carcinoma is excluded.
11. has a family history of medullary carcinoma of the thyroid or multiple endocrine
neoplasm type-2 syndrome.
12. has active diabetic proliferative retinopathy or a history of maculopathy.
Note: subjects with non-proliferative diabetic retinopathy may be enrolled.
13. has human immunodeficiency virus (HIV) as assessed by medical history.


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14. has:

blood dyscrasias or any disorders causing hemolysis or unstable red blood cells, 
or

clinically important hematological disorders (such as aplastic anemia, 
myeloproliferative or myelodysplastic syndromes, thrombocytopenia).
15. has a medical history of active liver disease (other than non-alcoholic hepatic 
steatosis), including chronic hepatitis B or C (assessed by medical history), primary 
biliary cirrhosis, or active symptomatic gallbladder disease.
16. is on a weight loss medication or has undergone bariatric surgery.
17. has undergone a surgical procedure within 12 weeks prior to signing the ICF or has 
planned major surgery during the trial.
Note:  A subject who has undergone minor surgery within the 8 weeks prior to Visit 
1/Screening and is fully recovered or a subject who has planned minor surgery may 
participate.  Minor surgery is defined as a surgical procedure involving local 
anesthesia
18. has donated blood or blood products within 6 weeks of Visit 1/Screening or who 
plans to donate blood or blood products at any time during the trial.
19. has participated in other studies involving investigational drug(s) (Phase I-IV) within 
30 days prior to Visit 1/Screening.
20. has a history of acute or chronic pancreatitis of any etiology.
21. has a mean value for triplicate sitting systolic blood pressure >160 mm Hg and/or 
diastolic blood pressure >90 mm Hg (after at least a 5-minute seated rest).
The approach to blood pressure assessment described in section 7.1.2.1 should 
be carefully followed. 
Note: If the subject meets this exclusion criterion AND the investigator believes that 
the value can be explained by reversible cause (e.g. anxiety, recent exertion etc.), the 
blood pressure measurements should be repeated (in triplicate with 2 minutes 
between measurements) after the subject has rested for at least 10 minutes.
At the discretion of the investigator, subjects with elevated systolic and/or diastolic blood 
pressure levels may have blood pressure medication initiated or adjusted and continue in the 
trial if repeat blood pressure measurements no longer meet the exclusion criterion at Visit 
3/Day 1.  Any adjustments to blood pressure medication must occur prior to Visit 2/Week -2 
and subjects must be on a stable regimen for at least 4 weeks prior to Visit 3/Day 1.
Subjects requiring AHA washout can have initiation or adjustment of blood pressure 
medication made concurrently with the AHA washout.  If AHA washout is not required, the 
screening period (Visit 1 to Visit 2) should be extended so that subjects are on a stable 
regimen for at least 4 weeks prior to Visit 3/Day 1.
Investigators are encouraged to maximize blood pressure control according to current 
guidelines.  Unscheduled visits may occur as necessary for pre-randomization blood pressure 
management.


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22. has a mean value for triplicate sitting HR>88.
The approach to heart rate assessment detailed in section 7.1.2.1 should be 
carefully followed.
Note:  If the subject meets this exclusion criterion AND the investigator believes that 
the value can be explained by reversible cause (e.g. anxiety, recent exertion etc.), the 
HR measurements should be repeated (in triplicate with 2 minutes between 
measurements) after the subject has rested for at least 10 minutes.  If the subject has a 
resting sitting HR>88 upon repeat (mean of three consecutive measurements), the 
subject must be excluded.
23. had an event of severe hypoglycemia with neuroglycopenia (i.e., with seizure or loss 
of consciousness) in the past 12 months (unless the subject was previously treated 
with insulin or a sulfonylurea and the event was clearly associated with their use).
24. has symptomatic hyperglycemia that, in the investigator’s opinion, requires 
immediate initiation, adjustment, or addition of antihyperglycemic therapy.
Exclusion Criteria Based on Laboratory Abnormalities
25. has exclusionary laboratory values as listed in Table 3:
Table 3  Laboratory Exclusion Criteria
Parameter1
Population 
(if applicable)
Trial Limit for Exclusion
Creatinine 
Male
Female
≥1.3 mg/dL(≥115 µmol/L)
≥1.2 mg/dL (≥106 µmol/L)
Estimated glomerular filtration rate (eGFR) 2
<60 mL/min/1.73 m2
Alanine aminotransferase (ALT)
>2 times Upper Limit of Normal (ULN)
Aspartate aminotransferase (AST)
>2 times ULN
Thyroid-stimulating hormone (TSH)3
Outside laboratory normal range
Lipase
> ULN
Hemoglobin
Male
Female
<12.0 g/dL (120 g/L)
<11.0 g/dL (110 g/L)
Triglycerides (TG)4
>600 mg/dL (>6.78 mmol/L)
1
Screening laboratories may be repeated once if the investigator’s assessment is that the value is inconsistent with prior 
values or inconsistent with the subject’s clinical status.  The last laboratory draw/result should be used to assess 
eligibility.
2 Calculated using the 4-variable MDRD equation.     
3
A subject excluded because of the TSH criterion may be re-screened after being on a stable thyroid-replacement 
regimen for at least 6 weeks.
4
At the discretion of the investigator, subjects with elevated TG levels may have lipid-lowering medication initiated or 
adjusted and continue in the trial if a repeat measurement (at Visit 2/Week -2) no longer meets the exclusion criterion.  
Any adjustments to lipid-lowering medication must occur prior to Visit 2/Week -2 and subjects must be on a stable 
regimen for at least 4 weeks prior to Visit 3/Day 1.  Subjects requiring AHA washout can have initiation or adjustment 
of lipid-lowering medication made concurrently with the AHA washout.  If AHA washout is not required, the 
screening period (Visit 1 to Visit 2) should be extended so that subjects are on a stable regimen for at least 4 weeks 
prior to Visit 3/Day 1.  Unscheduled visits may occur as necessary.


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Other Criteria
26. has a positive urine pregnancy test.
27. is pregnant or breast-feeding, or is planning to conceive during the trial, including 14
days following the last dose of investigational product.
28. routinely consumes >1 alcoholic drinks per day or >7 alcoholic drinks per week or 
engages in binge drinking.
Note (1): One alcoholic drink is defined as 5 oz. (150 mL) of wine, or 12 oz. (350 
mL) of beer, or 1.5 oz. (50 mL) of 80-proof liquor.
Note (2): Binge drinking is defined as a pattern of 5 or more alcoholic drinks (male), 
or 4 or more alcoholic drinks (female) in about 2 hours.
29. routinely consumes ≥480mg /day caffeine in caffeinated beverages (1 cup of coffee 
contains approximately 120 mg of caffeine. Refer to label of caffeinated products for 
individual caffeine content or the Investigator Trial File Binder (or equivalent)).
30. is currently a user of nicotine or nicotine containing products or does not agree to 
refrain from using nicotine during the trial, including 14 days following the last dose 
of investigational product.
31. is currently a user of any illicit drugs (including any marijuana use) or has a history of 
drug (including alcohol) abuse within approximately 5 years.
32. has other severe acute or chronic medical or psychiatric condition or laboratory 
abnormality that may increase the risk associated with study participation or blinded 
investigational product administration or may interfere with the interpretation of 
study results and, in the judgment of the investigator, would make the subject 
inappropriate for entry into this trial.
33. is or has an immediate family member (spouse or children) who is investigational site 
or sponsor staff directly involved with this trial.
Visit 2/Week -2
34. has a positive urine pregnancy test.
35. has a clinically significant ECG abnormality at Visit 2/Week -2 that requires further 
diagnostic evaluation or intervention (e.g., new arrhythmia or a conduction 
disturbance).
36. has a history of symptoms or signs during the Visit 2/Week -2 physical exam 
suggestive of clinically significant diabetic autonomic neuropathy (e.g., orthostatic 
changes in BP defined as a sustained drop in systolic (>20 mmHg) or diastolic (>10 
mmHg) BP after 1 minute and 3 minutes of standing).
37. has a ≥5% change in body weight since Visit 1/Screening.
38. has a mean value for triplicate sitting HR>88.
Note:  If the subject meets this exclusion criterion AND the investigator believes that 
the value can be explained by reversible cause (e.g. anxiety, recent exertion etc.), the 
HR measurements should be repeated (in triplicate with 2 minutes between 


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measurements) after the subject has rested for at least 10 minutes.  If the subject has a 
resting sitting HR>88 upon repeat (mean of three consecutive measurements), the 
subject must be excluded.
39. has exclusionary laboratory values as listed in Table 3
Note: This applies only for subjects for whom Visit 2/Week -2 is 2 weeks after Visit 
1/Screening (this will include all subjects undergoing AHA washout).
Blood samples for these laboratories should not be drawn at Visit 2/Week -2 if this 
occurs ≤2 weeks of Visit 1/Screening.
Table 4  Visit 2/Week -2 Laboratory Exclusion Criteria
Parameter1
Population 
(if applicable)
Trial Limit for Exclusion
Creatinine3
Male
Female
≥1.3 mg/dL(≥115 µmol/L)
≥1.2 mg/dL (≥106 µmol/L)
Estimated glomerular filtration rate (eGFR)2,3
<60 mL/min/1.73 m2
Alanine aminotransferase (ALT)3
>2 times Upper Limit of Normal (ULN)
Aspartate aminotransferase (AST)3
>2 times ULN
Hemoglobin3
Male
Female
<12.0 g/dL (120 g/L)
<11.0 g/dL (110 g/L)
Triglycerides (TG)4
>600 mg/dL (>6.78 mmol/L)
1 Visit 2/Week -2 laboratories may be repeated once if the investigator’s assessment is that the value is 
inconsistent with prior values or inconsistent with the subject’s clinical status.  The last laboratory 
draw/result should be used to assess eligibility.
2 Calculated using the 4-variable MDRD equation
3 Only applicable if Visit 2/Week -2 occurs >2 weeks after Visit 1/Screening
4 Only applicable for subjects who did not satisfy the Visit 1/Screening TG criterion
Visit 3/Randomization (Day 1)
40. has missed more than one daily dose of placebo run-in medication (i.e., 2 injections 
on the same day or 2 single injections on separate days).  Refer to Section 7.1.1.8.7.
41. has a positive urine pregnancy test.
42. has a mean value for triplicate sitting HR>88.
Note:  If the subject meets this exclusion criterion AND the investigator believes that 
the value can be explained by reversible cause (e.g. anxiety, recent exertion etc.), the 
HR measurements should be repeated (in triplicate with 2 minutes between 
measurements) after the subject has rested for at least 10 minutes.  If the subject has a 
resting sitting HR>88 upon repeat, the subject MUST be excluded.
43. has a mean value for triplicate sitting systolic blood pressure >160 mm Hg and/or 
diastolic blood pressure >90 mm Hg (after at least a 5-minute seated rest).


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44. has a fasting finger-stick glucose (FFSG) <130 mg/dL (7.2 mmol/L) or >260 mg/dL 
(14.4 mmol/L).
Note: If the subject meets this exclusion criterion AND the investigator believes that 
the value is not consistent with the subject’s current self-monitoring blood glucose 
(SMBG) values and Visit 2/Week -2 FPG value, the subject should not be excluded 
at this time.  This visit should be changed to an Unscheduled Visit and the subject 
should be rescheduled for Visit 3/Day 1 within 7 days.  Additional single-blind 
placebo run-in medication should be dispensed if needed.  If the subject meets this 
FFSG exclusion criterion at the rescheduled Visit 3/Day 1, the subject MUST be 
excluded.
Trial Treatment(s)
5.2
The treatment(s) to be used in this trial are outlined below in Table 5.
Table 5  Trial Treatment
Dose/
Potency
Drug
Dose
Route of 
Administration
Treatment Period6
Use
Placebo 
Run-in (all 
treatment 
groups)
Matching 
placebo 
for 
MK-8521
180 
g, 
1.0mL
Vial A
0.1 mL QD
Subcutaneous
0.1 mL1 QD for 2 weeks
experimental
(trial drug)
Matching 
placebo 
for 
MK-8521
300 
g, 
1.0mL
Vial B
0.1 mL QD
Subcutaneous
0.1 mL1 QD for 2 weeks
experimental 
(trial drug)
MK-8521 
180 g 
Group
MK-8521 
180 
g 
0.6 mg/mL, 
1.0mL
Vial C
0.1 mL QD
to
0.3
mL
QD
Subcutaneous
Days 1-6: 0.1 mL1 QD
Days 7-13: 0.2 mL2 QD
Days 14-84: 0.3 mL3 QD
experimental 
(trial drug)
Matching 
placebo 
for 
MK-8521
300 
g, 
1.0mL
Vial D
0.1 mL QD
to 0.5
mL 
QD
Subcutaneous
Days 1-6: 0.1 mL1 QD
Days 7-13: 0.2 mL2 QD
Days 14-20: 0.3 mL3 QD
Days 21-84: 0.5 mL4 QD
experimental 
(trial drug)
MK-8521 
300 g 
Group
Matching 
placebo 
for 
MK-8521
180 
g, 
1.0mL
Vial C
0.1 mL QD 
to 0.3
mL 
QD
Subcutaneous
Days 1-6: 0.1 mL1 QD
Days 7-13: 0.2 mL2 QD
Days 14-84: 0.3 mL3 QD
experimental 
(trial drug)
MK-8521 
300 
g 
0.6 mg/mL, 
1.0mL
Vial D
0.1 mL QD
to 0.5 mL 
QD
Subcutaneous
Days 1-6: 0.1 mL1 QD
Days 7-13: 0.2 mL2 QD
Days 14-20: 0.3 mL3 QD
Days 21-84: 0.5 mL4 QD
experimental 
(trial drug)


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Dose/
Potency
Drug
Dose
Route of 
Administration
Treatment Period6
Use
Placebo 
Group
Matching 
placebo 
for 
MK-8521
180 
g, 
1.0mL
Vial C
0.1 mL QD 
to 0.3
mL 
QD
Subcutaneous
Days 1-6: 0.1 mL1 QD
Days 7-13: 0.2 mL2 QD
Days 14-84: 0.3 mL3 QD
experimental 
(trial drug)
Matching 
placebo 
for 
MK-8521
300 
g, 
1.0mL
Vial D
0.1 mL QD 
to 0.5 mL 
QD
Subcutaneous
Days 1-6: 0.1 mL1 QD
Days 7-13: 0.2 mL2 QD
Days 14-20: 0.3 mL3 QD
Days 21-84: 0.5 mL4 QD
experimental 
(trial drug)
Liraglutide 
Group –
Open-Label
liraglutide
6 mg/mL5
0.6 mg QD
to 1.8 mg
QD
Subcutaneous
Days 1-6: 0.6 mg QD
Days 7-13: 1.2 mg QD
Days 14-84: 1.8 mg QD
active-
comparator
1.
Equivalent to 10 Units in an insulin syringe.
2.
Equivalent to 20 Units in an insulin syringe.
3.
Equivalent to 30 Units in an insulin syringe.
4.
Equivalent to 50 Units in an insulin syringe.
5.
Liraglutide will be supplied locally by the trial site.
6.
Treatment periods are approximate.  See Section 6.0 for allowable visit windows.
The first dose of trial treatment will be administered at the trial site at Visit 3/Randomization 
(Day 1).  All doses taken at scheduled clinic visits will be administered by the subject as a 
witnessed dose.  Subsequent dosing will be performed once daily by the subject (i.e., 
unsupervised at his/her home) at approximately the same time each day.
All supplies indicated in Table 5 above will be provided centrally by the Sponsor or locally 
by the trial site, subsidiary or designee, depending on local country operational or regulatory 
requirements.
For any commercially available product that is provided by the trial site, subsidiary or 
designee every attempt will be made to source these supplies from a single lot/batch number. 
The trial site will be responsible for recording the lot number, manufacturer and expiry date 
of any locally purchased product.
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of trial 
treatments in accordance with the protocol and any applicable laws and regulations.
Dose Selection/Modification
5.2.1
5.2.1.1
Dose Selection (Preparation)
The rationale for selection of doses to be used in this trial is provided in Section 4.0 –
Background & Rationale.  There are no specific calculations or evaluations required to be 
performed in order to administer the proper dose to each subject.


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5.2.1.2
Dose Escalation of Investigational Product
MK-8521 or MK-8521 Placebo Treatment Groups
Subjects randomized to MK-8521 or MK-8521 placebo will begin the trial (Visit 3/Day 1) on 
0.1 mL from each vial (60 g/day for subjects randomized to active MK-8521).
At Visit 4/Day 7, the dose should be increased to 0.2 mL from each vial (120 g/day for 
subjects randomized to active MK-8521).
At Visit 5/Day 14, the dose should be increased to 0.3 mL from each vial (180 g/day for 
subjects randomized to active MK-8521).
At Visit 6/Day 21, the dose from the MK-8521 300 g vial (labelled Vial D) should be 
increased to 0.5 mL/day (300 g/day for subjects randomized to the MK-8521 300 g 
treatment group).
Note the following related to the dose escalation: 
• The dose escalation regimen for MK-8521 may be modified by the investigator to 
appropriately manage observed GI intolerance.  Specifically, the investigator may 
decide to delay one scheduled dose increase for up to 7 days based upon tolerability 
(e.g., GI adverse events). 
• The dose from both vials of MK-8521 or MK-8521 placebo must reach 0.3 mL/day
(180 g/day for subjects randomized to active MK-8521) by Day 21.  
• The dose from Vial D should reach 0.5 mL/day (300 g/day for subjects 
randomized to the MK-8521 300 g treatment group) by Day 28.  
• Subjects who cannot tolerate 0.5 mL/day from Vial D may continue in the trial on 
0.3 mL/day (180 g/day for subjects randomized to active MK-8521) from each vial.
• No dose changes are allowed beyond Day 28.
• See Table 6 for guidance on dose escalation.  
•An asymptomatic increase in HR that does not meet discontinuation criteria (Section 
5.9) should not delay dose escalation.
The rationale for this dose escalation regimen can be found in Section 4.2.2.1.


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Table 6  Dose Escalation for Subjects Randomized to MK-8521 or Placebo
Vial
Visit 3/
Day 1
Visit 4/
Day 7
Visit 5/
Day 14
Visit 6/
Day 21
Visit 7/
Day 28
MK-8521 
180 g or 
matching 
placebo1
Vial C
initiate 
0.1 mL/day
increase to 
0.2 mL/day
increase to 
0.3 mL/day3
continue
0.3 mL/day3
continue
0.3 mL/day3
MK-8521 
300 g or 
matching 
placebo1
Vial D
initiate 
0.1 mL/day
increase to 
0.2 mL/day
increase to 
0.3 mL/day3
increase to 
0.5 mL/day2,3
If any step is 
delayed, the 
final dose of 
0.5 mL/day 
must be 
reached at Visit 
7/Day 282,3
1.
The investigator may delay one step of the dose escalation by one week; however, the dose from each vial 
must reach 0.3 mL/day no later than Day 21.
2.
Subjects who cannot tolerate the 0.5 mL/day dose from Vial D may continue on a dose of 0.3 mL/day from 
each vial.
3.
Subjects who cannot tolerate at least 0.3 mL/day from each vial should be discontinued (See Section 
7.1.4.1).
Liraglutide Treatment Group
Subjects randomized to open-label liraglutide will begin the trial (Visit 3/Day 1) on 
0.6 mg/day liraglutide.
At Visit 4/Day 7, the dose of liraglutide should be increased to 1.2 mg/day.
At Visit 5/Day 14, the dose of liraglutide should be increased to 1.8 mg/day.
The titration regimen for liraglutide may be modified to appropriately manage observed GI 
intolerance.  The liraglutide dose should be titrated to the full target dose (1.8 mg/day) no 
later than Day 21.  Subjects who cannot tolerate the 1.8 mg/day dose of liraglutide may 
continue in the trial on the 1.2 mg/day dose.
Timing of Dose Administration
5.2.2
On days without a clinic visit, MK-8521 300 g, MK-8521 180 g, or matching MK-8521 
placebo SC injections; or open-label liraglutide will be administered in the morning at 
approximately the same time each day.  Background metformin is to be taken as prescribed 
by their primary care physician.  MK-8521 or matching placebo injections will be 
administered SC in the abdominal wall.  The injection site should be rotated within the 
abdominal wall area.
On the days of clinic visits, subjects will take their investigational product, as well as 
background metformin, after all study procedures are completed.
At Visit 2/Week -2, subjects will enter a single-blind placebo run-in period.  Subjects will be 
taught how to self-administer and will be expected to perform self-administration of the 
single-blind placebo SC injections during the 2-week single-blind placebo run-in period in 
preparation for the double-blind dosing period.


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At Visit 3/Day 1, MK-8521 300 g, MK-8521 180 g, or matching MK-8521 placebo SC 
injections, or open-label liraglutide will be administered (see Section 4.2.2.1 for initial doses
and Section 5.2.1.2 for dose escalation) by the subject as a witnessed dose after the 
completion of study procedures.  Background metformin should be taken after all study 
procedures are completed.  Investigational site staff should assure that the administration 
technique is appropriate, and provide additional training on study drug administration, as 
necessary.
Subjects will be asked to bring the remaining investigational product (used and unused 
vials/pens) to the clinic for review at each scheduled visit.
Trial Blinding/Masking
5.2.3
A double-blind/masking technique will be used. MK-8521 and placebo will be packaged
identically so that blind/masking is maintained. The subject, the investigator and Sponsor 
personnel or delegate(s) who are involved in the treatment or clinical evaluation of the 
subjects are unaware of the group assignments.
The liraglutide treatment arm will be open-label therefore, the Sponsor, investigator and 
subject will know the treatment administered.
See Section 7.1.4.2, Blinding/Unblinding, for a description of the method of unblinding a 
subject during the trial, should such action be warranted.
Randomization or Treatment Allocation
5.3
Randomization will occur centrally using an interactive voice response system / integrated 
web response system (IVRS/IWRS). There are 4 treatment arms.  Subjects will be assigned 
randomly in a 1:1:1:1 ratio to MK-8521 300 g, MK-8521 180 g, MK-8521 matching 
placebo, or open-label liraglutide, respectively.
Stratification
5.4
Randomization will be stratified according to the following factors:
1. A1C*: <8.5% or ≥8.5%
2. BMI*: <30 kg/m2 or ≥30 kg/m2
3. AHA washout status: yes or no.
*The Visit 1/Screening value will be used for stratification if Visit 2/Week -2 occurs ≤2 
weeks of Visit 1/Screening.  The Visit 2/Week -2 value will be used for stratification if 
Visit 2/Week -2 is >2 weeks after Visit 1/Screening (this will include all subjects 
undergoing AHA washout).
Concomitant Medications/Vaccinations (Allowed & Prohibited)
5.5
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial.  If there is a clinical indication for any medication or vaccination
specifically prohibited during the trial, discontinuation from trial therapy or vaccination may 
be required.  The investigator should discuss any questions regarding this with the Sponsor
Clinical Director.  The final decision on any supportive therapy or vaccination rests with the 


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investigator and/or the subject's primary physician.  However, the decision to continue the 
subject on trial therapy or vaccination schedule requires the mutual agreement of the 
investigator, the Sponsor and the subject.
AHAs taken by the subject at any time prior to Visit 1/Screening, and any other medications 
taken within 8 weeks of Visit 1/Screening, should be recorded on the appropriate electronic 
case report form (eCRF).  The site may rely on subject report for this information.  
Concomitant medications taken during the trial must also be recorded.  Subjects should be 
questioned about their use of concomitant medications at the time points indicated in the 
Trial Flow Chart – Section 6.0.  Subjects should be instructed to contact the study 
investigator before initiating any prescription or non-prescription medications during study 
participation.  If medical necessity requires initiation of a medication prior to discussion with 
the study investigator, the subject should communicate with the study investigator as soon as 
possible.
Prohibited Medications
Medications listed below are prohibited while subjects are receiving investigational product 
during the treatment period (see Section 5.9 - Subject Withdrawal/Discontinuation from 
Treatment Criteria):
1. All Antihyperglycemic Medications: with the exception of background metformin
≥1000 mg/day) and double-blind (MK-8521 or placebo) or open-label (liraglutide) 
study medication.
2. Corticosteroids: Treatment for ≥14 consecutive days or repeated courses of 
pharmacologic doses of corticosteroids.
Note:  Inhaled, nasal, and topical corticosteroids and physiological replacement doses 
of adrenal steroids are permitted.
3. Weight-loss Medications: Treatment with or initiation of a weight-loss medication 
(e.g., orlistat, phentermine, topiramate, lorcaserin) is prohibited (see Section 5.1.3).
Note:  Subjects who are on treatment with other medication(s) associated with weight 
changes (e.g., anti-psychotic agents) and who are weight-stable (i.e., <5% change in 
body weight within 6 months of Visit 1/Screening) at Visit 1/Screening are eligible 
to participate in the study and permitted to continue these medications during the trial.
4. Beta Blockers: Treatment with or initiation of a beta blocker is prohibited.
Note:  Systemic and ophthalmic beta blockers are prohibited.
5. Marijuana: Legal (including medicinal marijuana use) or illegal use is prohibited.
6. Medications with sympathomimetic activity: Treatment with or initiation of
medications 
with 
sympathomimetic 
activity 
(e.g. 
pseudoephedrine, 
phenylpropanolamine, inhaled albuterol, methylphenidate) is prohibited


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Guidance for Other Medications
The investigator or subject’s physician/health care provider is permitted to make adjustments 
in the subject’s non-AHA therapies throughout the trial if clinically warranted.  Guidance for 
specific medications which are permitted during the study is provided below.
1. All subjects must be on a stable dose of metformin (≥1000 mg/day metformin IR or 
metformin XR) for ≥12 weeks prior to randomization.  
2. Acetaminophen and NSAIDs may be used for minor ailments (e.g. minor injuries, 
osteoarthritis, upper respiratory tract infections) without prior consultation with the 
Sponsor Clinical Monitor. Individual acetaminophen doses should be 500 mg or less, 
with a total daily dose of 2000 mg or less.
3. Blood Pressure and Lipid-lowering Medications: Concomitant lipid-lowering 
medications are permitted.  Antihypertensive medications with the exception of beta–
blockers are permitted.  It is preferable that doses of these medications remain stable 
during the double-blind treatment period.
4. Hormonal Replacement Therapy: Hormone replacement therapy are permitted, but 
subjects should be on stable regimens, and are expected to remain on their stable 
regimen while receiving blinded investigational product during the double-blind 
treatment period and for 14 days after the last dose of blinded investigational product.
5. Thyroid Hormone Replacement Therapy: Thyroid replacement medication (e.g., 
thyroxine) is permitted, but subjects should be on a stable dose for at least 6 weeks 
prior to Visit 1/Screening.  Subjects who meet the TSH exclusion criterion specified 
in Table 3 may be re-screened after being on a stable thyroid replacement regimen for 
at least 6 weeks.
6. Nicotine/Nicotine products:  The use of nicotine containing products is prohibited 
during the trial and for 14 days after the last dose of investigational product.  This 
includes but is not limited to: cigarettes, cigars, pipes, smokeless tobacco, e-cigarettes
and nicotine replacement therapies (nicotine patches, gum, inhalers, nasal sprays, 
topical gels, and lozenges).
7. Supplements and/or Traditional Medicines: The use of herbal supplements and other 
natural products should be discouraged.  Subjects who do not discontinue the use of 
such supplements prior to Visit 2/Week -2 should be instructed not to change the use 
or dose of the supplement during the trial.  Subjects should be instructed not to 
initiate new supplements during the trial.
Rescue Medications & Supportive Care
5.6
No rescue or supportive medications are specified to be used in this trial.


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Diet/Activity/Other Considerations
5.7
Diet
5.7.1
Subjects will be seen by a dietician or qualified healthcare professional for dietary and 
exercise counseling.
For subjects who do not require AHA washout, initial dietary and exercise counseling will 
occur at Visit 2/Week -2.
For subjects who do require AHA washout, initial dietary and exercise counseling will occur 
at Visit 1A prior to the initiation of washout. 
The subject will receive counseling on diet consistent with the American Diabetes 
Association.
At each subsequent visit, the subject’s diet should be monitored, and counseling provided, as 
appropriate.  Detailed dietary information will not be captured.
5.7.2. Alcohol, Caffeine and Tobacco

Subjects will be counseled to limit alcohol use to moderate amounts (i.e., ≤1 drinks 
per day and no more than 7 drinks per week).  One alcoholic drink is defined as 5 oz. 
(150 mL) of wine, or 12 oz. (350 mL) of beer, or 1.5 oz. (50 mL) of 80-proof liquor.

Ingestion of caffeine will be prohibited for at least 10 hours prior to scheduled ECGs, 
HR and blood pressure determinations.

Nicotine-containing products are prohibited during the trial.
Activity
5.7.3
Subjects will be counseled to maintain a medically appropriate, routine exercise program and 
consistent physical activity level during the trial.  Subjects must not engage in physically 
strenuous exercise (for example: heavy lifting, weight training, calisthenics, and aerobics) 
within 48 hours before each blood sample collection for clinical laboratory tests for the 
duration of participation in the trial.
Subject Withdrawal/Discontinuation Criteria
5.8
Subjects may withdraw consent at any time for any reason or be dropped from the trial at the 
discretion of the investigator should any untoward effect occur.  In addition, a subject may be 
withdrawn by the investigator or the Sponsor if enrollment into the trial is inappropriate, the 
trial plan is violated, or for administrative and/or other safety reasons.  Specific details 
regarding discontinuation or withdrawal procedures; including specific details regarding 
withdrawal from Future Biomedical Research, are provided in Section 7.1.4 – Other 
Procedures.
Discontinuation from treatment is “permanent”.  Once a subject is discontinued, he/she shall 
not be allowed to restart treatment.


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A subject must be discontinued from the trial for any of the following reasons:
●
The subject withdraws consent.
(i.e., does not agree to any follow-up)
Note:  Since follow-up health status information is important to the full evaluation of 
any new agent in development, including MK-8521, the investigator should 
determine if a subject who no longer agrees to actively participate (i.e., no longer 
attend visits at the investigational site, take blinded investigational 
product/open-label liraglutide, and have other study-related procedures 
conducted at the investigational site) is agreeable to providing additional follow-
up information through interval telephone contacts (with the site collecting only 
important health status information (e.g., SAEs). Subjects who agree to follow-up 
contacts should be discontinued due to “Subject decision to stop active 
participation” (see  5.9 criteria “1” below), and not “withdrawal of consent.” 
See Section 5.9.1 for additional details about monitoring subjects who discontinue 
treatment with blinded investigational product/open-label liraglutide.
Subject Withdrawal/Discontinuation from Treatment Criteria
5.9
Discontinuation from treatment is “permanent”.  Once a subject is discontinued, he/she shall 
not be allowed to restart treatment.  As outlined below, subjects who no longer wish to 
participate may be withdrawn from active participation, but followed in the trial, or 
withdrawn from the trial (i.e., no ongoing follow-up), as described below.
A subject must be discontinued from treatment (but may continue to be monitored in the 
trial) for any of the following reasons:
1. Subject’s decision to stop active participation:  Subject no longer agrees to actively 
participate in the study (i.e., take double-blind study medication/open-label liraglutide
or other required concomitant study medication, attend study visits, or otherwise 
comply with study procedures), but agrees to allow follow-up contact.  Subject will 
be contacted at times of regular study visits to collect status (i.e., SAEs), unless the 
subject specifically withdraws consent for follow-up.
Note:  If a subject indicates his or her intention to stop active participation in the trial 
(i.e., chooses to no longer attend visits at the investigational site, take investigational 
product, and have other study-related procedures conducted at the investigational 
site), the investigator must clarify with the subject if he/she is willing to continue in 
the study with contact at intervals (as described above) to provide a brief and focused 
update on health status (e.g., evaluate if the subject experienced any SAEs).  It will 
be essential for the subject to understand the importance of complete collection 
of information, and also the limited requirements for continuing to provide this 
information (i.e., a brief telephone contact occurring at the time of the originally 
planned study visits). Thus, subjects may discontinue investigational product and 
continue in the study with telephone calls or they may indicate that they do not wish
to have further contact with the site (i.e., withdrawal of consent).


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2. Hyperglycemia:
Subject meets (repeated and confirmed) glycemic thresholds specified in Table 7 for 
the specific time point in the trial, without a reasonable explanation (e.g., intercurrent 
illness or medication omission).
Table 7  Glycemic Thresholds For Discontinuation
Visit Interval
Glycemic Thresholds
(Fasting plasma glucose [FPG])
After 
Visit 
3/Day 
1
through 
Visit 8/Week 6:
FPG consistently >270 mg/dL (15.0 mmol/L)
After 
Visit 
8/Week 
6
through 
Visit 10/Week 12:
FPG consistently >240 mg/dL (13.3 mmol/L)
Note: A consistent value for FPG is defined as a repeat measurement performed within 7 days of 
notification from the central laboratory.  Site should reinforce diet/exercise counseling prior to repeat 
measurement.
3. Hypoglycemia: Repeated (2 or more episodes since the prior visit) FPG or fingerstick 
glucose

<50 mg/dL (<2.8 mmol/L) with or without symptoms of hypoglycemia, or

≤70 mg/dL (≤3.9 mmol/L) with symptoms of hypoglycemia, and without a 
reasonable explanation (such as increased physical activity or skipped meal) or 
with a reasonable explanation and likely to reoccur.
Note:  The investigator should make sure that the subject's glucose meter and test
strips are functioning accurately and that the test procedure is being correctly 
performed by the subject prior to discontinuation.
4. Abnormal liver function tests meeting criteria specified below (see the Management 
of Subjects with Elevated Liver Enzymes [ALT or AST ≥3X ULN] guidance 
document in the Investigator Trial File Binder [ITFB] for additional details on 
management and discontinuation of investigational product for subjects with elevated 
liver enzymes):

ALT or AST ≥3X ULN with total bilirubin (TBL) ≥2X ULN and alkaline 
phosphatase (ALP) <2X ULN and without an established etiology; or

ALT or AST ≥8X ULN or ≥3X ULN with symptoms consistent with liver 
injury and without an established etiology; or

ALT or AST ≥5X ULN for 2 weeks or longer; or 

ALT or AST ≥3X ULN and subject is unwilling or unable to undergo repeat 
ALT and AST testing at the frequency defined in the Management of Subjects 
with Elevated Liver Enzymes (ALT or AST ≥3X ULN) guidance document.
5. Elevation in circulating serum lipase ≥3X ULN that is associated with clinical 
evidence of pancreatitis (e.g., symptoms of nausea/vomiting, abdominal pain).


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6. Parameters of Renal Function

Serum creatinine concentrations consistently ≥1.5 mg/dL (133 mol/L) in 
men or ≥1.4 mg/dL (124 μmol/L) in women.

eGFR consistently <45 mL/min/1.73 m2 (MDRD formula).
Note 1: A consistent value is defined as a repeat measurement performed within 7 
days of notification from the central laboratory.
Note 2: If the eGFR or serum creatinine value continues to meet discontinuation 
criterion but demonstrates improvement relative to the prior result, an additional 
repeat may be performed (within 7 days).  If this repeat continues to meet the 
discontinuation criteria, the subject must be discontinued from investigational 
product.
7. Has HR increases as detailed below:
Note: Heart rate assessments are based on mean of three consecutive values assessed 
as detailed in Section 7.1.2.  See Section 7.1.2 for detailed HR monitoring 
instructions

Tachycardia (mean sitting HR >100 bpm) of any duration associated with 
symptoms that the study investigator considers potentially related to cardiac 
ischemia, congestive heart failure and/or hemodynamic compromise.  Concerning 
symptoms might potentially include chest discomfort, chest pain, shortness of 
breath, and/or lightheadedness. 
Note: Subjects with a minimally symptomatic event, non-sustained or recurrent, 
not meeting other criteria may be continued.

Sustained mean resting HR >100 bpm measured in the sitting position (sustained 
defined as continuing after 30 minutes and after 60 minutes of rest in a sitting 
position: if the 30-minute mean HR is <100, reassessment after 60 minutes should 
not be done, and reassessment should be performed after 24 hours (see note 
below)).  
Note: If mean HR >100 and ≤120 or if HR decreases during the 30 minute (or 60 
minute) follow up to <100 bpm the dose of investigational product may be 
administered and the subject will be asked to return for repeat measurement 
within 24 hours. If mean HR is still >100 after 24 hours, the subject should be 
discontinued from the study medication. 

Sustained increase from baseline in mean resting HR ≥30 bpm measured in the 
sitting position (sustained defined as continuing after 30 minutes and after 60 
minutes of rest in a sitting position) that persists for ≥2 weeks.  If the 30-minute 
mean HR is <30 bpm higher than baseline, the 60-minute repeat does not need to 
be performed and the subject may continue in the trial.


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Note: An ECG should be conducted if a subject is suspected of meeting one of 
the HR discontinuation criteria detailed above. The ECG should be interpreted by 
the PI to confirm the measured HR and to diagnose any potential cardiac rhythm 
or rate abnormality.  If confirmed, the discontinuation visit should be performed 
including an ECG.
8. Requirement for one of the prohibited medications listed in Section 5.5.
9. Develops any condition for which metformin is contraindicated.
10. For subjects randomized to MK-8521 or placebo, subject cannot tolerate at least 0.3 
mL from each vial (i.e., 180 g/day dose for subjects on active MK-8521).
For 
subjects randomized to open-label liraglutide, subject cannot tolerate at least 1.2 
mg/day dose.
11. For subjects randomized to open-label liraglutide, develops any condition for which
liraglutide is contraindicated.
12. Pregnancy
Note: A positive urine pregnancy test requires immediate interruption of blinded 
investigational product until serum β-hCG can be performed and found to be 
negative. If pregnancy is confirmed by a positive serum pregnancy test, subject must 
be permanently discontinued, and pregnancy should be reported and followed per 
Section 7.2.2.
13. Any medical condition or personal circumstance which, in the opinion of the 
investigator, exposes the subject to risk by continuing investigational product or study 
procedures or does not allow the subject to adhere to the requirements of the protocol.
14. Subject undergoing bariatric surgery.
15. For subjects randomized to double-blind investigational product (i.e., MK-8521 or 
matching placebo), the investigator or subject becomes unblinded to the subject’s 
treatment assignment (i.e., through the IVRS system or emergency unblinding call 
center).
The Sponsor should be contacted immediately when a subject is discontinued from 
investigational product or investigational product is interrupted because of any SAE or AE 
assessed by the investigator as related to investigational product or laboratory abnormality 
assessed by the investigator as related to investigational product.  The Sponsor should also be 
immediately contacted when a subject is discontinued from investigational product due to 
HR criteria (see Section 7.2.3.2 for reporting of Events of Clinical Interest).
In this trial, a subject may discontinue investigational product for any of the reasons listed 
above (items #1 through 15) but continue to participate in the trial (with follow-up contacts), 
as long as the subject does not withdraw consent.  Follow-up procedures for subjects who 
discontinue investigational product are described in Section 5.9.1.


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Monitoring Subjects Who Discontinue Investigational Product (Blinded or 
5.9.1
Open-Label)
If the subject withdraws consent from participating in the trial, including specifically refusing 
further follow-up, no further evaluations should be performed, and no additional data should 
be collected.  The Sponsor may retain and continue to use any data collected before the 
subject’s withdrawal of consent.
Subjects who discontinue treatment with investigational product (blinded or open-label) for 
reasons other than withdrawn consent should attend the clinic for a Discontinuation Visit 
followed by a post-treatment visit 14 days after the last dose of investigational product.  
Thereafter, subjects will be followed by telephone contacts according to the study visit 
schedule until the end of the trial (Week 12), but will not have the other procedures listed in 
the trial flow chart.  The purpose of the telephone contacts is to collect information about 
subjects’ health status (e.g., evaluate if the subject experienced any SAEs).
Subjects who meet criteria for discontinuation of investigational product should have the 14-
day post-treatment study visit and continued follow-up contacts at the time of originally 
planned study visits, as described above but will not undergo procedures outlined in the trial 
flow chart (see Section 6.0).
Subjects who discontinue investigational product but who continue to participate in the trial 
by providing follow-up information can have medical and diabetes management by their 
managing physician or investigator, as appropriate.  These subjects may initiate any other 
therapy as needed (previously prohibited medication will not apply to them).  Procurement of 
other AHAs, including background metformin, is the responsibility of the subject.
If the trial site loses contact with the subject, the site should make at least three attempts for a 
telephone contact.  If the three attempts of telephone contact are unsuccessful, the site should 
make at least two attempts to reach the subject via certified letter.  All attempts to contact a 
subject and information received during contact attempts must be documented in the 
subject’s medical record.  If attempts to contact the subject via telephone contacts and 
certified letters are unsuccessful, alternative measures should be implemented, which may 
include contacting family members and health care providers and, when applicable, using 
subject location services.  In any circumstance, every effort should be made to document 
subject outcome, if possible.
Subject Replacement Strategy
5.10
A subject who discontinues from the trial will not be replaced.
Beginning and End of the Trial
5.11
The overall trial begins when the first subject signs the informed consent form.  The overall 
trial ends when the last subject completes the last study-related phone call or visit, 
discontinues from the trial or is lost to follow-up (i.e. the subject is unable to be contacted by 
the investigator).


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Clinical Criteria for Early Trial Termination
5.12
The trial may be terminated early based on evaluation by the siDMC if pre-specified criteria 
for safety-targeted siDMC review are met (refer to Section 8.2.9).  Additionally, if futility 
criteria are met at the planned interim analysis with regards to A1C and body weight the 
decision may be made to terminate the study early (refer to Section 8.2.9).


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6.0 TRIAL FLOW CHART
Trial Period:
Screening
Run-
In
Random-
ization
Treatment
Post-Treatment
Visit Title
Screen-
ing
Wash-
out
Run-
in
Random-
ization
Week 1
Week 2
Week 3
Week 4
Week 6
Week 9
Week 12
Discontinu
ation Visit
Follow-up 
Day 14
Visit Number
1
1Aw
2
3
4
5
6
7
8
9
10
Discontin-
uation
14-Day Post 
Treatment 
Follow-Up 
Visitb
Scheduled Week 
-10
-2
(Day
-14)
0
(Day 1)
1
(Day 7)
2
(Day 14)
3
(Day 21)
4
(Day 28)
6
(Day 42)
9
(Day 63)
12
(Day 85)
At time of 
discontin-
uationa
14 days 
after last 
dose
Suggested Visit Window
+/- 3 days
+/- 3
days
+/- 3 days 
+/- 3 days
+/- 3 days
+/- 3 days
+/- 3 days
+/- 3 days
+/- 3 days
Administrative Procedures
Informed Consentc
X
Informed Consent for 
Future Biomedical 
Researchd
X
Assignment of Screening 
Number
X
Contact IVRS system
X
X
X
X
X
X
X
X
X
X
X
Subject Identification 
Card
X
Assignment of 
Randomization Number
X
Inclusion/Exclusion 
Criteria
X
X
X
Prior/Concomitant 
Medication Review
X
X
X
X
X
X
X
X
X
X
X
X
Review use of any 
prohibited medications, 
including AHAs; counsel 
subjects on importance of 
not taking other AHAsaa
X
X
X
X
X
X
X
X
X
X
X
X
Diet and Activity 
Counseling/Monitoringf
X
X
X
X
X
X
X
X
X


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Trial Period:
Screening
Run-
In
Random-
ization
Treatment
Post-Treatment
Visit Title
Screen-
ing
Wash-
out
Run-
in
Random-
ization
Week 1
Week 2
Week 3
Week 4
Week 6
Week 9
Week 12
Discontinu
ation Visit
Follow-up 
Day 14
Visit Number
1
1Aw
2
3
4
5
6
7
8
9
10
Discontin-
uation
14-Day Post 
Treatment 
Follow-Up 
Visitb
Scheduled Week 
-10
-2
(Day
-14)
0
(Day 1)
1
(Day 7)
2
(Day 14)
3
(Day 21)
4
(Day 28)
6
(Day 42)
9
(Day 63)
12
(Day 85)
At time of 
discontin-
uationa
14 days 
after last 
dose
Suggested Visit Window
+/- 3 days
+/- 3
days
+/- 3 days 
+/- 3 days
+/- 3 days
+/- 3 days
+/- 3 days
+/- 3 days
+/- 3 days
Dispense Hypoglycemia 
Assessment Log (HAL) 
and Instruct on 
Hypoglycemia Symptoms 
and Management
X
Xy
Dispense Glucose Meter, 
Fingerstick Glucose Logs, 
and Provide SMBG 
Instruction
X
Xy
Telephone Contact 
Between Clinic Visitsg
      X------------------------------------------------------------------------------------------------------------------X
Investigational Product
Washout Second AHAw. 
Continue Metformin 
Monotherapy. Do Not 
Change Metformin Dose
X
Instruct Self-
Administration Of 
Medicationh
X
X
X
X
X
Dispense Single-Blind 
Placebo Run-in
X
Dispense Double-Blind 
Investigational Product / 
Open-Label Liraglutide
X
X
X
X
X
X
X
Witness Dose of Blinded 
Investigational Product / 
Open-Label Liraglutide in 
Clinici
X
X
X
X
X
X
X
X


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Trial Period:
Screening
Run-
In
Random-
ization
Treatment
Post-Treatment
Visit Title
Screen-
ing
Wash-
out
Run-
in
Random-
ization
Week 1
Week 2
Week 3
Week 4
Week 6
Week 9
Week 12
Discontinu
ation Visit
Follow-up 
Day 14
Visit Number
1
1Aw
2
3
4
5
6
7
8
9
10
Discontin-
uation
14-Day Post 
Treatment 
Follow-Up 
Visitb
Scheduled Week 
-10
-2
(Day
-14)
0
(Day 1)
1
(Day 7)
2
(Day 14)
3
(Day 21)
4
(Day 28)
6
(Day 42)
9
(Day 63)
12
(Day 85)
At time of 
discontin-
uationa
14 days 
after last 
dose
Suggested Visit Window
+/- 3 days
+/- 3
days
+/- 3 days 
+/- 3 days
+/- 3 days
+/- 3 days
+/- 3 days
+/- 3 days
+/- 3 days
Assess Trial Medication 
Compliance.  Collect 
Unused and Used
Investigational Product / 
Open Label Liraglutideg
X
X
X
X
X
X
X
X
X
Clinical Procedures/Assessments
Demographics and 
Medical History
X
Height
X
X
Body Weight
X
X
X
X
X
X
X
X
X
X
X
X
Vital 
Signs 
(HR
and 
Blood Pressure)j
X
X
X
X
X
X
X
X
X
X
X
X
Postural Blood 
Pressure/HRk
X
Full Physical 
Examination (excluding 
rectal and urogenital 
examination)
X
Brief Physical 
Examinationl
X
X
X
X
12-Lead ECGm
X
X
X
X
Fasting Fingerstick 
Glucose in Clinic
X
Review of SMBG 
Measurements and HAL
X
X
X
X
X
X
X
X
X
Adverse Events 
Monitoring
X---------------------------------------------------------------------------------------------------------------------------------X
X
X


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Trial Period:
Screening
Run-
In
Random-
ization
Treatment
Post-Treatment
Visit Title
Screen-
ing
Wash-
out
Run-
in
Random-
ization
Week 1
Week 2
Week 3
Week 4
Week 6
Week 9
Week 12
Discontinu
ation Visit
Follow-up 
Day 14
Visit Number
1
1Aw
2
3
4
5
6
7
8
9
10
Discontin-
uation
14-Day Post 
Treatment 
Follow-Up 
Visitb
Scheduled Week 
-10
-2
(Day
-14)
0
(Day 1)
1
(Day 7)
2
(Day 14)
3
(Day 21)
4
(Day 28)
6
(Day 42)
9
(Day 63)
12
(Day 85)
At time of 
discontin-
uationa
14 days 
after last 
dose
Suggested Visit Window
+/- 3 days
+/- 3
days
+/- 3 days 
+/- 3 days
+/- 3 days
+/- 3 days
+/- 3 days
+/- 3 days
+/- 3 days
Laboratory Procedures/Assessments
FPG
X
X
X
X
X
X
X
X
X
X
X
A1Cn,x
X
Xx
X
X
X
X
X
Fasting C-peptideo
X
Lipid Panelp
X
X
X
Chemistry Panel
X
Xx
X
X
X
X
X
X
Hematology
X
Xx
X
X
X
X
X
Fasting Triglycerides
X
Xz
Serum Lipase
X
X
X
X
X 
Serum Calcitonin Level
X
X
X
Fasting Insulin (potential 
analysis, for archive) and 
C-peptideq
X
X
X
Immunogenicity Assay 
(Anti-drug AB)
X
X
X
X
X
Glucagon receptor 
activation biomarkers 
(including ketones,
Glucagon, FGF-21 and 
Kisspeptin) (potential 
analysis, for archive)r
X
X
X
X
X
X
X
Plasma PK Sample for 
MK-8521bb
X
X
X
X
X
X
X
Plasma PK Sample for 
Liraglutide (potential 
analysis, for archive)s, bb
X
X
X
X
X
X
X
Urine Collection for 
Dipstick/Urinalysist
X
X
X
X


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Trial Period:
Screening
Run-
In
Random-
ization
Treatment
Post-Treatment
Visit Title
Screen-
ing
Wash-
out
Run-
in
Random-
ization
Week 1
Week 2
Week 3
Week 4
Week 6
Week 9
Week 12
Discontinu
ation Visit
Follow-up 
Day 14
Visit Number
1
1Aw
2
3
4
5
6
7
8
9
10
Discontin-
uation
14-Day Post 
Treatment 
Follow-Up 
Visitb
Scheduled Week 
-10
-2
(Day
-14)
0
(Day 1)
1
(Day 7)
2
(Day 14)
3
(Day 21)
4
(Day 28)
6
(Day 42)
9
(Day 63)
12
(Day 85)
At time of 
discontin-
uationa
14 days 
after last 
dose
Suggested Visit Window
+/- 3 days
+/- 3
days
+/- 3 days 
+/- 3 days
+/- 3 days
+/- 3 days
+/- 3 days
+/- 3 days
+/- 3 days
Urine Pregnancy Test 
(women of childbearing 
potential only)u
X
X
X
X
X
X
X
X
Plasma and Serum for 
Future Biomedical 
Researchd
X
X
X
X
Blood (DNA) for Genetic 
Analysise
X


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a.
Subjects who discontinue taking investigational product prematurely (without withdrawal of consent) should complete procedures for the Discontinuation Visit and perform the 
14-Day Post-Treatment Visit two weeks following the last dose.  These subjects will also be contacted via telephone by the investigator/qualified designee according to the same 
schedule as if the subject were still taking investigational product to collect SAEs (see Section 5.9.1).
b.
The 14-Day Post-Treatment Visit should be completed 14 days after the last dose of investigational product to collect body weight, vital signs, chemistry, hematology, 
immunogenicity assay, and SAEs.
c.
A subject ICF must be signed before any trial procedures are performed and may be signed prior to Visit 1/Screening.
d.
The Future Biomedical Research (FBR) informed consent must be obtained before FBR samples for plasma and serum are collected.  The plasma and serum samples for FBR 
should be collected at Visit 3/Day 1 (pre-dose), Visit 8/Week 6, and Visit 10/Week 12 (or Discontinuation Visit).  For the FBR serum and plasma, samples should be collected at 
all time points, even if the pre-dose or other time point was not collected.
e.
This sample should be drawn for planned genetic analysis of DNA and drug response unless there is either a documented law or regulation prohibiting collection, or unless the
IRB/IEC does not approve of the collection of the sample for these purposes.  If the sample is collected, any leftover extracted DNA will be stored for future biomedical research if 
the subject signs the FBR consent.
f.
Eligible subjects will be seen by a dietician or qualified healthcare professional for dietary and exercise counseling at Visit 2/Week -2 (for subjects who do not require AHA 
washout) or at Visit 1A/Washout (for subjects requiring AHA washout); follow-up at subsequent visits may be done by other appropriate site personnel evaluating the subject.
g.
Telephone contact by the investigator/qualified designee will be made on Day -7 and at the midpoint between treatment visits (from Visit 3 to Visit 10) to assess for adverse events 
and compliance to study drug administration.  Subjects who are found to be <100% compliant should be contacted by the investigator/qualified designee at least twice per week
until compliance improves.  Unscheduled visit(s) may be performed as needed if the subject requires retraining on study drug administration.  Assessment of compliance to study 
medication should include subject report, used vial count (or used pens for subjects randomized to liraglutide), an estimation of vial volume as compared to an unopened vial.
h.
At Visit 2/Week -2, subjects will be taught self-administration of placebo for MK-8521.  Subjects will be expected to self-administer during the
2-week run-in period in order to develop proficiency in self-administration.  Telephone contact will be made on Day -7 to assess for compliance with self-administration and 
adverse events.  Re-instruction to be provided by clinical staff on Visit 3/Day 1 and as appropriate.
Subjects on open-label liraglutide will be taught self-administration of 
liraglutide on Visit 3/Day 1.
i.
The witnessed self-administered dose will be taken after completion of all procedures for the trial visit, including the collection of all fasting blood samples.
j.
Sitting triplicate blood pressure and heart rate should be collected as instructed in Section 7.1.2.1.
k.
Supine and standing blood pressure and heart rate should be collected as instructed in Section 7.1.2.2.
l.
Brief physical examination includes assessment of heart, lungs, abdomen, skin and extremities.
m.
Visit 2/Week -2 ECG is read locally at the investigative site.  ECG for all other time points should be submitted to be read centrally.
n.
A1C should not be drawn if Discontinuation Visit occurs within 4 weeks after Visit 3/Day 1.
o.
Fasting C-peptide at Visit 1/Screening is only for subjects assessed by the investigator as possibly having T1DM.
p.
Includes total cholesterol, high-density lipoprotein (HDL-C) cholesterol, low-density lipoprotein (LDL-C) cholesterol, triglycerides, non-HDL cholesterol, and apolipoprotein A-I 
at all time-points.  Apolipoprotein A-I will only be measured if the results are considered important for future dual peptide programs. 
q.
Fasting insulin and C-peptide samples are to be collected in all study subjects at Visit 3/ Day 1 and Visit 10/Week 12 (or the Discontinuation Visit), and these, along with fasting 
glucose values, will be used to calculate HOMA-β and HOMA-IR.  Fasting insulin will only be measured if the results are considered important for future dual peptide programs.  
Due to sample stability, C-peptide samples will be analyzed as they are received by the central laboratory but the results will not be provided to the site.
r.
Glucagon receptor activation biomarkers will only be measured if the results are considered important for future dual peptide programs.
s.
Liraglutide PK will only be measured if the results are considered important for future dual peptide programs.  
t.
If dipstick (midstream urine specimen) is positive for blood, WBC (e.g., leukocyte esterase, nitrites), or protein, then a urine sample for a complete urinalysis (dipstick and 
microscopy) should be sent to the central laboratory.
u.
Women of childbearing potential will have a urine pregnancy test (and serum pregnancy test if required by site's Institutional Review Board [IRB]/Ethics Committee [EC]).  
Subjects with a positive urine pregnancy test during the treatment period will interrupt investigational product and undergo a serum pregnancy test.
v.
Subjects on metformin monotherapy who meet all Visit 1/Screening eligibility criteria can proceed directly to Visit 2/Week -2.  Subjects on metformin monotherapy who meet all 
Visit 1/Screening eligibility requirements except for TG and/or blood pressure criteria should have initiation or adjustment of lipid-lowering/blood pressure medication made prior 
to Visit 2/Week -2, with unscheduled visits, as needed.  The screening period (Visit 1 to Visit 2) should be extended so that subjects are on a stable regimen for at least 4 weeks 


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prior to Visit 3/Day 1.
w.
Only subjects who are on dual therapy with metformin and a second AHA will perform Visit 1A/Washout.  Allowable AHAs for washout at Visit 1A/Washout include: DPP-4 
inhibitors, α-glucosidase inhibitors, sulfonylureas and glinides.
x.
Performed at Visit 2/Week -2 only if Visit 2/Week -2 occurs >2 weeks after Visit 1/Screening.
y.
Not applicable for Visit 2/Week -2 if these items were already dispensed/performed at Visit 1A/Washout.
z.
Only applicable for subjects who did not satisfy the Visit 1/Screening TG criterion.  A fasting TG sample should not be obtained for subjects who satisfied the Visit 1/Screening 
TG criterion.
aa.
Subjects should be reminded to not to take any other AHA medications other than metformin and randomized therapy (MK-8521/placebo or open-label liraglutide) during their 
participation in the study.  They should be counseled that if another physician prescribes such a treatment (i.e., any AHA), the subject and/or the prescribing physician should 
immediately contact the investigational site prior to initiation of such therapy (unless alternative AHA therapy is considered clinically to be immediately required).  Subjects who 
were washed off of another AHA should be reminded to remain off this agent while participating in the current trial, and to not re-start this agent post-study unless advised by their 
diabetes care-giver (whether the investigator or another physician).
bb. Subjects randomized to Liraglutide should only have PK samples for Liraglutide obtained and sent to the central laboratory (PK samples for MK-8521 should not be obtained). 
Conversely, subjects randomized to MK-8521/placebo should only have PK samples for MK-8521 obtained and sent to the central laboratory (PK samples for Liraglutide should 
not be obtained).


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


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7.1.1.2
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee 
to ensure that the subject qualifies for the trial.
7.1.1.3
Subject Identification Card
All subjects will be given a Subject Identification Card identifying them as participants in a 
research trial.  The card will contain trial site contact information (including direct telephone 
numbers) to be utilized in the event of an emergency.  The investigator or qualified designee 
will provide the subject with a Subject Identification Card immediately after the subject 
provides written informed consent.
7.1.1.4
Medical History
A medical history will be obtained by the investigator or qualified designee.  The use of 
tobacco should be collected as a part of the medical history.
7.1.1.5
Prior and Concomitant Medications Review
7.1.1.5.1 Prior Medications
The investigator or qualified designee will review prior medication use.  AHAs taken by the 
subject at any time prior to Visit 1/Screening and any other medications taken within 8 weeks
of Visit 1/Screening should be recorded on the appropriate eCRF.  The site may rely on 
subject report for this information.
7.1.1.5.2 Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the subject 
during the trial on the appropriate eCRF.
7.1.1.6
Assignment of Screening Number
All consented subjects will be given a unique screening number that will be used to identify 
the subject for all procedures that occur prior to randomization or allocation.  Each subject 
will be assigned only one screening number.  Screening numbers must not be re-used for 
different subjects.  
Any subject who is screened multiple times will retain the original screening number 
assigned at the initial screening visit.
Specific details on the screening visit requirements (screening/rescreening) are provided in 
Section 7.1.5.1.
7.1.1.7
Assignment of Randomization Number
All eligible subjects will be randomly allocated and will receive a randomization number.  
The randomization number identifies the subject for all procedures occurring after 
randomization.  Once a randomization number is assigned to a subject, it can never be re-
assigned to another subject.


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A single subject cannot be assigned more than 1 randomization number.
7.1.1.8
Trial Compliance (Medication/Diet/Activity/Other)
Adherence to treatment will be assessed by subject report (facilitated by site review of 
returned used vial count (or used pens for subjects randomized to liraglutide), an estimation 
of vial volume as compared to an unopened vial and inspection of injection sites on the 
abdominal wall) during the double-blind treatment period.  Every effort will be made to 
maintain adherence as close to 100% as possible.
Interruptions from the protocol specified treatment for >= 2 days OR compliance <= 90%
require consultation between the investigator and the Sponsor and written documentation of 
the collaborative decision on subject management.
7.1.1.8.1 Diet and Exercise Counseling and Monitoring
Refer to Section 5.7 for further details.
7.1.1.8.2 Dispense Hypoglycemia Assessment Log and Instruct on Hypoglycemia 
Symptoms and Management
The activities in this section will occur at Visit 2/Week -2 for subjects who are not
undergoing washout. They will occur at Visit 1A/Washout for subjects who are undergoing 
washout. 
The site will review the symptoms and management of hypoglycemia with the subject.  The 
site will counsel the subject to immediately perform a fingerstick glucose measurement if any 
symptoms occur that may be related to hypoglycemia (e.g., weakness, dizziness, shakiness, 
increased sweating, palpitations, or confusion), but also to avoid delay in treating these 
symptoms.
The subject will be instructed to complete the Hypoglycemia Assessment Log (HAL) for any 
symptomatic episodes he or she believes may represent hypoglycemia.  If a fingerstick 
glucose has been obtained before or shortly (i.e., within a few minutes) after treating, the 
value should be recorded in the log.  In addition, subjects will be instructed to record in the 
log any fingerstick glucose values ≤70 mg/dL (3.9 mmol/L) regardless of the presence of 
symptoms.
Subjects should be instructed to contact the investigational site to report:

Any episode of hypoglycemia for which assistance was required (i.e., severe 
hypoglycemia).

Any episode of fingerstick glucose ≤70 mg/dL (3.9 mmol/L) with or without symptoms.
Note:  As indicated, subjects will record symptoms and/or fingerstick glucose 
measurements that they believe are related to hypoglycemia on the HAL.  Each episode 
should be evaluated by the investigator.  For episodes 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 Hypoglycemia 
Assessment (HA) eCRF must also be completed.  Each event of symptomatic 
hypoglycemia must be reported as an adverse event on the adverse eCRF.  Each episode 


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of asymptomatic hypoglycemia considered by the investigator to be an adverse event 
should also be reported on the adverse event eCRF (see Section 7.1.2.10.2.1 for guidance 
on reporting).
7.1.1.8.3 Dispense Glucose Meter and SMBG Instructions
The activities in this section will occur at Visit 2/Week -2 for subjects who are not
undergoing washout. They will occur at Visit 1A/Washout for subjects who are undergoing 
washout. 
Glucose meters and Fingerstick Glucose Logs will be supplied to all subjects in order to 
perform SMBG.  Subjects will be instructed on the procedure to perform fingerstick glucose 
measurements.  Subjects will monitor their fingerstick glucose concentrations with a 
frequency determined appropriate by the investigator (based upon his/her assessment of the 
subject’s risk of increasing glucose concentrations) with a minimum of two fasting 
determinations per week.
From the time the glucose meters are supplied, through Visit 3/randomization, subjects 
should be counseled to contact the trial site if fasting fingerstick glucose levels are above 260 
mg/dL (14.4 mmol/L) ≥2 times per week.  Subjects will also be instructed to contact the site 
if their fingerstick glucose values are ≤70 mg/dL (≤3.9 mmol/L).  
Furthermore, in order to assess the need for discontinuation from investigational product, 
subjects should be instructed to contact the site for fasting fingerstick glucose values that are 
>270 mg/dL (15.0 mmol/L) after Visit 3/Randomization (Day 1) through Visit 8/Week 6, or 
>240 mg/dL (13.3 mmol/L) after Visit 8/Week 6 through Visit 10/Week 12.
7.1.1.8.4 Witnessed Dosing
Administration of investigational product (blinded or open-label) will be witnessed by the 
investigator and/or trial staff at all clinic visits (when investigational product administration 
is continuing) after completion of all trial procedures including the collection of all fasting 
blood samples.
7.1.1.8.5 Dispense Single-Blind Placebo Run-in Investigational Product
Subjects will be dispensed single-blind investigational product (MK-8521 300 g and MK-
8521 180 g matching placebos) at Visit 2/Week -2 and instructed to take one injection
(0.1 mL) per day from each vial at approximately the same time of day in the morning.  The 
last dose of placebo run-in should be taken on the day prior to Visit 3/Day 1.
Refer to Section 5.2.2 for further details.
7.1.1.8.6 Dispense Double-Blind/Open-Label Investigational Product
Subjects will be dispensed double-blind investigational product at all treatment visits from 
Visit 3/Day 1 through Visit 9/Week 9.  Open-label liraglutide can be dispensed such that the 
subject will not run out prior to the next trial visit.  Suggested liraglutide dispensing guidance 
can be found in Table 8.


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Table 8  Suggested Liraglutide Dispensing Guidance
Visit #/Week # (window)
# of Liraglutide Pens Dispensed
Visit 3/Day 1 (14 days)
1a
Visit 5/Week 2 (7 days)
1
Visit 6/Week 3 (7 days)
1
Visit 7/Week 4 (14 days)
2
Visit 8/Week 6 (21 days)
3
Visit 9/Week 9 (21 days)
3
a  One 18-mg pen is sufficient (0.6 mg x 6 days + 1.2 mg x 7 days = 12 mg used) to 
cover the liraglutide titration period (Visit 3 to Visit 5).
Subjects randomized to MK-8521 (either dose) or placebo should be instructed to take one 
injection subcutaneously per day from each vial in the morning at approximately the same 
time each day.
Subjects randomized to liraglutide should be instructed to take one injection subcutaneously 
per day in the morning at approximately the same time each day.
Refer to Section 5.2.2 for further details.
7.1.1.8.7 Medication Compliance Monitoring
Subjects will be directed to bring all vials/pens (used and unused) to each visit.  The 
investigator must maintain a complete and current accountability record for the 
investigational product.
Compliance with the placebo run-in medication should be monitored by study personnel at 
the site at the end of the placebo run-in at Visit 3/Day 1.  Compliance should be assessed by 
all of the following: 
1. subject report
2. used vial count
3. estimation of used vial volume (when compared to an unused vial). 
Subjects who miss more than one daily dose (i.e., 2 injections on the same day or 2 single 
injections on separate days)
of the placebo run-in medication are ineligible for 
randomization.
During the remainder of the trial, compliance with blinded investigational product will be 
assessed using the same approach noted above: (1) subject report, (2) used vial count and (3) 
estimation of vial volume as compared to an unopened vial.
For subjects randomized to open-label liraglutide, compliance will be assessed based on (1) 
subject report and (2) visual inspection of used pen(s).


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Every effort will be made to maintain compliance at 100%: 
•
The investigator or designee will counsel subjects who report taking <100% of 
the prescribed investigational product following randomization.  
•
The investigator or designee will determine factors that resulted in <100% 
compliance with the investigational product and will take steps to improve 
compliance.  
•
Subjects will be counseled on the importance of taking their medication as 
prescribed.  
•
Subject counseling will be documented in source documents.
Clinical Procedures/Assessments
7.1.2
7.1.2.1
Vital Signs (Sitting Blood Pressure and Heart Rate)
Vital sign measurements include a triplicate measurement of sitting blood pressure and heart
rate.  Blood pressure and heart rate will be measured using an automated, oscillometric blood 
pressure measuring device at all visits as noted in the Trial Flow Chart - Section 6.0.  Site 
personnel should use the same blood pressure measuring device throughout the study for 
each subject.
The following method should be used to record sitting blood pressure and heart rate for 
subjects in triplicate:

Subjects will refrain from ingesting caffeine for at least 10 hours preceding the 
measurements.

Subjects should be seated in a chair with their back supported, feet flat on the floor 
and arm bared (free of restrictions such as rolled up sleeves) and supported at heart 
level.

The appropriate cuff size must be used to ensure accurate measurement.  Each 
subject’s cuff size should be noted in his/her source file to assure the same cuff size is 
used throughout the trial.

Measurements should be taken on the same arm at each visit (preferably the non-
dominant arm).

Measurements should begin after at least 5 minutes of rest.

The three measurements of both the blood pressure and heart rate must be taken 
approximately 2 minutes apart.  
o
Note: Measurements will be collected until the 3 consecutive systolic BP 
readings do not differ by more than 5 mm Hg of each other and the 3 
consecutive diastolic BP readings do not differ by more than 5 mm Hg of each 
other with the last triplicate set recorded in the eCRFs.  
o
The mean (average) of the last triplicate set of BP readings (at Visit 1 and if 
necessary, at Visit 3) will be used to determine eligibility.


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
Assessment of heart rate can be manual (rather than using an automated device); 
however, when done manually, heart rate must be measured in the brachial/radial 
artery for at least 30 seconds.  
o
Note: Measurements will be collected until the 3 consecutive heart rate
readings do not differ by more than 5 bpm of each other with the last triplicate 
set recorded in the eCRFs.  
o
The mean (average) of the last triplicate set of heart rate readings will be used 
to determine eligibility (Visit 1, Visit 2, and Visit 3), baseline HR (Visit 3), 
and discontinuation criteria (all post-randomization visits).
Other procedures should not be performed during the time of the blood pressure and heart
rate measurements.
7.1.2.2
Postural (Orthostatic) Blood Pressure and Heart Rate
Supine and standing blood pressure and heart rate will be taken in order to evaluate postural 
changes in blood pressure and heart rate at Visit 2/Week -2.  These measurements will be in
addition to the sitting blood pressure and heart rate measurements taken at this clinic visit.
Postural blood pressure changes will be measured according to the following procedure:

Subject in supine position for a minimum of 5 minutes.

Measure blood pressure and heart rate in the supine position in duplicate (at least 1 
minute apart).

Stand subject and measure blood pressure and heart rate in the standing position in 
duplicate according to the following instructions.  
o
The first measurement of standing blood pressure and heart rate will be 
measured after at least 1 minute of standing.  
o
The second measurement of standing blood pressure and heart rate will be 
measured after the subject has been standing for at least 3 minutes
Note: The mean supine systolic blood pressure value will be compared to the mean of the 
standing systolic blood pressure values obtained as noted above, in order to determine 
eligibility.
7.1.2.3
Body Weight
Body weight will be measured using a standardized, digital scale (provided by the Sponsor) 
at each of the pre-defined nominal time points outlined in the Trial Flow Chart – Section 6.0 
as follows:

Weight will be taken in duplicate throughout the trial at approximately the same time 
of day, after voiding (i.e., forced void) and while wearing only a gown and underwear 
(no street clothes, no shoes or socks).  Investigator sites without access to gowns 
should weigh subject in light clothing.

Subjects should be instructed to step gently onto the scale, place both feet together in 
the center of the scale and stand straight with eyes directed ahead.  Subjects should be 


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instructed to stand still and not sway.  Measurement will be recorded after the weight 
has stabilized.

Body weight should be reported with precision to one decimal place (e.g., 0.1 kg or 
0.1 lb).  The 2 measurements should be recorded in the source documents.  If the 2 
measurements differ by more than 0.2 kg or by 0.4 lb, (1) check the subject to ensure 
proper positioning as indicated above and/or conduct an accuracy check on the scale 
as instructed below and (2) a different set of duplicate measurements must be 
obtained, and the 2 new measurements should be recorded in the source documents.

Only the final body weight measurement should be recorded in the eCRF.
A 10-kg certified weight will be purchased by the Sponsor and sent to each investigational 
site.  To assess the accuracy of the scale, the trial coordinator or appointed designee will 
weigh him or herself alone, then the weight alone, and finally, the individual together with 
the weight.  Deviations of more than one scale division (±0.1 kg) will require corrective 
action and the Sponsor must be contacted.  Accuracy check will be performed monthly and 
the record of scale accuracy must be sent to the Sponsor at the end of the trial.
7.1.2.4
Height
Height will be measured without shoes, using a stadiometer or other appropriate device.
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.
7.1.2.5
Physical Examination
A complete physical examination (excluding rectal and urogenital examination) will be 
performed at Visit 2/Week -2.  A brief physical examination including assessment of the 
heart, lungs, abdomen, skin and extremities will be performed at time points noted in the 
Trial Flow Chart – Section 6.0.  Abnormalities considered clinically significant should be 
reported as adverse events.  Other body systems may be evaluated as per the judgment of the 
investigator or as needed to evaluate adverse events.
7.1.2.6
Electrocardiogram (12-lead ECG)
Single, supine 12-lead ECGs will be obtained at visits noted in the Trial Flow Chart –
Section 6.0.  ECG equipment with an instruction manual will be provided by the Sponsor.

Subjects will refrain from ingesting caffeine for at least 10 hours preceding the 
procedure.

12-lead ECGs should be performed after the subject has rested quietly for at least 10 
minutes in a supine position.
12-lead ECGs should be obtained prior to the nominal time assessment of blood pressure, 
and heart rate as well as prior to blood collection.
The Visit 2/Week -2 ECG is read locally at the investigative site.  ECGs for all other time 
points should be reviewed at the investigative site for subject safety monitoring, as well as 


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electronically transmitted to a central vendor for reading and interpretation centrally.  The 
investigator is responsible for retaining all copies of the ECG reports.
Information to be reported to the investigator by the central scoring site will include the 
subject’s demographic information, HR (BPM), overall interpretation, rhythm type, and HR
intervals PR, QRS, QT, QTcB, and QTcF (msec), and any comments.
7.1.2.7
Fasting Fingerstick Glucose (FFSG)
FFSG values performed in the clinic will be used to assess exclusion criteria prior to 
randomization at Visit 3/Day 1.
7.1.2.8
Review of SMBG Measurements and Hypoglycemia Assessment Log (HAL)
SMBG measurements and the HAL will be reviewed at all clinic visits after Visit
1A/Washout (in subjects undergoing AHA washout), or Visit 2/Week -2 (in subjects not 
undergoing AHA washout) and will be used to assess for events of hypoglycemia, and to 
determine need for discontinuation from blinded investigational product due to 
hypoglycemia.
7.1.2.9
Assess Subject for Discontinuation Based on Central Laboratory FPG
During the double-blind treatment period, FPG values obtained at the central laboratory will 
be used to assess if the subject meets criteria for discontinuation of investigational product.  
Refer to Section 5.9 for further details regarding discontinuation.
7.1.2.10 Adverse Event Monitoring
7.1.2.10.1 Hyperglycemia
A subject should be considered to have an adverse event of hyperglycemia if the subject has 
one or more symptoms (e.g., increased thirst, polyuria) typically associated with an increased 
glucose level.  At the discretion of the investigator, this may be captured as an adverse event 
of “hyperglycemia.”  This diagnosis may be supported by, but does not require, results from 
a glucose meter or the trial central laboratory.  Further, at the discretion of the investigator, 
an elevated blood glucose value without associated symptoms that is considered to be an 
adverse event may be reported as an adverse event of “blood glucose increased.”  General 
guidance regarding the determination as to whether an event is considered to be an adverse 
event should be followed (see Section 7.2).
7.1.2.10.2
Hypoglycemia
Based on review of the subject-completed HAL at each clinic visit to the site, the investigator 
must assess the glucose values as well as any symptoms of hypoglycemia reported by the 
subject.
Reporting Events of Hypoglycemia
7.1.2.10.2.1
All episodes considered as likely to represent symptomatic hypoglycemia by the investigator 
should be captured as an adverse even of “symptomatic hypoglycemia.”  This diagnosis may 
be supported by, but does not require, confirmatory blood glucose results (such as those 


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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 (see Section 7.2).
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).
Laboratory Procedures/Assessments
7.1.3
Details regarding specific laboratory procedures/assessments to be performed in this trial are 
provided below. The total amount of blood/tissue to be drawn/collected over the course of 
the trial (from pre-trial to post-trial visits), including approximate blood/tissue volumes 
drawn/collected by visit and by sample type per subject can be found in the Lab Manual.
7.1.3.1
Laboratory Safety and Efficacy Evaluations
Laboratory tests are specified in Table 9.
Table 9  Laboratory Tests
Hematology
Chemistry
Dipstick/
Urinalysis
Others

Hemoglobin

Hematocrit

RBC Count

Platelet Count

WBC Count

Total Neutrophils

Eosinophils

Monocytes

Basophils 

Lymphocytes

BUN

Serum Creatinine (eGFR 
calculated 
using 
the 
MDRD formula)

Calcium (total)

Sodium

Potassium

Chloride

Total 
Carbon 
Dioxide 
(Bicarbonate)

Magnesium

Phosphate

Uric Acid

AST (SGOT)

ALT (SGPT)

Alkaline Phosphatase

Total Bilirubin

Direct 
(conjugated) 
Bilirubina

Indirect 
(unconjugated) 
Bilirubina

Albumin

Total Protein

pH

Protein 
(qual)

Blood (qual)

Ketones

Leukocyte 
Esterase

Nitrites

Glucose

Microscopyb

TSH

C-peptide

Insulinc

A1C

FPG

Pregnancy Tests (where 
applicable)

Lipid Panel (i.e., Total 
Cholesterol, HDL-C, non-
HDL-C 
LDL-C, 
and 
Triglycerides, 
apolipoprotein A-Id)

Lipase

Calcitonin

PK for MK-8521

PK for liraglutided

Immunogenicity 
Assay 
(Anti-drug AB)

Glucagon 
receptor 
activation 
biomarkers 
[including ketones (beta-
hydroxybutyrate
and  
acetoacetate), 
FGF-21 
, 
glucagon and kisspeptin]d

Blood for DNA analysis

Plasma and serum for FBR


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Hematology
Chemistry
Dipstick/
Urinalysis
Others
a.
Both direct and indirect bilirubin measured only when total bilirubin is greater than ULN.
b.
Microscopy performed if the site dipstick evaluation is positive for blood, nitrites, leukocytes and/or protein.
c.
Insulin will only be measured if the results are considered important for future dual peptide programs.
d.
Apolipoprotein A-I, PK for liraglutide, and Glucagon receptor activation biomarkers will only be measured if the results are 
considered important for future dual peptide programs.
All routine study laboratory measurements will be performed by the central laboratory after 
an overnight fast (i.e., no food, investigational product, background metformin therapy, or 
drink except water and non-AHA non-investigational product as prescribed) ≥10 hours in 
duration.
7.1.3.2
Pharmacokinetic/Pharmacodynamic Evaluations
The site will emphasize to the subject not to take their morning dose of investigational 
product prior to arrival at the study site on days when PK samples will be taken.  On the 
morning of any visit that includes pharmacokinetic sampling, investigational product dosing 
will occur after the pre-dose sample is taken. If a subject is randomized to Liraglutide (open 
label), only the PK samples for Liraglutide should be obtained and sent to the central 
laboratory (and PK samples for MK-8521 should not be obtained). Conversely, if a subject is 
randomized to MK-8521/placebo only PK samples for MK-8521 should be obtained and sent 
to the central laboratory (and PK samples for Liraglutide should not be obtained).
Blood samples (approximately 4 mL) to provide approximately 2 mL of plasma for 
pharmacokinetic analysis will be collected at visits specified in the Trial Flow Chart –
Section 6.0.  The exact date and time of the blood draw and the date and time of the last dose 
of investigational product reported by the subject prior to the blood draw should be captured 
on the eCRF.  The actual times may change, but the number of samples will remain the same.
Samples will be centrifuged at approximately 1700 g for about 10 minutes at 4°C (if a 
refrigerated centrifuge is not available, place sample in an ice water bath for at least 10 
minutes before centrifugation).  The plasma will be stored in appropriately labeled screw-
capped polypropylene tubes at approximately -20°C within 1 hour of collection.
Detailed instructions for the sample collection, storage and shipment of plasma samples will 
be provided in the operations/laboratory manual (supplied by the central laboratory).
As part of understanding the pharmacokinetics of the investigational product, samples may 
be used for metabolite identification and/or evaluation of the bioanalytical method.  These 
data will be used for internal (i.e. Sponsor) exploratory purposes and will not be included in 
the clinical study report.
7.1.3.3
Future Biomedical Research
The following specimens are to be obtained as part of Future Biomedical Research:

DNA for future research

Plasma for future biomedical research

Serum for future biomedical research


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Other Procedures
7.1.4
7.1.4.1
Withdrawal/Discontinuation
Subjects who discontinue/withdraw from treatment (see Section 5.9.1) prior to completion of 
the trial should be encouraged to continue to be followed for all remaining study visits.
When a subject discontinues/withdraws from participation in the trial, all applicable activities 
scheduled for the Discontinuation Visit should be performed at the time of discontinuation.  
Any adverse events which are present at the time of discontinuation/withdrawal should be 
followed in accordance with the safety requirements outlined in Section 7.2 - Assessing and 
Recording Adverse Events.
7.1.4.1.1 Withdrawal From Future Biomedical Research
Subjects may withdraw their consent for Future Biomedical Research and have their 
specimens and all derivatives destroyed.   Subjects may withdraw consent at any time by 
contacting the principal investigator for the main trial.  If medical records for the main trial 
are still available, the investigator will contact the Sponsor using the designated mailbox 
(
 and a form will be provided by the Sponsor to 
obtain appropriate information to complete specimen withdrawal.  Subsequently, the 
subject's specimens will be removed from the biorepository and be destroyed.  A letter will 
be sent from the Sponsor to the investigator confirming the destruction. It is the 
responsibility of the investigator to inform the subject of completion of destruction.  Any 
analyses in progress at the time of request for destruction or already performed prior to the 
request being received by the Sponsor will continue to be used as part of the overall research 
trial data and results.   No new analyses would be generated after the request is received.
In the event that the medical records for the main trial are no longer available (e.g., if the 
investigator is no longer required by regulatory authorities to retain the main trial records) or 
the specimens have been completely anonymized, there will no longer be a link between the 
subject’s personal information and their specimens.  In this situation, the request for 
specimen destruction cannot be processed.
7.1.4.2
Blinding/Unblinding
When the investigator or sub-investigator needs to identify the drug used by a subject and the 
dosage administered in case of emergency e.g., the occurrence of serious adverse 
experiences, he/she will contact the emergency unblinding call center by telephone and make 
a request for emergency unblinding.  As requested by the investigator or sub-investigator the 
emergency unblinding call center will provide the information to him/her promptly and 
report unblinding to the sponsor.  The emergency unblinding call-center will make a record 
promptly however, the investigator or sub-investigator must enter the intensity of the adverse 
experiences observed,   their relation to study drug, the reason thereof, etc., in the medical 
chart etc., before unblinding is performed.  
Additionally, the investigator must go into the IVRS system and perform the unblind in the
IVRS system to update drug disposition.  In the event that the emergency unblinding call 
center is not available for a given site in this trial, IVRS/IWRS should be used for emergency 
unblinding in the event that this is required for subject safety.
PPD


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In the event that unblinding has occurred, the circumstances around the unblinding (e.g., date 
and reason) must be documented promptly, and the Sponsor Clinical Director notified as 
soon as possible.  Only the principal investigator or delegate and the respective subject’s 
code should be unblinded.  Trial site personnel and Sponsor personnel directly associated 
with the conduct of the trial should not be unblinded.
7.1.4.3
Calibration of Critical Equipment
The investigator or qualified designee has the responsibility to ensure that any critical device
or instrument used for a clinical evaluation/test during a clinical trial that provides important 
information about inclusion/exclusion criteria and/or safety or efficacy parameters shall be 
suitably calibrated and maintained to ensure that the data obtained is reliable and/or 
reproducible.  Documentation of equipment calibration must be retained with the study 
documentation as source documentation at the trial site.
Critical Equipment for this trial includes:
Digital scale for body weight (see Section 7.1.2.3)
Visit Requirements
7.1.5
Visit requirements are outlined in Section 6.0 - Trial Flow Chart.   Specific procedure-related 
details are provided above in Section 7.1 - Trial Procedures.
7.1.5.1
Fasting Prior to Scheduled Visits
Subjects should be counseled to fast (i.e., no food, investigational product, background 
metformin therapy, or drink except water and non-AHA non-investigational product as 
prescribed) for at least 10 hours prior to all study visits.  
Subjects who do not fast before a scheduled visit will be required to return fasting for a study 
visit within three days.  
Subjects who have not fasted prior to Visit 1/Screening should obtain a fasting lipid profile 
and FPG at or prior to Visit 1A/Washout (in subjects undergoing AHA washout), or Visit 
2/Week -2 (in subjects not undergoing AHA washout) rather than Visit 1/Screening.
7.1.5.2
Scheduling Visits
At the end of each trial visit, the next trial visit should be scheduled.  Every effort should be 
made to adhere to the visit schedule (see Trial Flow Chart – Section 6.0), and in general 
visits should be scheduled within ±3 days of the designated time-point to ensure subject has 
an adequate drug supply to comply with protocol dosing instructions.  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 treatment period is as close 
as possible to 12 weeks.  Post-randomization, visits should be scheduled relative to the 
date of Visit 3/Day 1.  If a visit is scheduled at a time other than the protocol designated 
time, careful consideration must be given to the amount of investigational product the 
subject has available.
Trial sites should phone the IVRS at each of the scheduled subject visits (except Visit 
1A/Washout which is not registered in the IVRS) for purposes of enrollment tracking.


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Visit 2/Week -2 Timing: Subjects not Requiring AHA Washout (on Metformin 
Monotherapy at Screening)
For subjects who do not require AHA washout and also do not require lipid-lowering and/or 
blood pressure medication adjustments, the duration of time between Visit 1/Screening and 
Visit 2/Week -2 should be approximately 1 week.  
If a laboratory is repeated to determine eligibility, that repeat should occur as soon as 
possible after the Visit 1/Screening results are available.  The repeated result needs to be 
available before performing Visit 2/Week -2.
For subjects who do not require AHA washout but do require lipid-lowering and/or blood 
pressure medication adjustment, the duration of time between Visit 1/Screening and Visit 
2/Week -2 should be such that that the subject is on a stable regimen for at least 4 weeks 
prior to Visit 3/Day 1.
Visit 1A/Washout and Visit 2/Week -2 Timing: Subjects Requiring AHA Washout
For subjects who require AHA washout, the duration of time between Visit 1/Screening and 
Visit 1A/Washout should be approximately 1 week.  If a laboratory is repeated to determine 
eligibility, that repeat should occur as soon as possible after the Visit 1/Screening results are 
available.  The repeated result needs to be available before performing Visit 1A/Washout.
The duration of time between Visit 1A/Washout and the Visit 2/Week -2 should be at least 
8 weeks.  For these subjects, lipid-lowering/blood pressure medication initiation/adjustment 
should be made concurrently with the AHA washout if necessary.
Remaining Visit Scheduling
For Visit 3/Day 1 through Visit 10/Week 12: the treatment period begins at Visit 3/Day 1.  
All subsequent visits should be scheduled relative to Visit 3/ Day 1.
7.1.5.3
Subject Contacts
7.1.5.3.1 Adverse Event and Study Medication Compliance Telephone Contacts
Telephone contact by the investigator/qualified designee will be made at the midpoint 
between Visit 1A and Visit 2 (for subjects undergoing AHA washout), on Day -7 and at the 
midpoint between treatment visits (from Visit 3 to Visit 10) to assess for adverse events and 
compliance to study drug administration.
Section 7.1.1.8 summarizes the approach to assessment of compliance as well as addressing 
non-compliance when necessary.
7.1.5.3.2 Visit Reminders
Prior to each visit, subjects should be contacted to be reminded of:

The date and time of next appointment.

The requirement to fast for at least 10 hours prior to their visit.

The recommendation to abstain from alcohol consumption and strenuous activity for 
48 hours prior to their clinic visit.


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
The requirement not to take investigational product and background metformin at 
home the morning of their visit (non-investigational products that are not 
antihyperglycemic medications should be taken as directed by the prescribing 
physician).

The requirement to bring their investigational product, glucose meter, Hypoglycemia 
Assessment Log (HAL), and any collected SMBG information to the clinic.
7.1.5.3.3 Safety Follow-up Telephone Contacts
Subjects who discontinue study medication but agree to further contact, should be contacted 
by telephone per their normal visit schedule after the 14-Day Post Treatment Follow-Up 
Visit is performed.  Refer to Section 5.9 and Section 5.9.1.  These safety follow-up contacts 
are entered in the Safety Follow-up (SFF) eCRF.
7.1.5.4
Screening Visits
7.1.5.4.1 Visit 1/Screening
Subjects will be consented and screened according to Visit 1/Screening Inclusion/Exclusion 
Criteria and will receive a baseline screening number.  The subject’s medical history and 
concomitant medications will be reviewed, and vital signs, body weight, and height will be 
measured.  For subjects assessed as eligible to participate in the trial, fasting blood and urine 
samples will be obtained.
Review of concomitant medications, assessment of vital signs, and adverse event monitoring 
will be maintained throughout the trial.
For detailed list of Visit 1/Screening procedures refer to Trial Flow Chart (Section 6.0).
7.1.5.4.2 Visit 1A/Washout
Eligible subjects on dual therapy with metformin and a second AHA will begin an 8-week 
AHA washout period at Visit 1A/Washout and will be scheduled for Visit 2/Week -2.  
Allowable AHAs for washout are: DPP-4 inhibitors, α-glucosidase inhibitors, sulfonylureas 
and glinides. Metformin should be continued at the Visit 1/Screening dose throughout the 
trial.
Subjects’ prior/concomitant medications and adverse events will be reviewed.  All subjects 
will (1) have diet/exercise counseling, (2) receive glucose meters and training in performing 
SMBG, and (3) receive instruction on hypoglycemia symptoms, hypoglycemia management, 
and completion of the HAL.
Subjects will be instructed to monitor their fingerstick glucose concentrations with a 
frequency determined appropriate by the investigator (based upon his/her assessment of the 
subject’s glycemic control) with a minimum of two fasting determinations per week.
See sections 5.7.1 and 7.1.1.8.2 and 7.1.1.8.3 for additional information regarding 
dietary/and exercise counseling, HAL training and SMBG training, respectively.


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7.1.5.4.3 Run-in (Visit 2/Week-2)  
Subjects’ prior/concomitant medications and adverse events will be reviewed.  Vital signs,
body weight, and height will be measured and laboratory samples will be obtained.  
Note: If Visit 2/Week -2 occurs ≤2 weeks after Visit 1/Screening, it is not necessary to repeat 
A1C, hematology and chemistry panel tests at Visit 2/Week -2.  The Visit 1 results from 
these assessments may be used to satisfy entry criteria (see Section 6, Trial Flow Chart).
A full physical exam, locally read 12-lead ECG and postural blood pressure and pulse will be 
performed.
All non-washout subjects (these subjects will not have a Visit 1A) will (1) have diet/exercise 
counseling, (2) receive glucose meters and training in performing SMBG, and (3) receive 
instruction on hypoglycemia symptoms, hypoglycemia management, and completion of the 
HAL.  
All non-washout subjects will be instructed to monitor their fingerstick glucose 
concentrations with a frequency determined appropriate by the investigator (based upon 
his/her assessment of the subject’s glycemic control) with a minimum of two fasting 
determinations per week.
Subjects undergoing AHA washout (who previously received dietary counseling/glucose 
meters/SMBG training/HAL training at Visit 1A) will have SMBG measurements, and HAL 
reviewed at Visit 2/Week -2.  Appropriate die/exercise counseling will also be performed.  
See sections 5.7.1 and 7.1.1.8.2 and 7.1.1.8.3 for additional information regarding 
dietary/and exercise counseling, HAL training and SMBG training, respectively.
Subjects who meet all enrollment criteria applicable through Visit 2/Week-2 (as detailed in 
Section 5.1) will enter the 2-week, single-blind, placebo run-in period.  The placebo run-in 
may be initiated at Visit 2/Week -2 while laboratory data, including A1C, are pending, but 
randomization may not occur until all eligibility criteria are confirmed.
The first doses of single-blind placebo must be taken as witnessed doses in the clinic visit 
after completion of all Visit 2/Week -2 procedures and fasting blood samples.  Subjects will 
then be dispensed single-blind investigational product (MK-8521 180 g and MK-8521 300 
g matching placebos) and instructed to take one injection (0.1 mL) per day from each vial at 
approximately the same time of day in the morning for two weeks prior to randomization.  
Subjects should be reminded to withhold single-blind investigational product on the day of 
Visit 3/ Day 1.
7.1.5.5
Treatment Period (Visit 3 through Visit 10)
7.1.5.5.1
Randomization (Visit 3/Day 1)
At Visit 3/Day 1, subjects who meet all trial enrollment criteria (see Section 5.1) will have 
all baseline laboratory tests and trial procedures performed and will be randomized in a 
1:1:1:1 ratio to MK-8521 300 g QD, MK-8521 180 g QD, placebo QD, or open-label 
liraglutide QD.


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Each subject will be assigned only one randomization number; assignment of a 
randomization number will occur only at Visit 3/Day 1.
Investigational 
product
(double-blind
and 
open-label) 
will 
be 
dispensed 
at 
Visit 3/Randomization (Day 1).  The first dose(s) of investigational product should be 
taken as a witnessed dose after completion of all trial procedures.
7.1.5.5.2
Week 1 through Week 12: Treatment Period
Prior to each trial visit, subjects should be contacted and instructed to withhold 
investigational product and background metformin on the day of the trial visit (see Section 
7.1.5.3).  Subjects should continue to take their non-trial medications, as directed by their 
physician.
The investigational product doses must be taken sub cutaneous in the morning at 
approximately the same time each day.  If a subject misses a dose of investigational product 
during the trial, they should be instructed to take it as soon as they remember unless it is time 
for the next dose.  Subjects should be instructed not to "make up" for the missed dose by 
taking two doses at the same time.
Note:  See Section 5.2.2 for timing of dosing investigational product on the day of trial 
visits.
7.1.5.6
Follow-up Day 14: Post Treatment Visit
A clinic visit will be performed 14 days after the last dose of investigational product to 
collect specific laboratory measurements (see Trial Flow Chart, Section 6.0), SAEs, body 
weight, and vital signs (BP and HR).
7.1.5.7
Follow-up for Subjects Who Discontinue Investigational Product
Subjects who prematurely discontinue investigational product (blinded or unblinded) should 
be followed according to Section 5.9.1.
Assessing and Recording Adverse Events
7.2
An adverse event is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily 
have to have a causal relationship with this treatment. An adverse event can therefore be any 
unfavourable and unintended sign (including an abnormal laboratory finding, for example), 
symptom, or disease temporally associated with the use of a medicinal product or protocol-
specified procedure, whether or not considered related to the medicinal product or protocol-
specified procedure.  Any worsening (i.e., any clinically significant adverse change in 
frequency and/or intensity) of a preexisting condition that is temporally associated with the 
use of the Sponsor’s product, is also an adverse event.
Changes resulting from normal growth and development that do not vary significantly in 
frequency or severity from expected levels are not to be considered adverse events.  
Examples of this may include, but are not limited to, teething, typical crying in infants and 
children and onset of menses or menopause occurring at a physiologically appropriate time.


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Sponsor's product includes any pharmaceutical product, biological product, device, 
diagnostic agent or protocol-specified procedure, whether investigational (including placebo 
or active comparator medication) or marketed, manufactured by, licensed by, provided by or 
distributed by the Sponsor for human use.
Adverse events may occur during clinical trials, or as prescribed in clinical practice, from 
overdose (whether accidental or intentional), from abuse and from withdrawal.
All adverse events that occur after the consent form is signed but before treatment 
allocation/randomization must be reported by the investigator if they cause the subject to be 
excluded from the trial, or are the result of a protocol-specified intervention, including but 
not limited to washout or discontinuation of usual therapy, diet, placebo treatment or a 
procedure. From the time of treatment allocation/randomization through 14 days following 
cessation of treatment, all adverse events must be reported by the investigator. Such events 
will be recorded at each examination on the Adverse Event case report forms/worksheets.  
The reporting timeframe for adverse events meeting any serious criteria is described in 
section 7.2.3.1. The investigator will make every attempt to follow all subjects with non-
serious adverse events for outcome.
Electronic reporting procedures can be found in the Electronic Data Capture (EDC) data 
entry guidelines. Paper reporting procedures can be found in the Investigator Trial File 
Binder (or equivalent).
Definition of an Overdose for This Protocol and Reporting of Overdose to the 
7.2.1
Sponsor
In this trial, an overdose is any dose higher than the prescribed dose of MK-8521 or matching 
placebo and any dose higher than 1.8 mg/day of liraglutide.
If an adverse event(s) is associated with (“results from”) the overdose of Sponsor's product or 
vaccine, the adverse event(s) is reported as a serious adverse event, even if no other 
seriousness criteria are met.
If a dose of Sponsor's product or vaccine meeting the protocol definition of overdose is taken 
without any associated clinical symptoms or abnormal laboratory results, the overdose is 
reported as a non-serious Event of Clinical Interest (ECI), using the terminology “accidental 
or intentional overdose without adverse effect.”
All reports of overdose with and without an adverse event must be reported within 24 hours 
to the Sponsor either by electronic media or paper.  Sponsor Contact information can be 
found in the Investigator Trial File Binder (or equivalent).
Reporting of Pregnancy and Lactation to the Sponsor
7.2.2
Although pregnancy and lactation are not considered adverse events, it is the responsibility of 
investigators or their designees to report any pregnancy or lactation in a subject 
(spontaneously reported to them) that occurs during the trial.


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Pregnancies and lactations that occur after the consent form is signed but before treatment 
allocation/randomization must be reported by the investigator if they cause the subject to be 
excluded from the trial, or are the result of a protocol-specified intervention, including but 
not limited to washout or discontinuation of usual therapy, diet, placebo treatment or a 
procedure.  Pregnancies and lactations that occur from the time of treatment 
allocation/randomization through 14 days following cessation of Sponsor’s product must be 
reported by the investigator.  All reported pregnancies must be followed to the 
completion/termination of the pregnancy. Pregnancy outcomes of spontaneous abortion, 
missed abortion, benign hydatidiform mole, blighted ovum, fetal death, intrauterine death, 
miscarriage and stillbirth must be reported as serious events (Important Medical Events). If 
the pregnancy continues to term, the outcome (health of infant) must also be reported.
Such events must be reported within 24 hours to the Sponsor either by electronic media or 
paper. Electronic reporting procedures can be found in the EDC data entry guidelines. Paper 
reporting procedures can be found in the Investigator Trial File Binder (or equivalent).
Immediate Reporting of Adverse Events to the Sponsor
7.2.3
7.2.3.1
Serious Adverse Events
A serious adverse event is any adverse event occurring at any dose or during any use of 
Sponsor's product that:
●
Results in death;
●
Is life threatening;
●
Results in persistent or significant disability/incapacity;
●
Results in or prolongs an existing inpatient hospitalization;
●
Is a congenital anomaly/birth defect;
●
Is a cancer;
●
Is associated with an overdose;
●
Is an other important medical event 
Refer to Table 10 for additional details regarding each of the above criteria.
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any serious adverse event, or follow up to a serious adverse event, 
including death due to any cause, that occurs to any subject must be reported within 24 hours 
to the Sponsor if it causes the subject to be excluded from the trial, or is the result of a 
protocol-specified intervention, including but not limited to washout or discontinuation of 
usual therapy, diet, placebo treatment or a procedure.
For the time period beginning at treatment allocation/randomization through 14 days 
following cessation of treatment, any serious adverse event, or follow up to a serious adverse 
event, including death due to any cause, whether or not related to the Sponsor's product, must 
be reported within 24 hours to the Sponsor either by electronic media or paper. Electronic 
reporting procedures can be found in the EDC data entry guidelines. Paper reporting
procedures can be found in the Investigator Trial File Binder (or equivalent).
Additionally, any serious adverse event, considered by an investigator who is a qualified 
physician to be related to the Sponsor's product that is brought to the attention of the 


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investigator at any time outside of the time period specified in the previous paragraph also 
must be reported immediately to the Sponsor. 
All subjects with serious adverse events must be followed up for outcome.
7.2.3.2
Events of Clinical Interest
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI)  and must be reported to the Sponsor.
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any ECI, or follow up to an ECI, that occurs to any subject must be 
reported within 24 hours to the Sponsor if it causes the subject to be excluded from the trial, 
or is the result of a protocol-specified intervention, including but not limited to washout or 
discontinuation of usual therapy, diet, placebo treatment or a procedure.
For the time period beginning at treatment allocation/randomization through 14 days 
following cessation of treatment, any ECI, or follow up to an ECI, whether or not related to 
the Sponsor’s product, must be reported within 24 hours to the Sponsor, either by electronic 
media or paper.  Electronic reporting procedures can be found in the EDC data entry 
guidelines.  Paper reporting procedures can be found in the Investigator Trial File Binder (or 
equivalent).
Events of clinical interest for this trial include:
1. an overdose of Sponsor's product, as defined in Section 7.2.1 - Definition of an Overdose 
for This Protocol and Reporting of Overdose to the Sponsor, that is not associated with 
clinical symptoms or abnormal laboratory results. 
2. an elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of 
normal and an elevated total bilirubin lab value that is greater than or equal to 2X the 
upper limit of normal and, at the same time, an alkaline phosphatase lab value that is less 
than 2X the upper limit of normal, as determined by way of protocol-specified laboratory 
testing or unscheduled laboratory testing.*
*Note:  These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may require 
an additional evaluation for an underlying etiology.  The trial site guidance for 
assessment and follow up of these criteria can be found in the Investigator Trial File 
Binder (or equivalent).
3. Any subject meeting HR discontinuation criteria (see Section 5.9).
Evaluating Adverse Events
7.2.4
An investigator who is a qualified physician will evaluate all adverse events with respect to 
the elements outlined in Table 10. The investigator’s assessment of causality is required for 
each adverse event.  Refer to Table 10 for instructions in evaluating adverse events.


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


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


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Sponsor Responsibility for Reporting Adverse Events
7.2.5
All Adverse Events will be reported to regulatory authorities, IRB/IECs and investigators in 
accordance with all applicable global laws and regulations.
TRIAL GOVERNANCE AND OVERSIGHT
7.3
Executive Oversight Committee
7.3.1
The Executive Oversight Committee (EOC) comprises members of Sponsor Senior 
Management.  The EOC will receive and decide upon any recommendations made by the
standing internal Data Monitoring Committee (siDMC) regarding the trial.
Data Monitoring Committee
7.3.2
To supplement the routine monitoring outlined in this protocol, a separate Standing Internal 
Data Monitoring Committee (siDMC) will review any interim data that is triggered by 
prespecified safety criteria or is conducted for administrative planning purposes. The siDMC 
comprises members of Sponsor Senior Management, none of whom are directly associated 
with the conduct of this trial. The siDMC will monitor the trial at an appropriate frequency 
(see Section 8.1.4 and Section 8.2.9 - Interim Analyses) for evidence of adverse effects of 
trial treatment, as described in the detailed monitoring guidelines. In addition to the trigger
based siDMC review, an interim analysis will be performed when at least 50% of the subjects 
have either completed Week 12 or have discontinued the study. The planned interim analysis 
will be performed for the purpose of determining whether interim efficacy and safety data 
justify continuation of the study conduct (potential termination for futility), and, if study 
continuation is warranted, to consider sample size re-estimation (refer to Section 8.2.9) based 
on assessment of variance.  When an interim analysis is performed, the siDMC will review 
the data and provide guidance based on criteria detailed in the siDMC charter. The siDMC 
will determine whether the trial should continue (or other modifications, pre-specified or 
otherwise, should be made) according to the protocol, considering the overall risk and benefit 
to trial participants. The siDMC will also make recommendations to the Sponsor protocol 
team regarding steps to ensure both subject safety and the continued ethical integrity of the 
trial.
Specific details regarding responsibilities of the siDMC will be described in a separate 
charter that is reviewed and approved by the siDMC.
8.0 STATISTICAL ANALYSIS PLAN
Statistical Analysis Plan Summary
8.1
This section contains a brief summary of the statistical analyses for this trial. Full detail is in 
the Statistical Analysis Plan (SAP) (Section 8.2).
Efficacy Analysis
8.1.1
The primary and key secondary efficacy endpoints, primary analysis population, and 
statistical methods that will be employed for the efficacy analyses are presented in Table 11
below.


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Table 11  Summary of Analysis Strategy for Key Efficacy Endpoints
Endpoint
Statistical 
Method
Analysis 
Population
Missing Data 
Approach
Primary efficacy endpoint: A1C – Change 
from baseline at Week 12
cLDA
FAS
Model-based
Body Weight – Change from baseline at Week 
12
cLDA
FAS
Model-based
Fasting Plasma Glucose –
Change from 
baseline at Week 12
cLDA
FAS
Model-based
For the primary efficacy analyses, a constrained longitudinal data analysis (cLDA) method 
proposed by Liang and Zeger [22] will be used.  The cLDA model will include terms for 
treatment (4 arms), time, stratification factors of A1C (<8.5%, ≥8.5%), BMI (<30 kg/m2, ≥30 
kg/m2) and AHA washout status (Yes, No), and the interaction of time by treatment, with the 
restriction of a common baseline mean across treatment groups. An unstructured covariance 
matrix will be used to model the correlation among repeated measurements. 
The primary comparisons for efficacy endpoints are each of the MK-8521 doses versus 
placebo.  The primary population for all efficacy analyses will be the Full Analysis Set 
(FAS), comprised of all subjects who received at least one dose of trial therapy and have a 
baseline measurement or a post-randomization measurement.
Safety Analysis
8.1.2
The All-Subjects-as-Treated (ASaT) population will be used for safety analyses.  Safety and 
tolerability will be assessed following a tiered approach by clinical review of all relevant 
parameters including AEs, laboratory tests, vital signs, and ECG.  For safety endpoints 
designated as Tier 1 (adverse events of symptomatic hypoglycemia), p-values and 95% CIs 
for between-treatment differences (each of the two doses of MK-8521 versus placebo and 
versus liraglutide) will be provided.
Power and Sample Size
8.1.3
Approximately 160 subjects will be randomized in a 1:1:1:1 ratio to 300 µg dose and 180 µg
dose of MK-8521, MK-8521 placebo or liraglutide. After 12 weeks of MK-8521, a reduction 
of  0.8% in A1C and 2 kg in body weight, relative to placebo, is expected. This sample 
size will provide approximately 85% power to detect a true difference of 0.8% in the mean 
change from baseline in A1C between a MK-8521 dose and placebo at the 2-sided 0.05
significance level. The same sample size will provide approximately 87% power to detect a 
true difference of 2 kg in body weight between a MK-8521 dose and placebo. The same 
sample size will also provide approximately 88% power to detect a true difference of 30 
mg/dL in FPG. The sample size may be increased as a result of the interim analysis.  Details 
are provided in Section 8.2.9.
Interim Analysis
8.1.4
In the event of ≥5 subjects discontinuing blinded investigational product (MK-8521 or 
matching placebo) due to meeting the defined discontinuation criteria for an increase in HR, 
a review of unblinded safety data by the siDMC will be triggered.  An siDMC review may 
also be triggered for other potentially important safety signals from the blinded ongoing 


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safety results identified during medical monitoring, to be detailed in a separate siDMC 
charter.
In addition to the trigger-based safety review, an interim analysis will be performed for the 
purpose of determining whether interim efficacy and safety data justify continuation of the 
study.  If not, study termination for futility will be considered.  If the study is not terminated, 
an additional goal will be sample size re-estimation based on assessment of variance
(described in Section 8.2.9).  The results of this interim analysis will be reviewed by the 
siDMC.
The endpoints, timing, and purpose of the interim analysis are summarized in Table 14 in 
Section 8.2.9.  An unblinded statistician and programmer not associated with the day-to-day 
conduct of the study will provide unblinded information to the siDMC.  The approach to the 
interim analysis is described in more detail in Section 8.2.9.
Statistical Analysis Plan
8.2
Responsibility for Analyses/In-House Blinding
8.2.1
The statistical analysis of the data obtained from this study will be the responsibility of the 
Clinical Biostatistics department of the SPONSOR. 
This study will be conducted as a 
double-blind study under in-house blinding procedures.  At the end of the trial, the official, 
final database will be frozen and unblinded after medical/scientific review has been 
performed, protocol violators have been identified (if applicable), and data have been 
declared final and complete.
As discussed in Section 8.1.4 and Section 8.2.9, an interim analysis will be performed to 
assist in the MK-8521 development program planning (including earlier initiation of 
planning for subsequent studies of MK-8521 and/or of dual peptide back-up programs) and 
to terminate the study for futility or to adjust the sample size, as warranted. It is expected 
that most of the planned 160 subjects will have been randomized at the time of the interim 
analysis.   Blinding to treatment assignment will be maintained at all investigational sites.
Results of interim analyses will not be shared with the Investigators prior to the completion 
of the study.
Subject-level unblinding will include an internal unblinded statistician and 
scientific programmer performing the interim analysis, who will have no other 
responsibilities associated with the study. The results of this interim analysis will be 
reviewed by the siDMC.  If interim data are felt to warrant consideration of administrative 
action with regard to other aspects of the development program or if study termination is 
under consideration due to meeting futility criteria, the unblinded interim data will be 
reviewed with additional individuals with programmatic oversight.  Individuals directly 
involved with study conduct will not be unblinded until the end of the study.  
If, after the trial has begun, but prior to any unblinding, changes are made to primary 
hypotheses 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).  No 
separate Statistical Analysis Plan (SAP) will be issued for this trial.
The Clinical Biostatistics department will generate the randomized allocation schedule for 
study treatment assignment. Randomization will be implemented in an interactive voice 
response system (IVRS).


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Hypotheses
8.2.2
Objectives and hypotheses of the study are stated in Section 3.
Analysis Endpoints
8.2.3
Efficacy and safety endpoints that will be evaluated for within- and/or between-treatment 
differences are listed below.
The primary time point of the study is Week 12.
The baseline value will be defined as the Visit 3/Day 1 (Randomization) measurement. If 
this measurement is not available, the following pre-randomization measurement will be used 
as the baseline value. 
Regimen at Visit 1/Screening
Baseline value
On metformin monotherapy (no
washout)
If the Visit 3 measurement is missing, the Visit 1 
measurement will be used. If neither measurement is 
available, the baseline value will be treated as missing
On dual therapy metformin and a 
second AHA (enter washout)  
If the Visit 3 measurement is missing, the Visit 2 
measurement will be used. If neither measurement is 
available, the baseline value will be treated as missing
The mapping of relative day ranges to Week is provided in Section 12.4.
8.2.3.1
Efficacy Endpoints
Primary Endpoints:

Change from baseline in A1C at Week 12
Key Secondary Endpoints:

Change from baseline in body weight at Week 12

Change from baseline in FPG at Week 12
Other Secondary Endpoints

Change from baseline and percent change from baseline in fasting lipids (including 
LDL-cholesterol level, HDL-cholesterol level and triglyceride level) at Week 12  
Change from baseline in systolic and diastolic blood pressure at Week 12
Other Endpoints of Interest

Change from baseline in glucagon receptor activation biomarkers (including ketones, 
glucagon,  FGF-21 and kisspeptin) 

Change from baseline in fasting measures of insulin secretion (HOMA-) and insulin 
resistance (HOMA-IR), at Week 12


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8.2.3.2
Safety Endpoints
Safety and tolerability will be assessed by a clinical review of all relevant adverse 
experiences and monitoring variables related to blood chemistry, hematology, vital signs, and 
ECG.
Tier 1 safety endpoints are adverse events of symptomatic hypoglycemia (see Table 13).
Tier 2 safety endpoints include changes from baseline in HR at different time points.
Adverse events (overall summary, specific AEs, and AEs by system organ class) and PDLCs 
in laboratory and vital signs parameters (including proportion of subjects with HR>100 bpm 
or HR increase > 30 bpm) will be classified as belonging to "Tier 2" or "Tier 3", based on the 
number of events observed.
8.2.3.3
Pharmacokinetics Endpoints
CTrough will be assessed (see Section 4.2.3.3).
Analysis Populations
8.2.4
8.2.4.1
Efficacy Analysis Populations
The Full Analysis Set (FAS) population will serve as the primary population for the analysis 
of efficacy data in this study. The FAS population includes subjects who take at least one 
dose of study therapy and have at least one efficacy measurement either at baseline or during 
the treatment period. Subjects will be included in the treatment group to which they were 
randomized.  
A secondary population for analyzing primary and key secondary efficacy endpoints at Week 
12 will be the Per-Protocol (PP) population. All randomized subjects who take at least one 
dose of study medication, with a measurement at baseline and the time point of interest 
(Week 12), without the protocol deviations described below will be included in this
population.
Protocol deviations used to determine the PP population are not just a repetition of the 
exclusion and inclusion criteria in the protocol, but a clinical assessment of deviations from 
the protocol-specified criteria that will either affect or confound the measures of efficacy. 
The following rules define protocol violators during the trial period of interest (Day 1 
through Week 12) and will be used to identify such subjects prior to unblinding. Subjects 
with any of the following violations will be excluded from the PP population at all time 
points.

Drug compliance: A subject will be excluded from the PP population due to low 
compliance if either of the following applies:
o
Compliance assessed by prime therapy records provided by the investigator in 
the eCRF is <90%.
o
<75% of evaluable trough PK samples have quantifiable concentrations.  This 
criterion is applicable only to subjects in the MK-8521 and liraglutide groups.


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Additionally, a site will be deemed to have low compliance and all subjects from that 
site (including those randomized to the placebo group) will be excluded from the PP 
population if either of the following applies:
o
For sites with exactly 2 subjects randomized to active groups, both of these 
subjects have low compliance based on trough PK criterion noted above.
o
For sites with 3 or more subjects randomized to active groups, ≥50% of 
subjects have low compliance based on the trough PK criterion noted above.

Use of prohibited medications:  The list of prohibited medications can be found in 
Section 5.5.
o
If a subject
takes any prohibited antihyperglycemic medications after 
randomization (Visit 3/Day 1) for a total of ≥14 days or ≥7 consecutive days, 
he/she will be identified as a protocol violator.
o
A subject with pharmacologic doses of corticosteroid use ≥2 consecutive weeks 
after randomization will be identified as a protocol violator.

Incorrect double-blind study medications: If a subject receives incorrect double-
blind study medication for a total of ≥14 days during the trial period of interest, then 
he/she will be identified as a protocol violator.

Subjects who cannot tolerate 0.5 mL/day from Vial D: If a subject does not 
tolerate the full target dose of 0.5 mL/day MK-8521 from Vial D, he/she will be 
identified as a protocol violator. This criterion will only be applied to subjects 
randomized to the MK-8521 300 µg group. 
The final determination on protocol deviations, and thereby the composition of the PP 
population, will be made prior to the final unblinding of the database and will be 
documented.  
An additional secondary population to analyze the efficacy endpoints will be the modified 
FAS (mFAS). The modified FAS population is a subset of FAS population that excludes sites 
identified as having low compliance (as described in the drug compliance description for the 
PP population above).  
The number of subjects included in the FAS, PP and mFAS populations may vary across 
endpoints due to the degree of missing data for each endpoint. Any substantial differences 
between conclusions based on the FAS, PP population, and mFAS population will be 
investigated.  
8.2.4.2
Safety Analysis Populations
The all subjects as treated (ASaT) population will be the primary population for the analysis 
of safety data in this study.  The ASaT population consists of all randomized subjects who 
received at least one dose of study treatment. Subjects will be included in the treatment 
group corresponding to the study treatment they actually received for the analysis of safety 
data using the ASaT population. For most subjects this will be the treatment group to which 
they were randomized. Subjects who took incorrect study treatment for the entire treatment 


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period will be included in the treatment group corresponding to the study treatment they 
actually received.
Supplementary safety analyses will be performed in the modified ASaT population, which is 
the subset of the ASaT population that excludes sites identified as having low compliance (as 
described in the drug compliance description for the PP population in Section 8.2.4).
Statistical Methods
8.2.5
Statistical testing and inference methods for efficacy and safety analyses are described in 
Section 8.2.5.1 and Section 8.2.5.2, respectively.  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 8.2.6 - Multiplicity.  Nominal p-values may be computed for other 
efficacy analyses as a measure of strength of association between the endpoint and the 
treatment effect rather than formal tests of hypotheses.  All statistical tests will be conducted 
at the 2-sided 0.05 significance level.
8.2.5.1
Efficacy Analyses
To address the primary objective, the analysis of change from baseline in A1C at Week 12 
will be performed using a constrained longitudinal data analysis (cLDA) method proposed by 
Liang and Zeger.  This repeated measures model assumes a common mean across treatment 
groups at baseline and a different mean for each treatment at each of the post-baseline time 
points. The response vector consists of baseline and the values observed at each post-
baseline time point.  The cLDA model will include terms for treatment, time, stratification 
factors of A1C (<8.5%, ≥8.5%), BMI (<30 kg/m2, ≥30 kg/m2) and AHA washout status (Yes, 
No), and the interaction of time by treatment.  Time is treated as a categorical variable so that 
no restriction is imposed on the trajectory of the mean over time. 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 
Kenward-Roger adjustment will be used with restricted (or residual) maximum likelihood 
(REML) to make proper statistical inference. 
The cLDA model uses the maximum 
likelihood principle to estimate the parameters and account for missing data in an implicit 
fashion.
The primary hypothesis will be assessed by an ordered testing procedure, comparing each of
the two MK-8521 doses to placebo at Week 12, using the above cLDA model.  This testing 
procedure first tests the 300 µg dose. If a statistically significant result (i.e., p<0.05) is 
observed on the 300 µg dose, the primary hypothesis (for A1C) is considered met and then 
the 180 µg dose is tested. The secondary hypotheses (for body weight and FPG) will be 
assessed only if the primary hypothesis is met, regardless of the outcome of the 180 µg vs 
placebo comparison. 


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In the event that fewer than 75% of the subjects in the 300 µg dose group receive the full 
target dose, suggestive of dose-intolerance, the hypothesis test MK-8521 180 µg vs. placebo 
will be performed first. In this case if the 180 µg dose vs. placebo is statistically significant, 
the primary hypothesis (for A1C) will be considered met and then the 300 µg dose will be
tested.
If success is achieved in the test of the primary hypothesis (i.e., at least one dose of MK-8521 
provides significantly greater reduction in A1C relative to placebo following the testing 
procedure described above), then each of the MK-8521 doses will be compared to liraglutide 
using the same ordered testing procedure above.  Continuous efficacy endpoints such as 
FPG, body weight, LDL-cholesterol level, HDL-cholesterol level, triglyceride level, systolic 
blood pressure (SBP), and diastolic blood pressure (DBP) will be analyzed using the above 
cLDA method described for A1C.  Change and percent change from baseline in triglycerides 
will be analyzed using multiple imputation (MI) of missing values (if any) in conjunction 
with a robust regression (RREG) approach that uses M-estimation. Because the percent 
change in triglycerides typically has a skewed distribution, the cLDA model which is based 
on the symmetric normal distribution is not appropriate. 
The primary (A1C) and key secondary endpoints (FPG and body weight) will also be 
analyzed in the PP population using an ANCOVA model. The ANCOVA model will include 
treatment, stratification factors of A1C (<8.5%, ≥8.5%), BMI (<30 kg/m2, ≥30 kg/m2) and 
AHA washout status (Yes, No), and baseline value. By definition, there will be no missing 
outcome data in the PP population.
Key efficacy endpoints will also be analyzed in the mFAS population using the same 
statistical methods stated for the FAS population.
Table 12 summarizes the analysis strategy for all efficacy endpoints.  The strategy to address 
multiplicity issues with regard to multiple treatment comparisons and multiple endpoints is 
described in Section 8.2.6, Multiplicity.
Table 12  Analysis Strategy for Efficacy Endpoints
Endpoint
(All at Week 12)
Approach
Statistical 
Method
Analysis 
Population
Missing Data 
Approach
Primary
Change from baseline in A1C 
P
cLDA
FAS
Model-based
S
ANCOVA
PP
NA
S
cLDA
mFAS
Model-based
Key Secondary 
Change from baseline in FPG
P
cLDA
FAS
Model-based
S
ANCOVA
PP
NA
S
cLDA
mFAS
Model-based
Change from baseline in body weight
P
cLDA
FAS
Model-based
S
ANCOVA
PP
NA
S
cLDA
mFAS
Model-based
Other Endpoints
Change and percent change from baseline in LDL and
HDL
Change from baseline in SBP and DBP
P
cLDA
FAS
Model-based
Change and percent change from baseline in 
triglycerides
P
Robust 
Regression
FAS
Multiple 
Imputation
P=Primary; S=Secondary


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The following exploratory efficacy analyses may be performed. Analysis methods will be 
described in a separate document, as appropriate.

Insulin secretion (HOMA-β) and insulin resistance (HOMA-IR). A decision for the 
analysis will be based on potential for utility in light of emerging clinical efficacy and 
safety outcomes.

Glucagon receptor activation biomarkers (including ketones, glucagon, FGF-21 and 
kisspeptin). Analyses may be performed if the primary hypothesis is met or if the 
results are considered important for future dual peptide programs. 

If fewer than 75% of the subjects in the 300 µg dose group receive the full target 
dose, an additional analysis with pooling of subjects on 180 µg dose may be 
performed. Those subjects not tolerating the 300 µg dose and continuing on the 180 
µg dose will be pooled with the subjects in the 180 µg dose group.

The relationship between genetic variation and response to the treatments 
administered, and variation across the human genome with clinical data collected in 
this study may be analyzed.  A decision for the analysis will be based on potential for 
utility in light of emerging clinical efficacy and safety outcomes.
Due to the limited duration of analyte stability in collected PK samples, it is necessary to 
conduct PK sample analysis on a rolling basis while the study is ongoing.  Early unblinding 
limited to staff critical for the conduct of PK sample analyses will occur to allow PK analysis 
of subjects who received the drug (MK-8521) being measured. No multiplicity adjustment is 
being made since the conduct of the study is not dependent on the unblinding for early PK 
analysis. Unblinded PK data or results will not be shared with the protocol team prior to 
study completion and database lock.
8.2.5.2
Safety Analyses
The ASaT population and modified ASaT population will be employed for safety analyses.
Safety and tolerability will be assessed following a tiered approach by clinical review of all 
relevant parameters including AEs, predefined limits of change (PDLC), laboratory tests, and 
vital signs. For all comparisons described below, each of the two doses of MK-8521 will be 
compared versus placebo and versus liraglutide.
The analysis of safety parameters will follow a tiered approach.  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% CIs provided for between-group 
comparisons using the Miettinen and Nurminen method [23], an unconditional, asymptotic 
method.  Other safety parameters will be considered Tier 2 or Tier 3.  Tier 2 parameters will 
be assessed via point estimates with 95% CI provided for between-group comparisons; only 
point estimates by treatment group are provided for Tier 3 safety parameters.
Membership in Tier 2 requires that at least 4 subjects in any treatment group exhibit the event 
or meet PDLC criterion; all other AEs and PDLCs will belong to Tier 3.
The threshold of at least 4 events was chosen because the 95% CI for the between-group 
difference in percent incidence will always include zero when treatment groups of equal size 


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each have less than 4 events and thus would add little to the interpretation of potentially 
meaningful differences.  Because many 95% CIs may be provided without adjustment for 
multiplicity, the CIs should be regarded as a helpful measure to be used as a flagging 
method—to identify events of potential clinical relevance, that require additional review—
and not a formal method for assessing the statistical significance of the between-group 
differences in AEs and PDLCs.
Table 13 summarizes the analysis strategy for safety endpoints. In addition, as some of the 
subjects in the MK-8521 300 µg and liraglutide arms may not get to the full target dose, 
sensitivity analyses including only subjects with the full dose may be performed for Tier 1 
safety parameters.  
Table 13  Analysis Strategy for Safety Endpoints
Tier
Safety Endpoint
p-Value
95% CI for 
Treatment 
Comparisons
Descriptive 
Statistics
Tier 1
AE of symptomatic hypoglycemia 
X
X
X
Tier 21
Change from baseline in HR
X
X
HR >100 bpm or HR increase >30 bpm
X
X
AE summary measures
X
X
Specific AEs2, SOCs, specific confirmed CV 
SAEs, and PDLCs
X
X
Tier 3
All endpoints listed under Tier 2 (above) that 
have incidence <4 subjects in all treatment 
groups 
X
Additional 
hypoglycemia 
adverse 
event 
endpoints
X
Change 
from 
baseline 
results 
(laboratory
measurements, ECG,  and vital signs)
X
1 Non-continuous endpoints listed here will qualify for Tier 2 only if the incidence is ≥4 subjects in at least one of 
the treatment groups.
2 Among those endpoints not pre-specified as Tier 1 endpoints.
AE=Adverse Event; CI=Confidence Interval; ECG=Electrocardiogram; PDLC=Pre-Defined Limit of Change;
SAE=Serious adverse event; SOC=System Organ Class; X = results will be provided.
Analysis of Hypoglycemia
The Tier 1 analysis for hypoglycemia will include the numbers and percentages of subjects 
experiencing one or more adverse events of symptomatic hypoglycemia, regardless of 
glucose value.
The Tier 2 analysis for hypoglycemia will include the numbers and percentages of subjects 
experiencing one or more of each the following:

Adverse events of hypoglycemia (symptomatic or asymptomatic), regardless of 
biochemical documentation.

Adverse events of documented hypoglycemia, defined as adverse events of 
symptomatic hypoglycemia with a concurrent glucose measurement of <70 mg/dL 
(<3.9 mmol/L)


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
Adverse events of severe hypoglycemia, defined as adverse events of symptomatic 
hypoglycemia that required assistance, either medical or non-medical, regardless of 
whether such assistance was obtained, and regardless of biochemical documentation.  
These events will be further sub-classified as:
o
Those that required medical assistance.  Adverse events of symptomatic 
hypoglycemia that included a markedly depressed level of consciousness, loss of 
consciousness, or seizure will be classified as having required medical assistance, 
whether or not medical assistance was obtained
o
Those that did not require medical assistance (i.e., those episodes that required 
non-medical assistance to treat).
The Tier 3 summary of hypoglycemia will include the following, based on episodes 
classified by the investigator as adverse events:

The numbers and percentages of subjects 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 subject's lowest glucose 
category will be classified as unknown only if no glucose measurements are available 
for that subject.
1. any episodes (symptomatic or asymptomatic)
2. symptomatic episodes
3. asymptomatic episodes

The numbers and percentages of subjects with episodes having precipitating factors

The number of episodes per subject

The number of each of the following (summed across all subjects).  The overall 
summary will include an indication of whether precipitating factors were present.
1. all episodes (symptomatic or asymptomatic)
2. symptomatic episodes
3. asymptomatic episodes
Categorization of episodes by glucose level will be performed based on the units (mg/dL or 
mmol/L) in which the glucose measurements were reported.
A summary of subjects 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 subjects had episodes that were not classified as adverse 
events, then additional summaries may be provided for the Tier 3 endpoints above, including 
all episodes reported on the HA eCRF (i.e., not restricted to adverse events).  It is expected 
that all symptomatic hypoglycemia episodes will be classified by the investigator as adverse 
events and, thus, that any episodes that are not classified as adverse events will be 
asymptomatic episodes.


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8.2.5.3
Summaries of Baseline Characteristics, Demographics, and Other Analyses
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 subjects screened, randomized, the primar y 
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, SD, median, range and proportion will be 
provided.

Continuous baseline demographic variables: age (years), weight (kg) and height (cm)

Baseline BMI, and distribution of at baseline BMI (<25, ≥25 to <30, ≥30 to <35, ≥35
kg/m2)

Categorical baseline demographic variables: age (<65 years, ≥65 years), gender 
(male, female), and race (White, Black, Asian, American Indian or Alaska Native, 
Native 
Hawaiian 
or 
Other 
Pacific 
Islander, 
or 
Multi-Racial), 
ethnicity 
(Hispanic/Latino or not).

Baseline A1C, and distribution of A1C at baseline (<8, ≥8 to <9, ≥9%)

Baseline FPG

Time since diagnosis of diabetes mellitus (years) (<5, ≥5 to <10, ≥10 years) 

AHA washout status (Yes, No)
The above summaries will be provided for all subjects who received at least one dose of 
study therapy.
Multiplicity
8.2.6
The Type-I error rate over the multiple treatment comparisons (i.e., two MK-8521 doses 
versus placebo) for the primary hypothesis will be controlled by an ordered testing 
procedure. This testing procedure will first test the 300 µg dose. If a statistically significant 
result is observed, then the 180 µg dose will be tested and the primary hypothesis test will be 
considered successful, regardless of the outcome of the 180 µg vs. placebo. 
In the event that fewer than 75% of the subjects in the 300 µg dose group receive the full 
target dose, the first test of MK-8521 vs. placebo will be performed at the 180 µg dose.  If 
the 180 µg dose vs. placebo is statistically significant, then the primary hypothesis will be 
considered successful.
The secondary hypotheses for body weight and FPG are deemed supportive and will only be 
tested if significance is achieved at the corresponding dose level for A1C.
Comparisons involving other efficacy endpoints and other treatment comparisons (MK-8521 
doses vs. liraglutide) are considered supportive or exploratory and will be made at α=0.05 


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nominal level (two-sided) and 95% CIs will be provided. No multiplicity adjustment will be 
performed for these other comparisons.
From a safety standpoint, application of a multiplicity adjustment could potentially mask a 
safety concern.  No multiplicity adjustment is planned for safety endpoints.
An interim analysis will be performed to assist in program planning, support sample size re-
estimation, and support assessment of whether the study should be terminated based on an 
assessment of the overall data and in consideration of programmatic goals (described in 
Section 8.2.9).  This is not a pivotal trial and the trial will not be stopped early for positive 
results.  Therefore, no alpha adjustment will be made for this interim analysis.
Sample Size and Power Calculations
8.2.7
After 12 weeks of MK-8521, a reduction of 0.8% in A1C and 2 kg in body weight, relative 
to placebo, is expected.
A total of approximately 160 subjects will be randomized in a 1:1:1:1 ratio to 300 µg dose 
and 180 µg dose of MK-8521, placebo or liraglutide. A sample size of 40 subjects per arm 
will provide approximately 85% power to detect a treatment difference of 0.8% in A1C 
reduction at Week 12 (alpha=0.05, two-sided test).  The half-width of the 95% CI of A1C is 
0.52%.  This calculation is based upon the following assumptions:
1. Cumulative attrition rates at Weeks 6 and 12 are 0.08 and 0.16, respectively.
2. The conditional standard deviation is 1.1%.
3. The conditional correlation between Weeks 6 and 12 is 0.76732.
The correlation between Weeks 6 and 12 is derived based on data from MK-0431 PN020.  
The high attrition rates are used to account for dropout risks due to the requirement of taking 
2 subcutaneous injections daily and any potential AEs in this first outpatient trial of MK-
8521.  The SD is assumed to be 1.1% to account for more variability in patients with higher 
baseline A1C.  The sample size of 40 subjects will be equivalent to an effective sample size 
of 35 subjects at Week 12, which accounts for information loss due to missing data and 
correlation among repeated measures and is derived using the method proposed by Lu, et al.
[24].
The sample size of 40 subjects per arm will provide approximately 87% power to detect a 
treatment difference of 2 kg in body weight loss at Week 12.  The half-width of the 95% CI 
of body weight is 1.23 kg.  This calculation is based on the same dropout rates and 
correlation for the A1C and on the conditional standard deviation of 2.7 kg.
The sample size of 40 subjects per arm will provide approximately 88% power to detect a 
treatment difference of 30 mg/dL in FPG at Week 12.  The half-width of the 95% CI of FPG 
is 18.9 mg/dL.  This calculation is based on the same dropout rates and correlation for the 
A1C and on the conditional standard deviation of 40 mg/dL.


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Subgroup Analyses
8.2.8
To assess whether the treatment effect at Week 12 is consistent across various subgroups, the
between-group treatment effect (with a nominal 95% CI) for A1C and body weight will be 
estimated and plotted within each category of the following classification variables:

Gender (female or male)

Age (> or ≤ median)

Stratification A1C (<8.5% or 8.5%)

Stratification BMI (<30 or 30 kg/m2)

AHA washout status (Yes, No)

Prior GLP-1 (Yes or No)
The consistency of the treatment effect will be assessed in the context of the primary efficacy 
analysis model.  In the case of subgroups that are defined by terms that are in the primary 
analysis model, the term that confounds with the subgroup factor will be excluded from the 
subgroup analysis model. Treatment effects and nominal 95% CIs by category for the 
classification variables listed above will be reported as well as presented graphically.  Formal 
statistical testing of treatment-by-subgroup interactions will not be performed for other 
subgroup factors.
The treatment effect across study centers will be summarized for A1C at Week 12 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.
Interim Analyses
8.2.9
8.2.9.1
Triggered Safety Review for Discontinuation Due to HR
In the event of ≥5 subjects discontinuing blinded investigational product (MK-8521 or 
matching placebo) due to meeting the defined discontinuation criteria for an increase in HR, 
a review of unblinded safety data by a Standing Internal Data Monitoring Committee will be 
triggered.  For further details on the siDMC, see Section 7.3.2. Review criteria will be 
provided in the siDMC charter.
8.2.9.2
Planned Efficacy and Safety Review 
An interim analysis will be performed when at least 50% subjects have completed the Week 
12 Visit or discontinued prior to the Week 12 Visit, to assist in program planning, support 
sample size re-estimation, and support assessment of whether the study should be terminated 
based on an assessment of the overall data and in consideration of programmatic goals. The 
treatment-level results will be reviewed by the siDMC.  This is not a pivotal trial and the trial 
will not be stopped early for positive results. Therefore, no alpha adjustment will be made 
for this interim analysis.
If interim data are considered to warrant consideration for administrative action with regard 
to other aspects of the development program, the unblinded interim data will be reviewed 


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with additional individuals with programmatic oversight.  Individuals directly involved with  
study conduct will not be unblinded.  
For the interim efficacy analysis, the Full Analysis Set (FAS) population will be used as 
described in Section 8.2.4.1. Additional analyses based on the per-protocol population and 
the modified FAS population will be performed.
The efficacy of the MK-8521 treatment groups will be assessed using the same analysis 
approach described in Section 8.2.5.1 and the key endpoints are outlined in Table 14. Study 
termination at the interim analysis will be considered if either of the following criteria is met 
for both doses of MK-8521:

A1C futility criterion: Potentially terminate the study for futility if the lower bound 
of the 95% CI for the treatment difference (MK-8521 minus liraglutide) in change 
from baseline is above 0.

Body weight futility criterion:  Potentially terminate the study for futility if the 
posterior probability is < 5% that the true placebo-adjusted weight loss with MK-
8521 is at least 4.5 kg. 
The futility criteria will be non-binding.  If either criterion is met, the unblinded interim data 
will be reviewed with additional individuals with programmatic oversight and the decision 
to terminate or continue the study will be made based on assessment of the overall data and 
in consideration of programmatic goals.
Details including safety endpoints (AEs and change from baseline in heart rate) and review 
criteria will be provided in the siDMC charter.
Power and sample size will be re-assessed based only on the conditional standard deviation at 
the interim analysis and will be performed by the unblinded statistician. If any sites are 
identified as having low compliance as defined in Section 8.2.4, the goal of the sample size 
adjustment will be to ensure adequate power in the mFAS population. The conditional 
standard deviation for A1C and body weight will be estimated from the cLDA model in the 
mFAS population. Implementation details will be provided in the siDMC charter.
As stated in Section 8.2.7, the initial sample size (40 per arm) will provide 85% power for the 
A1C hypothesis and 87% power for the body weight hypothesis, resulting in 74% overall 
power for success in testing both hypotheses. The sample size will be increased, if necessary,
so that there is at least 80% power for each individual hypothesis for A1C and body weight, 
and at least 74% overall power for both hypotheses in the mFAS population. A conservative 
estimate of SD will be used to calculate the power and sample size. The following rules will 
be used for adjusting the sample size:

For A1C, 0.1% will be added to the point estimate of conditional SD from the interim 
data. For example, if the point estimate is 1.1%, 1.2% will be used in the sample size 
computation;

For body weight, 0.2 kg will be added to the point estimate of conditional SD from 
the interim data. For example, if the point estimate is 2.7 kg, 2.9 kg will be used in 
the sample size computation.


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If necessary, the sample size will be increased to the minimum sample size that meets the 
power criteria above, subject to a maximum of 45 subjects per arm in the mFAS population
and a total maximum of 200 subjects randomized. If the power criteria above cannot be met 
within these sample size constraints, the trial will continue using the maximum permissible
sample size under these constraints. 
Table 14  Summary of Planned Efficacy and Safety Interim Analysis Strategy
Key Endpoints for Interim Analysis
Timing of Interim Analysis
Purpose of Interim 
Analysis
Change in A1C at Week 12
Change in body weight at Week 12
Change in HR at Week 12
Key safety endpoints (including serious 
adverse events, adverse events leading to 
discontinuation)
When at least 50% of 
randomized subjects either 
complete 
Week 
12 
or 
discontinue prior to Week 
12
Program planning
Sample 
size 
re-
estimation,
Study termination for 
futility.
Compliance (Medication Adherence)
8.2.10
The computation of compliance in the ASaT population will be based on the study 
medication case report form.  
For each subject, percent compliance will be calculated using the following formula:
Compliance  =
Number of Compliant Days
× 100%.
Number of Days in the Treatment Period
A day within the Treatment period will be considered a compliant day if the subject reports 
taking the prescribed number of injections from the correct vials.
The "Number of Days in Treatment Period" is defined for each subject as the total number of 
days from the first dose of study medication to the last day of study medication. 
Summary statistics will be provided on percent compliance by treatment group.
9.0 LABELING, PACKAGING,
STORAGE AND RETURN OF CLINICAL 
SUPPLIES
Investigational Product
9.1
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of 
investigational product in accordance with the protocol and any applicable laws and 
regulations.
Clinical Supplies will be provided by the Sponsor as summarized in Table 15
Clinical supplies will be packaged to support enrollment and replacement subjects as 
required.  When a replacement subject is required, the Sponsor or designee needs to be 
contacted prior to dosing the replacement supplies.


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Table 15  Product Descriptions
Product Name & Potency
Dosage Form
MK-8521: 0.6mg/mL and matching Placebo
Sterile Solution for Injection
All other supplies not indicated in Table 15 above will be provided centrally by the Sponsor 
or locally by the trial site, subsidiary or designee, depending on local country operational or 
regulatory requirements.
For any commercially available product that is provided by the trial site, subsidiary or 
designee every attempt will be made to source these supplies from a single lot/batch number. 
The trial site will be responsible for recording the lot number, manufacturer and expiry date 
of any locally purchased product.
Packaging and Labeling Information
9.2
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements.
Subjects will receive blinded weekly kits containing 20 vials of MK-8521 or MK-8521 
Placebo for the run in and treatment phases of the study. Syringes will NOT be provided in 
the kit boxes.
Clinical Supplies Disclosure
9.3
The liraglutide arm of this trial is open-label; therefore, the subject, the trial site personnel, 
the Sponsor and/or designee are not blinded. Treatment (name, strength or potency) is 
included in the label text; random code/disclosure envelopes or lists are not provided.
The emergency unblinding call center will use the randomization schedule for the trial to 
unblind subjects and to unmask treatment identity for MK-8521 or MK-8521 placebo groups
of this trial. In the event that the emergency unblinding call center is not available for a given 
site in this trial, the central electronic randomization system (IVRS/IWRS) should be used in 
order to unblind subjects and to unmask treatment/vaccine identity. 
The Sponsor will 
provide random code/disclosure envelopes or lists to the emergency unblinding call center.
Treatment identification information is to be unmasked ONLY if necessary for the welfare of 
the subject.  Every effort should be made not to unblind the subject unless necessary. 
In the event that unblinding has occurred, the circumstances around the unblinding (e.g., date 
and reason) must be documented promptly, and the Sponsor Clinical Director notified as 
soon as possible.  Only the principal investigator or delegate and the respective subject’s 
code should be unblinded.  Trial site personnel and Sponsor personnel directly associated 
with the conduct of the trial should not be unblinded.
Storage and Handling Requirements
9.4
Clinical supplies must be stored in a secure, limited-access location under the storage 
conditions specified on the label.  
Receipt and dispensing of trial medication must be recorded by an authorized person at the 
trial site.


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Clinical supplies may not be used for any purpose other than that stated in the protocol.
Returns and Reconciliation
9.5
The investigator is responsible for keeping accurate records of the clinical supplies received 
from the Sponsor or designee, the amount dispensed to and returned by the subjects and the 
amount remaining at the conclusion of the trial. 
For all trial sites, the local country Sponsor personnel or designee will provide appropriate 
documentation that must be completed for drug accountability and return.
Standard Policies
9.6
Trial site personnel will have access to a central electronic randomization system 
(IVRS/IWRS system) to allocate subjects, to assign treatment to subjects and to manage the 
distribution of clinical supplies. Each person accessing the IVRS system must be assigned an 
individual unique PIN.  They must use only their assigned PIN to access the system, and they 
must not share their assigned PIN with anyone.
10.0 ADMINISTRATIVE AND REGULATORY DETAILS
Confidentiality
10.1
Confidentiality of Data
10.1.1
By signing this protocol, the investigator affirms to the Sponsor that information furnished to 
the investigator by the Sponsor will be maintained in confidence, and such information will 
be divulged to the institutional review board, ethics review committee (IRB/ERC) or similar 
or expert committee; affiliated institution and employees, only under an appropriate 
understanding of confidentiality with such board or committee, affiliated institution and 
employees.  Data generated by this trial will be considered confidential by the investigator, 
except to the extent that it is included in a publication as provided in the Publications section 
of this protocol.
Confidentiality of Subject Records
10.1.2
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/ERC, or regulatory authority representatives may consult and/or copy trial documents in 
order to verify worksheet/case report form data.  By signing the consent form, the subject 
agrees to this process.  If trial documents will be photocopied during the process of verifying 
worksheet/case report form information, the subject will be identified by unique code only; 
full names/initials will be masked prior to transmission to the Sponsor.
By signing this protocol, the investigator agrees to treat all subject data used and disclosed in 
connection with this trial in accordance with all applicable privacy laws, rules and 
regulations.


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Confidentiality of Investigator Information
10.1.3
By signing this protocol, the investigator recognizes that certain personal identifying 
information with respect to the investigator, and all subinvestigators and trial site personnel, 
may be used and disclosed for trial management purposes, as part of a regulatory 
submissions, and as required by law.  This information may include:
1.
name, address, telephone number and e-mail address;
2.
hospital or clinic address and telephone number;
3.
curriculum vitae or other summary of qualifications and credentials; and
4.
other professional documentation.
Consistent with the purposes described above, this information may be transmitted to the 
Sponsor, and subsidiaries, affiliates and agents of the Sponsor, in your country and other 
countries, including countries that do not have laws protecting such information.  
Additionally, the investigator’s name and business contact information may be included 
when reporting certain serious adverse events to regulatory authorities or to other 
investigators.  By signing this protocol, the investigator expressly consents to these uses and 
disclosures.
If this is a multicenter trial, in order to facilitate contact between investigators, the Sponsor 
may share an investigator’s name and contact information with other participating 
investigators upon request.
Confidentiality of IRB/IEC Information
10.1.4
The Sponsor is required to record the name and address of each IRB/IEC member that 
reviews and approves this trial.  The Sponsor is also required to document that each IRB/IEC 
meets regulatory and ICH GCP requirements by requesting and maintaining records of the 
names and qualifications of the IRB/IEC members and to make these records available for 
regulatory agency review upon request by those agencies.
Compliance with Financial Disclosure Requirements
10.2
Financial Disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54).  It is the 
Sponsor's responsibility to determine, based on these regulations, whether a request for 
Financial Disclosure information is required.  It is the investigator's/subinvestigator's 
responsibility to comply with any such request.  
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21 
CFR Part 54, to provide his/her financial interests in and/or arrangements with the Sponsor to 
allow for the submission of complete and accurate certification and disclosure statements.  
The investigator/subinvestigator(s) further agree to provide this information on a 
Certification/Disclosure Form, commonly known as a financial disclosure form, provided by 
the Sponsor or through a secure password-protected electronic portal provided by the 
Sponsor.  The investigator/subinvestigator(s) also consent to the transmission of this 
information to the Sponsor in the United States for these purposes.  This may involve the 
transmission of information to countries that do not have laws protecting personal data.


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Compliance with Law, Audit and Debarment
10.3
By signing this protocol, the investigator agrees to conduct the trial in an efficient and 
diligent manner and in conformance with this protocol; generally accepted standards of Good 
Clinical Practice (e.g., International Conference on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human Use Good Clinical Practice: 
Consolidated Guideline and other generally accepted standards of good clinical practice); and 
all applicable federal, state and local laws, rules and regulations relating to the conduct of the 
clinical trial.
The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by Merck, is provided in Section 12.1 -
Merck Code of Conduct for Clinical Trials.
The investigator also agrees to allow monitoring, audits, IRB/ERC review and regulatory 
authority inspection of trial-related documents and procedures and provide for direct access 
to all trial-related source data and documents.
The investigator agrees not to seek reimbursement from subjects, their insurance providers or 
from government programs for procedures included as part of the trial reimbursed to the 
investigator by the Sponsor.
The investigator shall prepare and maintain complete and accurate trial documentation in 
compliance with Good Clinical Practice standards and applicable federal, state and local 
laws, rules and regulations; and, for each subject participating in the trial, provide all data, 
and, upon completion or termination of the clinical trial, submit any other reports to the 
Sponsor as required by this protocol or as otherwise required pursuant to any agreement with 
the Sponsor.
Trial documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the trial site upon request for inspection, 
copying, review and audit at reasonable times by representatives of the Sponsor or any 
regulatory authorities.  The investigator agrees to promptly take any reasonable steps that are 
requested by the Sponsor as a result of an audit to cure deficiencies in the trial documentation 
and worksheets/case report forms.
The investigator must maintain copies of all documentation and records relating to the 
conduct of the trial in compliance with all applicable legal and regulatory requirements.  This 
documentation includes, but is not limited to, the protocol, worksheets/case report forms, 
advertising for subject participation, adverse event reports, subject source data, 
correspondence with regulatory authorities and IRBs/ERCs, consent forms, investigator’s 
curricula vitae, monitor visit logs, laboratory reference ranges, laboratory certification or 
quality control procedures and laboratory director curriculum vitae.  By signing this protocol, 
the investigator agrees that documentation shall be retained until at least 2 years after the last 
approval of a marketing application in an ICH region or until there are no pending or 
contemplated marketing applications in an ICH region or until at least 2 years have elapsed 
since the formal discontinuation of clinical development of the investigational product.  
Because the clinical development and marketing application process is variable, it is 
anticipated that the retention period can be up to 15 years or longer after protocol database 
lock. The Sponsor will determine the minimum retention period and notify the investigator 


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when documents may be destroyed.  The sponsor also recognizes that documents may need 
to be retained for a longer period if required by local regulatory requirements. All trial 
documents shall be made available if required by relevant regulatory authorities. The 
investigator must consult with and obtain written approval by the Sponsor prior to discarding 
trial and/or subject files.  
ICH Good Clinical Practice guidelines recommend that the investigator inform the subject’s 
primary physician about the subject’s participation in the trial if the subject has a primary 
physician and if the subject agrees to the primary physician being informed.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this trial.
Persons debarred from conducting or working on clinical trials by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s trials.  The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the trial is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
In the event the Sponsor prematurely terminates a particular trial site, the Sponsor will 
promptly notify that trial site’s IRB/IEC.
According to European legislation, a Sponsor must designate an overall coordinating 
investigator for a multi-center trial (including multinational).  When more than one trial site 
is open in an EU country, Merck, as the Sponsor, will designate, per country, a national 
principal coordinator (Protocol CI), responsible for coordinating the work of the principal 
investigators at the different trial sites in that Member State, according to national 
regulations.  For a single-center trial, the Protocol CI is the principal investigator.  In 
addition, the Sponsor must designate a principal or coordinating investigator to review the 
trial report that summarizes the trial results and confirm that, to the best of his/her 
knowledge, the report accurately describes the conduct and results of the trial [Clinical Study 
Report (CSR) CI].  The Sponsor may consider one or more factors in the selection of the 
individual to serve as the Protocol CI and or CSR CI (e.g., availability of the CI during the 
anticipated review process, thorough understanding of clinical trial methods, appropriate 
enrollment of subject cohort, timely achievement of trial milestones).  The Protocol CI must 
be a participating trial investigator.
Compliance with Trial Registration and Results Posting Requirements
10.4
Under the terms of the Food and Drug Administration Amendments Act (FDAAA) of 2007, 
and the European Medicines Agency (EMA) clinical trial Directive 2001/20/EC, the Sponsor 
of the trial is solely responsible for determining whether the trial and its results are subject to 
the requirements for submission to http://www.clinicaltrials.gov, www.clinicaltrialregister.eu
or other local registries. Merck, as Sponsor of this trial, will review this protocol and submit 
the information necessary to fulfill these requirements. Merck entries are not limited to 
FDAAA or the EMA clinical trials directive mandated trials. Information posted will allow 
subjects to identify potentially appropriate trials for their disease conditions and pursue 
participation by calling a central contact number for further information on appropriate trial 
locations and trial site contact information.   


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By signing this protocol, the investigator acknowledges that the statutory obligations under 
FDAAA, the EMA clinical trials directive or other locally mandated registries are that of the 
Sponsor and agrees not to submit any information about this trial or its results to those 
registries.
Quality Management System
10.5
By signing this protocol, the Sponsor agrees to be responsible for implementing and 
maintaining a quality management system with written development procedures and 
functional area standard operating procedures (SOPs) to ensure that trials are conducted and 
data are generated, documented, and reported in compliance with the protocol, accepted 
standards of Good Clinical Practice, and all applicable federal, state, and local laws, rules and 
regulations relating to the conduct of the clinical trial.
Data Management
10.6
The investigator or qualified designee is responsible for recording and verifying the accuracy 
of subject data.  By signing this protocol, the investigator acknowledges that his/her 
electronic signature is the legally binding equivalent of a written signature.  By entering 
his/her electronic signature, the investigator confirms that all recorded data have been 
verified as accurate.
Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
Publications
10.7
This trial is intended for publication, even if terminated prematurely. Publication may include 
any or all of the following: posting of a synopsis online, abstract and/or presentation at a 
scientific conference, or publication of a full manuscript.  The Sponsor will work with the 
authors to submit a manuscript describing trial results within 12 months after the last data 
become available, which may take up to several months after the last subject visit in some 
cases such as vaccine trials.  However, manuscript submission timelines may be extended on 
OTC trials.  For trials intended for pediatric-related regulatory filings, the investigator agrees 
to delay publication of the trial results until the Sponsor notifies the investigator that all 
relevant regulatory authority decisions on the trial drug have been made with regard to 
pediatric-related regulatory filings. Merck will post a synopsis of trial results for approved 
products on www.clinicaltrials.gov by 12 months after the last subject's last visit for the 
primary outcome, 12 months after the decision to discontinue development, or product 
marketing (dispensed, administered, delivered or promoted), whichever is later.
These timelines may be extended for products that are not yet marketed, if additional time is 
needed for analysis, to protect intellectual property, or to comply with confidentiality 
agreements with other parties.  Authors of the primary results manuscript will be provided 
the complete results from the Clinical Study Report, subject to the confidentiality agreement. 
When a manuscript is submitted to a biomedical journal, the Sponsor's policy is to also 
include the protocol and statistical analysis plan to facilitate the peer and editorial review of 
the manuscript.  If the manuscript is subsequently accepted for publication, the Sponsor will 
allow the journal, if it so desires, to post on its website the key sections of the protocol that 
are relevant to evaluating the trial, specifically those sections describing the trial objectives 


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and hypotheses, the subject inclusion and exclusion criteria, the trial design and procedures, 
the efficacy and safety measures, the statistical analysis plan, and any amendments relating to 
those sections.  The Sponsor reserves the right to redact proprietary information.
For multicenter trials, subsequent to the multicenter publication (or after public disclosure of 
the results online at www.clinicaltrials.gov if a multicenter manuscript is not planned), an 
investigator and his/her colleagues may publish their data independently.  In most cases, 
publication of individual trial site data does not add value to complete multicenter results, 
due to statistical concerns.  In rare cases, publication of single trial site data prior to the main 
paper may be of value.  Limitations of single trial site observations in a multicenter trial
should always be described in such a manuscript.
Authorship credit should be based on 1) substantial contributions to conception and design, 
or acquisition of data, or analysis and interpretation of data; 2) drafting the article or revising 
it critically for important intellectual content; and 3) final approval of the version to be 
published. Authors must meet conditions 1, 2 and 3.  Significant contributions to trial 
execution may also be taken into account to determine authorship, provided that 
contributions have also been made to all three of the preceding authorship criteria.  Although 
publication planning may begin before conducting the trial, final decisions on authorship and 
the order of authors’ names will be made based on participation and actual contributions to 
the trial and writing, as discussed above. The first author is responsible for defending the 
integrity of the data, method(s) of data analysis and the scientific content of the manuscript.
The Sponsor must have the opportunity to review all proposed abstracts, manuscripts or 
presentations regarding this trial 45 days prior to submission for publication/presentation. 
Any information identified by the Sponsor as confidential must be deleted prior to 
submission; this confidentiality does not include efficacy and safety results. Sponsor review 
can be expedited to meet publication timelines.


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11.0 LIST OF REFERENCES
1. Mokdad AH, Ford ES, Bowman BA, Dietz WH, Vinicor F, Bales VS, Marks JS.  
Prevalence of Obesity, Diabetes, and Obesity-Related Health Risk Factors, 2001.  JAMA 
2003:289:76-79.
2. Centers for Disease Control and Prevention. Prevalence of Overweight and Obesity 
Among Adults with Diagnosed Diabetes - United States, 1988-1994 and 1999-2002. 
MMWR 2004:53:1066-1068.
3. Lorenz M, Evers A, Wagner M. Recent progress and future options in the development of 
GLP-1 receptor agonists for the treatment of diabesity. Bioorg Med Chem Lett. 2013 Jul 
15;23(14):4011-8
4. Geary N. Pancreatic glucagon signals postprandial satiety. Neurosci Biobehav Rev. 1990 
Fall;14(3):323-38.
5. Habegger KM, Stemmer K, Cheng C, Müller TD, Heppner KM, Ottaway N, Holland J, 
Hembree JL, Smiley D, Gelfanov V, Krishna R, Arafat AM, Konkar A, Belli S, Kapps 
M, Woods SC, Hofmann SM, D'Alessio D, Pfluger PT, Perez-Tilve D, Seeley RJ, 
Konishi M, Itoh N, Kharitonenkov A, Spranger J, DiMarchi RD, Tschöp MH. Fibroblast 
growth factor 21 mediates specific glucagon actions. Diabetes. 2013 May;62(5):1453-63.
6. Pocai A, Carrington PE, Adams JR, Wright M, Eiermann G, Zhu L, Du X, Petrov A, 
Lassman ME, Jiang G, Liu F, Miller C, Tota LM, Zhou G, Zhang X, Sountis MM, 
Santoprete A, Capito' E, Chicchi GG, Thornberry N, Bianchi E, Pessi A, Marsh DJ, 
SinhaRoy R. Glucagon-like peptide 1/glucagon receptor dual agonism reverses obesity in 
mice. Diabetes. 2009 Oct;58(10):2258-66.
7. Tan TM, Field BC, McCullough KA, Troke RC, Chambers ES, Salem V, Gonzalez 
Maffe J, Baynes KC, De Silva A, Viardot A, Alsafi A, Frost GS, Ghatei MA, Bloom SR. 
Coadministration of glucagon-like peptide-1 during glucagon infusion in humans results 
in increased energy expenditure and amelioration of hyperglycemia. Diabetes. 2013 
Apr;62(4):1131-8.
8. Wynne K, Park AJ, Small CJ, Patterson M, Ellis SM, Murphy KG, Wren AM, Frost GS, 
Meeran K, Ghatei MA, Bloom SR. Subcutaneous oxyntomodulin reduces body weight in 
overweight and obese subjects: a double-blind, randomized, controlled trial. Diabetes. 
2005 Aug;54(8):2390-5.
9. Wynne K, Park AJ, Small CJ, Meeran K, Ghatei MA, Frost GS, Bloom SR.
Oxyntomodulin increases energy expenditure in addition to decreasing energy intake in 
overweight and obese humans: a randomised controlled trial. Int J Obes (Lond). 2006 
Dec;30(12):1729-36.
10. Degn, K, Juhl, C, Sturris, J, et al. One Week’s Treatment With Long-acting Glucagon-
like Peptide 1 Derivative Liraglutide (NN211) Markedly Improves Glycemia and α and β 
Cell Function and Reduces Endogenous Glucose release in Patients with Type 2 
Diabetes. Diabetes. 2004 May, 53: (5) 1187-1194.


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11. Moens K, Berger V, Ahn JM, Van Schravendijk C, Hruby VJ, Pipeleers D, Schuit F. 
Assessment of the role of interstitial glucagon in the acute glucose secretory 
responsiveness of in situ pancreatic beta-cells. Diabetes. 2002 Mar;51(3):669-75.
12. FDA.  FDA Briefing Document NDA 206321 (Liraglutide Injection, 3mg).  
Endocrinologic and Metabolic Drugs Advisory Committee Meeting September 11, 2014.
13. Byetta™
(exenatide) 
Injection. 
 
Product 
Circular, 
2012. 
http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/022200Orig1s000lbledt.pdf) 
http://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204061Orig1s000PharmR.pdf
14. Victoza™
(liraglutide 
[rDNA 
origin] 
injection) 
Product 
Circular, 
2013.  
http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/022341s020lbl.pdf;) 
http://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204061Orig1s000PharmR.pdf
15. Marre M, Shaw J, Brändle M, Bebakar WM, Kamaruddin NA, Strand J, Zdravkovic M, 
Le Thi TD, Colagiuri S; LEAD-1 SU study group. Liraglutide, a once-daily human GLP-
1 analogue, added to a sulphonylurea over 26 weeks produces greater improvements in 
glycaemic and weight control compared with adding rosiglitazone or placebo in subjects 
with Type 2 diabetes (LEAD-1 SU). Diabet Med 2009 Mar;26(3):268-78.
16. Nauck M, Frid A, Hermansen K, Shah NS, Tankova T, Mitha IH, Zdravkovic M, Düring 
M, Matthews DR; LEAD-2 Study Group. Efficacy and safety comparison of liraglutide, 
glimepiride, and placebo, all inmcombination with metformin, in type 2 diabetes: the 
LEAD (liraglutide effect and action in diabetes)-2 study. Diabetes Care 2009 
Jan;32(1):84-90.
17. Garber A, Henry R, Ratner R, Garcia-Hernandez PA, Rodriguez-Pattzi H, Olvera-
Alvarez I, Hale PM, Zdravkovic M, Bode B; LEAD-3 (Mono) Study Group. Liraglutide 
versus glimepiride monotherapy for type 2 diabetes (LEAD-3 Mono): a randomised, 52-
week, phase III, double-blind, parallel-treatment trial. Lancet 2009 Feb 7;373(9662):473-
81.
18. Zinman B, Gerich J, Buse JB, Lewin A, Schwartz S, Raskin P, Hale PM, Zdravkovic M, 
Blonde L; LEAD-4 Study Investigators.Efficacy and safety of the human glucagon-like 
peptide-1 analog liraglutide in combination with metformin and thiazolidinedione in 
patients with type 2 diabetes (LEAD-4 Met+TZD). Diabetes Care 2009 Jul;32(7):1224-
30.
19. Russell-Jones D, Vaag A, Schmitz O, Sethi BK, Lalic N, Antic S, Zdravkovic M, Ravn 
GM, Simó R; Liraglutide Effect and Action in Diabetes 5 (LEAD-5) met+SU Study 
Group. Liraglutide vs insulin glargine and placebo in combination with metformin and
sulfonylurea therapy in type 2 diabetes mellitus (LEAD-5 met+SU): a randomized 
controlled trial. Diabetologia 2009 Oct;52(10):2046-55.
20. Buse JB, Rosenstock J, Sesti G, Schmidt WE, Montanya E, Brett JH, Zychma M, Blonde 
L; LEAD-6 Study Group. Liraglutide once a day versus exenatide twice a day for type 2 
diabetes: a 26-week randomised, parallel-group, multinational, open-label trial (LEAD-
6). Lancet 2009 Jul 4;374(9683):39-47.
21. http://www.ema.europa.eu/humandocs/PDFs/EPAR/victoza/H-1026-PI-en.pdf


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22. Liang, K., Zeger S. Longitudinal data analysis of continuous and discrete responses for 
pre-post design. Sankhya. The Indian Journal of Statistics 2000;(Series B):134-148.
23. Miettinen OS, Nurminen M. Comparative analysis of two rates.  Stat Med 1985;4:213-26.
24. Lu K, Mehrotra DV, Liu G. Sample size determination for constrained longitudinal data 
analysis. Statistics in Medicine 2009; 28:679-699.
25. American Diabetes Association.  Executive summary: Standards of medical care in
diabetes - 2012. Diabetes Care 2012;35 (Suppl. 1):S4–S10.


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


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


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Collection and Management of Specimens for Future Biomedical Research
12.2
1. Definitions
a.
Biomarker:  A biological molecule found in blood, other body fluids, or tissues that is a 
sign of a normal or abnormal process or of a condition or disease.  A biomarker may be 
used to see how well the body responds to a treatment for a disease or condition.1
b. Pharmacogenomics:  The investigation of variations of DNA and RNA characteristics as 
related to drug/vaccine response.2
c.
Pharmacogenetics:  A subset of pharmacogenomics, pharmacogenetics is the influence of 
variations in DNA sequence on drug/vaccine response.2
d. DNA:  Deoxyribonucleic acid.
e.
RNA:  Ribonucleic acid.
2. Scope of Future Biomedical Research
The plasma, serum and leftover DNAplasma, serum and leftover DNAplasma, serum and 
leftover DNAplasma, serum and leftover DNA specimen(s) collected in the current trial 
will be used to study various causes for how subjects may respond to a drug/vaccine.  
The plasma, serum and leftover DNAplasma, serum and leftover DNA specimen(s) will 
be stored to provide a resource for future trials conducted by Merck focused on the study 
of biomarkers responsible for how a drug/vaccine enters and is removed by the body, 
how a drug/vaccine works, other pathways a drug/vaccine may interact with, or other 
aspects of disease.  The specimen(s) may be used for future assay development and/or 
drug/vaccine development.
It is now well recognized that information obtained from studying and testing clinical 
specimens offers unique opportunities to enhance our understanding of how individuals 
respond to drugs/vaccines, enhance our understanding of human disease and ultimately 
improve public health through development of novel treatments targeted to populations 
with the greatest need.  All specimens will be used by Merck or designees and research 
will be monitored and reviewed by a committee of our scientists and clinicians.
3. Summary of Procedures for Future Biomedical Research
a.
Subjects for Enrollment
All subjects enrolled in the clinical trial will be considered for enrollment in the 
Future Biomedical Research sub-trial.
b. Informed Consent
Informed consent for specimens (i.e., DNA, RNA, protein, etc.) will be obtained 
during screening for protocol enrollment from all subjects or legal guardians, at a trial 
visit by the investigator or his or her designate.  Informed consent for Future 
Biomedical Research should be presented to the subjects on Visit 1.  If delayed, 
present consent at next possible Subject Visit. Informed consent must be obtained 
prior to collection of all Future Biomedical Research specimens.  Consent forms 
signed by the subject will be kept at the clinical trial site under secure storage for 
regulatory reasons.  Information contained on the consent form alone cannot be traced 


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to any specimens, test results, or medical information once the specimens have been 
rendered de-identified.
Subjects are not required to participate in the Future Biomedical Research sub-trial in 
order to participate in the main trial. Subjects who decline to sign the Future 
Biomedical Research informed consent will not have the specimen collected nor will 
they be discontinued from the main trial.
A template of each trial site’s approved informed consent will be stored in the 
Sponsor’s clinical document repository.  Each consent will be assessed for 
appropriate specimen permissions.  
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-trial'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 subject is having blood drawn for other trial purposes. Specimens like tissue and 
bone marrow will usually be obtained at a time when the subject is having such a 
procedure for clinical purposes.
Specimens will be collected and sent to the laboratory designated for the trial where 
they will be processed (e.g., DNA or RNA extraction, etc) following the Merck 
approved policies and procedures for specimen handling and preparation.
4. Confidential Subject Information for Future Biomedical Research 
In order to optimize the research that can be conducted with Future Biomedical Research 
specimens, it is critical to link subject' clinical information with future test results. In fact 
little or no research can be conducted without connecting the clinical trial data to the 
specimen. The clinical data allow specific analyses to be conducted. Knowing subject 
characteristics like gender, age, medical history and treatment outcomes are critical to 
understanding clinical context of analytical results.
To maintain privacy of information collected from specimens obtained for Future 
Biomedical Research, Merck has developed secure policies and procedures.  All 
specimens will be de-identified as described below. 
At the clinical trial site, unique codes will be placed on the Future Biomedical Research 
specimens for transfer to the storage facility.  This first code is a random number which 
does not contain any personally identifying information embedded within it. The link (or 
key) between subject identifiers and this first unique code will be held at the trial site.  No 
personal identifiers will appear on the specimen tube.  


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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 subjects over the use of a single code.  Access to both keys would 
be needed to link any data or specimens back to the subject'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 trial 
to be associated with the specimen.  This second key will be transferred under secure 
procedures by the Merck designated facility to an Entrusted Keyholder at Merck.  The 
second code will be logged into the primary biorepository database at Merck and, in this 
database, this identifier will not have identifying demographic data or identifying clinical 
information (i.e., race, sex, age, diagnosis, lab values) associated with it. The specimen 
will be stored in a designated biorepository site with secure policies and procedures for 
specimen storage and usage.
The second key can be utilized to reconstruct the link between the results of future 
biomedical research and the clinical information, at the time of analysis.  This linkage 
would not be possible for the scientist conducting the analysis, but can only be done by 
the Merck Entrusted Keyholder under strict security policies and procedures.  The Merck 
Entrusted Keyholder will link the information and then issue a de-identified data set for 
analysis.  The only other circumstance by which future biomedical research data would 
be directly linked to the full clinical data set would be those situations mandated by 
regulatory authorities (e.g., EMEA, FDA), whereby this information would be directly 
transferred to the regulatory authority.
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 subjects.
Analyses utilizing the Future Biomedical Research specimens may be performed by 
Merck, or an additional third party (e.g., a university investigator) designated by Merck.  
The investigator conducting the analysis will be provided with double coded specimens.  
Re-association of analysis results with corresponding clinical data will only be conducted 
by the Merck Entrusted Keyholder.  Any contracted third party analyses will conform to 
the specific scope of analysis outlined in this sub-trial.  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. Withdrawal From Future Biomedical Research 
Subjects may withdraw their consent for Future Biomedical Research and have their 
specimens and all derivatives destroyed.   Subjects may withdraw consent at any time by 


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contacting the principal investigator for the main trial.  If medical records for the main 
trial are still available, the investigator will contact Merck using the designated mailbox 
(
 and a form will be provided by Merck to 
obtain appropriate information to complete specimen withdrawal.  Subsequently, the 
subject's specimens will be removed from the biorepository and be destroyed. A letter 
will be sent from Merck to the investigator confirming the destruction. It is the 
responsibility of the investigator to inform the subject of completion of destruction.  Any 
analyses in progress at the time of request for destruction or already performed prior to 
the request being received by the Sponsor will continue to be used as part of the overall 
research trial data and results. No new analyses would be generated after the request is 
received.
In the event that the medical records for the main trial are no longer available (e.g., if the 
investigator is no longer required by regulatory authorities to retain the main trial 
records) or the specimens have been completely anonymized, there will no longer be a 
link between the subject’s personal information and their specimens. In this situation, the 
request for specimen destruction can not be processed. 
7. Retention of Specimens 
Future Biomedical Research specimens will be stored in the biorepository for potential 
analysis for up to 20 years from acquisition.  Specimens may be stored for longer if a 
regulatory or governmental authority has active questions that are being answered.  In 
this special circumstance, specimens will be stored until these questions have been 
adequately addressed.
Specimens from the trial site will be shipped to a central laboratory and then shipped to 
the 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.
8. Data Security
Separate databases for specimen information and for results from the Future Biomedical 
Research sub-trial 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 trial 
administrator research personnel and/or collaborators.  Database user authentication is 
highly secure, and is accomplished using network security policies and practices based in 
international standards (e.g., ISO17799) to protect against unauthorized access.  The 
Merck Entrusted Keyholder maintains control over access to all specimen data.  These 
data are collected for future biomedical research purposes only as specified in this sub-
trial will not be used for any other purpose.
9. Reporting of Future Biomedical Research Data to Subjects
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 
the trial participant.  Some guidelines advocate a proactive return of data in certain 
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instances.  No information obtained from exploratory laboratory studies will be reported 
to the subject or family, and this information will not be entered into the clinical database 
maintained by Merck on subjects.  Principle reasons not to inform or return results to the 
subject include: lack of relevance to subject health, limitations of predictive capability, 
concerns of misinterpretation and absence of good clinical practice standards in 
exploratory research typically used for diagnostic testing.
If any exploratory results are definitively associated with clinical significance for subjects 
while the clinical trial is still ongoing, investigators will be contacted with information as 
to how to offer clinical diagnostic  testing (paid for by Merck) to subjects 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 
subject information, inform all trial sites who participated in the Merck clinical trial and 
post anonymized results on our website or other accredited website(s) that allow for 
public access (e.g., disease societies who have primary interest in the results) in order that 
physicians and patients may pursue clinical diagnostic testing if they wish to do so.
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 subjects diagnosed and treated on Merck clinical 
trials for future biomedical research.  When trials with specimens are conducted and 
subjects identified to serve as controls, every effort will be made to group specimens 
from subjects and controls to represent the ethnic and gender population representative of 
the disease under current investigation.
11. Risks Versus Benefits of Future Biomedical Research 
For future biomedical research, risks to the subject have been minimized. Risks include those 
associated with venipuncture to obtain the whole blood specimen.  This specimen will be 
obtained at the time of routine blood specimens drawn in the main trial. 
Merck has developed strict security, policies and procedures to address subject data 
privacy concerns.  Data privacy risks are largely limited to rare situations involving 
possible breach of confidentiality.  In this highly unlikely situation there is risk that the 
information, like all medical information, may be misused.
It is necessary for subject-related data (i.e., ethnicity, diagnosis, drug therapy and dosage, 
age, toxicities, etc.) to be re-associated to double coded specimens at the time of data 
analysis.  These subject data will be kept in a separate, secure Merck database, and all 
specimens will be stripped of subject 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 
subject.


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12. Self-Reported Ethnicity
Subjects who participate in future biomedical research will be asked to provide self-
reported ethnicity.  Subjects who do not wish to provide this data may still participate in 
future biomedical research.
13. Questions
Any questions related to the future biomedical research should be e-mailed directly to 
14. References
1. National Cancer Institute: http://www.cancer.gov/dictionary/?searchTxt=biomarker
2. International Conference on Harmonization: DEFINITIONS FOR GENOMIC 
BIOMARKERS, PHARMACOGENOMICS, PHARMACOGENETICS, GENOMIC 
DATA 
AND 
SAMPLE 
CODING 
CATEGORIES 
-
E15; 
http://www.ich.org/LOB/media/MEDIA3383.pdf
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Understanding the Intent, Scope and Public Health Benefits of Exploratory Biomarker Research: A Guide for 
12.3
IRBs/IECs and Investigational Site Staff


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Mapping of Relative Day Ranges to Weeks
12.4
The following will be used to map the relative day ranges to weeks, as described in 
Section 8.2.
Mapping of Relative Day Ranges to Weeks
Required Phase
Relative Day Range
Week
Day Relative to Start of Trial
—
Visit <2 and Day <1
min(Day/7†, -2)
Placebo Run-in
Visit ≥2 and Visit <3 and Day <1
-2
Placebo Run-in
Visit ≥3 and Day ≤1
0
Treatment
   2 ≤ Day ≤52
6
Treatment
   53 ≤ Day ≤73
9
Treatment
74 ≤ Day
12
†
Truncated to the largest integer less than or equal to this ratio.


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