A Single Ascending Dose Clinical Trial to Study the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of MK-7252 in Healthy Subjects
Phase: PHASE1
Conditions: Pharmacokinetics, Cancer
Sponsor: Merck Sharp & Dohme LLC

Official Protocol Title: 
NCT number: 
NCT03326986
13-Jul-2018 
Document Date: 
A Single Ascending Dose Clinical Trial to Study the Safety, 
Tolerability, Pharmacokinetics and Pharmacodynamics of 
MK-7252 in Healthy Subjects  

Product:  MK-7252 
1
Protocol/Amendment No.: 001-03 
MK-7252-001-03 Final Protocol
13-Jul-2018
Confidential
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, New Jersey, 08889-0100, U.S.A.
Protocol-specific Sponsor Contact information can be found in the Investigator Trial File 
Binder (or equivalent).
TITLE:
A Single Ascending Dose Clinical Trial to Study the Safety, Tolerability, Pharmacokinetics 
and Pharmacodynamics of MK-7252 in Healthy Subjects 
  
EudraCT NUMBER:  2017-003407-22
 
 
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TABLE OF CONTENTS
SUMMARY OF CHANGES................................................................................................ 10
1.0
TRIAL SUMMARY.................................................................................................. 12
2.0
TRIAL DESIGN........................................................................................................ 12
Trial Design ........................................................................................................... 12
2.1
Trial Diagram........................................................................................................ 13
2.2
3.0
OBJECTIVE(S) & HYPOTHESIS(ES).................................................................. 14
Primary Objective(s) & Hypothesis(es) .............................................................. 14
3.1
Secondary Objective(s) & Hypothesis(es)........................................................... 14
3.2
Exploratory Objectives......................................................................................... 15
3.3
4.0
BACKGROUND & RATIONALE.......................................................................... 15
Background ........................................................................................................... 15
4.1
Pharmaceutical and Therapeutic Background .................................................... 15
4.1.1
Pre-clinical and Clinical Trials ........................................................................... 16
4.1.2
Ongoing Clinical Trials....................................................................................... 16
4.1.3
Rationale................................................................................................................ 25
4.2
Rationale for the Trial and Selected Subject Population .................................... 25
4.2.1
Rationale for Dose Selection/Regimen/Modification ......................................... 25
4.2.2
Rationale for the Use of Placebo ................................................................. 26
4.2.2.1
Starting Dose for This Trial ......................................................................... 26
4.2.2.2
Maximum Dose/Exposure for This Trial..................................................... 27
4.2.2.3
Rationale for Dose Interval and Trial Design .............................................. 28
4.2.2.4
Rationale for Endpoints ...................................................................................... 29
4.2.3
Efficacy Endpoints....................................................................................... 29
4.2.3.1
Safety Endpoints .......................................................................................... 29
4.2.3.2
Pharmacokinetic Endpoints ......................................................................... 29
4.2.3.3
Pharmacodynamic Endpoints....................................................................... 30
4.2.3.4
Planned Exploratory Biomarker Research................................................... 30
4.2.3.5
Future Biomedical Research........................................................................ 31
4.2.3.6
 
 
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Benefit/Risk ........................................................................................................... 31
4.3
5.0
METHODOLOGY ................................................................................................... 31
Entry Criteria........................................................................................................ 31
5.1
Diagnosis/Condition for Entry into the Trial ...................................................... 31
5.1.1
Subject Inclusion Criteria.................................................................................... 31
5.1.2
Subject Exclusion Criteria .................................................................................. 32
5.1.3
Trial Treatment(s) ................................................................................................ 34
5.2
Dose Selection/Modification .............................................................................. 35
5.2.1
Dose Selection (Preparation) ....................................................................... 35
5.2.1.1
Dose Modification (Escalation) ................................................................... 35
5.2.1.2
Timing of Dose Administration .......................................................................... 35
5.2.2
Trial Blinding...................................................................................................... 36
5.2.3
Randomization or Treatment Allocation............................................................ 36
5.3
Stratification.......................................................................................................... 37
5.4
Concomitant Medications/Vaccinations (Allowed & Prohibited).................... 37
5.5
Rescue Medications & Supportive Care............................................................. 38
5.6
Diet/Activity/Other Considerations..................................................................... 38
5.7
Diet and Fruit Juice Restrictions......................................................................... 38
5.7.1
Diet............................................................................................................... 38
5.7.1.1
Fruit Juice Restrictions ................................................................................ 39
5.7.1.2
Alcohol, Caffeine, Tobacco, Activity ................................................................. 40
5.7.2
Alcohol Restrictions..................................................................................... 40
5.7.2.1
Caffeine Restrictions.................................................................................... 40
5.7.2.2
Smoking Restrictions................................................................................... 40
5.7.2.3
Activity Restrictions .................................................................................... 40
5.7.2.4
Contraception...................................................................................................... 40
5.7.3
Other: Sun Exposure........................................................................................... 40
5.7.4
Stopping rules: .................................................................................................... 41
5.7.5
Subject Withdrawal/Discontinuation Criteria................................................... 41
5.8
Discontinuation of Treatment ............................................................................. 41
5.8.1
Withdrawal from the Trial .................................................................................. 42
5.8.2
Subject Replacement Strategy............................................................................. 43
5.9
 
 
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Beginning and End of the Trial ........................................................................... 43
5.10
Clinical Criteria for Early Trial Termination ................................................... 43
5.11
6.0
TRIAL FLOW CHART ........................................................................................... 45
7.0
TRIAL PROCEDURES ........................................................................................... 53
Trial Procedures ................................................................................................... 53
7.1
Administrative Procedures.................................................................................. 53
7.1.1
Informed Consent......................................................................................... 53
7.1.1.1
7.1.1.1.1
General Informed Consent.................................................................... 53
7.1.1.1.2
Consent and Collection of Specimens for Future Biomedical
Research................................................................................................ 54
Inclusion/Exclusion Criteria ........................................................................ 54
7.1.1.2
Subject Identification Card .......................................................................... 54
7.1.1.3
Medical History ........................................................................................... 54
7.1.1.4
Prior and Concomitant Medications Review ............................................... 54
7.1.1.5
7.1.1.5.1
Prior Medications.................................................................................. 54
7.1.1.5.2
Concomitant Medications..................................................................... 54
Assignment of Screening Number............................................................... 54
7.1.1.6
Assignment of Treatment/Randomization Number ..................................... 55
7.1.1.7
Trial Compliance (Medication).................................................................... 55
7.1.1.8
Clinical Procedures/Assessments........................................................................ 55
7.1.2
Physical Examination................................................................................... 55
7.1.2.1
Targeted Neurological Examination............................................................ 55
7.1.2.2
Body Weight and Height ............................................................................. 55
7.1.2.3
Body Mass Index (BMI) .............................................................................. 55
7.1.2.4
12-Lead ECG ............................................................................................... 56
7.1.2.5
Vital Sign Measurements (Heart Rate and Blood Pressure)........................ 57
7.1.2.6
Respiratory Rate Assessment....................................................................... 57
7.1.2.7
Body Temperature ....................................................................................... 57
7.1.2.8
Taste Assessment Questionnaire.................................................................. 58
7.1.2.9
Laboratory Procedures/Assessments .................................................................. 58
7.1.3
Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis) .. 58
7.1.3.1
Pharmacokinetic/Pharmacodynamic Evaluations ........................................ 60
7.1.3.2
 
 
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Blood Collection for Plasma MK-7252 ....................................................... 60
7.1.3.3
Urine Collection for Urinary MK-7252....................................................... 60
7.1.3.4
60
7.1.3.5
Planned Genetic Analysis Sample Collection.............................................. 60
7.1.3.6
Future Biomedical Research Samples ......................................................... 60
7.1.3.7
Other Procedures................................................................................................. 61
7.1.4
Withdrawal/Discontinuation........................................................................ 61
7.1.4.1
7.1.4.1.1
Withdrawal From Future Biomedical Research ................................... 61
7.1.4.1.2
Lost to Follow-up.................................................................................. 61
Subject Blinding/Unblinding ....................................................................... 62
7.1.4.2
Domiciling ................................................................................................... 62
7.1.4.3
Calibration of Critical Equipment................................................................ 62
7.1.4.4
Visit Requirements.............................................................................................. 63
7.1.5
Screening...................................................................................................... 63
7.1.5.1
Treatment Period Visit................................................................................. 63
7.1.5.2
Critical Procedures Based on Trial Objectives: Timing of Procedure......... 63
7.1.5.3
Trial 
Design/Dosing/Procedures Modifications Permitted 
within 
7.1.5.4
Protocol Parameters ..................................................................................... 65
Assessing and Recording Adverse Events .......................................................... 67
7.2
Definition of an Overdose for This Protocol and Reporting of Overdose to 
7.2.1
the Sponsor.......................................................................................................... 68
Reporting of Pregnancy and Lactation to the Sponsor ....................................... 68
7.2.2
Immediate Reporting of Adverse Events to the Sponsor.................................... 69
7.2.3
Serious Adverse Events ............................................................................... 69
7.2.3.1
Events of Clinical Interest............................................................................ 70
7.2.3.2
Evaluating Adverse Events ................................................................................. 71
7.2.4
Sponsor Responsibility for Reporting Adverse Events ...................................... 75
7.2.5
8.0
STATISTICAL ANALYSIS PLAN ........................................................................ 75
Statistical Analysis Plan Summary ..................................................................... 75
8.1
Statistical Methods.............................................................................................. 75
8.1.1
Power .................................................................................................................. 76
8.1.2
Responsibility for Analyses/In-House Blinding ................................................. 76
8.2
 
 
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Objective(s) & Hypotheses/Estimation ............................................................... 76
8.3
Analysis Endpoints ............................................................................................... 77
8.4
Analysis Populations............................................................................................. 77
8.5
Statistical Methods................................................................................................ 78
8.6
Multiplicity ............................................................................................................ 81
8.7
Sample Size and Power Calculations .................................................................. 81
8.8
9.0
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES ................................................................................................................. 81
Investigational Product ........................................................................................ 81
9.1
Packaging and Labeling Information ................................................................. 82
9.2
Clinical Supplies Disclosure................................................................................. 82
9.3
Storage and Handling Requirements.................................................................. 82
9.4
Discard/Destruction/Returns and Reconciliation .............................................. 83
9.5
10.0
ADMINISTRATIVE AND REGULATORY DETAILS....................................... 83
Confidentiality....................................................................................................... 83
10.1
Confidentiality of Data ....................................................................................... 83
10.1.1
Confidentiality of Subject Records ..................................................................... 83
10.1.2
Confidentiality of Investigator Information........................................................ 83
10.1.3
Confidentiality of IRB/IEC Information............................................................. 84
10.1.4
Compliance with Financial Disclosure Requirements....................................... 84
10.2
Compliance with Law, Audit and Debarment ................................................... 84
10.3
Compliance with Trial Registration and Results Posting Requirements ........ 86
10.4
Quality Management System............................................................................... 87
10.5
Data Management................................................................................................. 87
10.6
Publications ........................................................................................................... 87
10.7
11.0
LIST OF REFERENCES......................................................................................... 89
12.0
APPENDICES........................................................................................................... 90
Merck Code of Conduct for Clinical Trials........................................................ 90
12.1
Collection and Management of Specimens for Future Biomedical 
12.2
Research................................................................................................................. 92
Approximate Blood Volumes Drawn/Collected by Trial Visit and by 
12.3
Sample Types......................................................................................................... 96
 
 
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Algorithm for Assessing Out-of-Range Laboratory Values ............................. 97
12.4
12-Lead Electrocardiogram Abnormality Criteria ........................................... 98
12.5
Sample Taste Questionnaire .............................................................................. 100
12.6
Targeted Neurological Examination ................................................................. 103
12.7
Criteria for Limiting Dose Escalation and /or Discontinuation of Dosing .... 104
12.8
13.0
SIGNATURES......................................................................................................... 106
Sponsor's Representative ................................................................................... 106
13.1
Investigator.......................................................................................................... 106
13.2
 
 
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LIST OF TABLES
Table 1
Suggested Dose Escalation Scheme for MK-7252................................................. 14
Table 2
Summary Pharmacokinetic Parameter Values for MK-7252 Following 
Administration of Single Oral 1 to 162 mg Doses to Healthy Fasted Subjects 
(Preliminary Results).............................................................................................. 17
Table 3
Subjects with Adverse Events (Incidence >0% in One or More Treatment 
Group) .................................................................................................................... 19
Table 4
Trial Treatment....................................................................................................... 34
Table 5
Sample Allocation Schedule .................................................................................. 37
Table 6
Contents of the Standard, High-Fat Breakfast........................................................ 39
Table 7
Laboratory Tests..................................................................................................... 59
Table 8
PK (Blood) Collection Windows (QD Dosing) ..................................................... 64
Table 9 
PK (Blood) Collection Windows (BID Dosing) .................................................... 64
Table 10 PK (Urine) Collection Windows............................................................................ 64
Table 11 Scheduled Time Collection Windows.................................................................... 65
Table 12 Evaluating Adverse Events .................................................................................... 72
Table 13 Product Descriptions .............................................................................................. 82
 
 
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LIST OF FIGURES
Figure 1
Study Diagram .................................................................................................... 13
 
 
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SUMMARY OF CHANGES
PRIMARY REASON(S) FOR THIS AMENDMENT:
Section Number (s)
Section Title(s)
Description of Change (s)
Rationale
1.0
2.1
2.2
5.2
5.3
6.0
Trial Summary
Trial Design
Trial Diagram
Trial Treatments
Randomization or Treatment 
Allocation
Trial Flow Chart
Panel C was added to the protocol. 
Upon review of the interim 
safety and preliminary PK data 
of human exposure to date (up 
to 162 mg), Panel C will be 
included to study higher 
MK-7252 doses.  
ADDITIONAL CHANGE(S) FOR THIS AMENDMENT:
Section Number (s)
Section Title (s)
Description of Change (s)
Rationale
2.2 
3.2 
4.2.3.3
5.7.1.1
7.1.5.2
7.1.5.4
8.0
Trial Diagram
Secondary Objectives and 
Hypothesis
Pharmacokinetic Endpoints
Diet
Treatment Period Visit
Trial Design/Dosing/Procedures 
Modifications Permitted within 
Protocol Parameters
Statistical Analysis Plan
Added food effect secondary 
objective and language to all 
necessary sections to support the food 
effect evaluation in Panel C.
Food effect was not evaluated in 
Panel A and B so flexible 
language has been added to 
allow for fed period in Panel C.
 
 
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Section Number (s)
Section Title (s)
Description of Change (s)
Rationale
4.2.2
4.2.3.3
6.0
Rationale for Dose 
Selection/Regimen/Modification
Pharmacokinetic Endpoints
Trial Flow Chart
Rationale provided to include a BID 
dosing option.  A separate study 
flowchart add for the BID dosing 
procedures.
The flexibility to dose BID at 
any period has been added and 
will be based on subject 
tolerability of previous period.  
The separate BID flowchart was 
added to ease operational clarity 
should the BID dosing be 
implemented.   
4.1.3
Ongoing Clinical Trials
Added PK and safety data from 
Panels A and B up to 162 mg.
This data supports Panel C 
dosing and dose selection.
4.2.2
Rationale 
for 
Dose 
Selection/Regimen/Modification
Added justification for Panel C doses.
4.2.2.3
Maximum Dose/Exposure for 
this Trial
Added PK projections for the top dose 
of 540 mg in Panel C.
4.2.2.4
Rationale for Dose Interval and 
Trial Design
Updated trial design and PK pauses 
for Panel C.
Added protocol language to 
reflect the addition of Panel C. 
5.2
Trial Treatments
Add Panel C doses.
5.3
Randomization or Treatment 
Allocation
Added Panel C Sample Allocation 
Schedule.
12.3
Approximate Blood Volumes 
Drawn/Collected by Trial Visit 
by Sample Type
Added Panel C blood volume table.
 
 
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1.0 TRIAL SUMMARY
Abbreviated Title
Single Ascending Dose Study of MK-7252 in Healthy Subjects
Sponsor Product Identifiers
MK-7252
Trial Phase
Phase I
Clinical Indication
Oncology
Trial Type
Interventional
Type of control
Placebo
Route of administration
Oral
Trial Blinding
Double-blind
Treatment Groups
Panel A: 1 mg or Placebo/ 6 mg or Placebo/ 24 mg or Placebo/ 72 mg 
or Placebo/ 108 mg or Placebo
Panel B: 3 mg or Placebo/ 12 mg or Placebo/ 48 mg or Placebo/ 72
mg or Placebo/ 162 mg or Placebo
Panel C: 120 mg or Placebo/ 240 mg or Placebo/ 360 mg or Placebo/
540 mg or Placebo/ 120 mg or Placebo fed
Number of trial subjects
Approximately 24 subjects will be enrolled.
Estimated duration of trial
The Sponsor estimates that the trial will require approximately 1 year 
and 1 month 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 approximately ~21 weeks 
in Panels A and B and ~18 weeks in Panel C from the time the subject 
signs the Informed Consent Form (ICF) through the final contact.  
After a screening phase of ~4 weeks, each subject will be receiving 
assigned treatment for approximately 11 weeks in Panels A and B and 
approximately 16 weeks in Panel C.  After the end of treatment, each 
subject will be followed for 2 weeks.
2.0 TRIAL DESIGN
Trial Design
2.1
This is a randomized, placebo-controlled, double-blind, single ascending-dose trial to 
evaluate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of MK-
7252 in healthy men and women of non-childbearing potential (WONCBP) to be conducted 
in conformance with Good Clinical Practices.
Three panels (Panels A, B and C) of up to 8 subjects each (n=6 active, n=2 placebo) will be 
dosed orally.  In Panels A and B, subjects will receive a single-rising dose in 5 alternating 
dosing periods.  In Panel C, subjects will receive a single-rising dose in or up to 5 periods. 
Subjects will be monitored for safety throughout the study by reviewing potential adverse 
experiences (AEs), laboratory safety tests, vital signs, and electrocardiogram (ECGs).
Randomization Ratio
3:1
 
 
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In all panels, the subjects and investigator will be blinded to the allocation of subjects who 
receive active or placebo in each treatment period.  Treatment will be determined based on a 
computer-generated randomized allocation schedule. Subjects will only participate in one 
panel. For each study participant, there will be a minimum of a 7-day washout between each 
period or dose administration, which will be sufficient to review safety and tolerability data 
up to 24 hr post dose, including AEs, laboratory safety test, VS and ECGs as outlined in 
Figure 1.  In Panels A and B, following administration of MK-7252 at each dose level, there 
will be at least 3 days before the administration of the next higher dose in the subsequent 
panel. 
There will be four PK pauses: (1) after Panel B in Period 2, (2) after Panel A in Period 4, (3) 
after Panel C Period 1 and (4) after Panel C Period 3, to review the interim PK data in 
addition to the ongoing review of safety data. 
Specifically, PK samples up to Panel B Period 2 will be reviewed prior to dosing Panel A 
Period 3; PK samples up to Panel A Period 4 will be reviewed prior to dosing Panel B Period 
4; PK samples up to Panel C Period 1 will be reviewed prior to dosing Panel C Period 2 and 
PK samples up to Panel C Period 3 will be reviewed prior to dosing Panel C Period 4. 
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.
Because this is a Phase I assessment of MK-7252 in humans, the pharmacokinetic, 
pharmacodynamic and safety profiles of the compound are still being elucidated. This 
protocol is therefore written with some flexibility to accommodate the inherent dynamic 
nature of Phase I clinical trials. Please refer to Section 7.1.5 – Visit Requirements for 
examples of modifications permitted within the protocol parameters.
Trial Diagram
2.2
The trial design is depicted in Figure 1 and Table 1 below.
Figure 1
Study Diagram
 
 
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Table 1
Suggested Dose Escalation Scheme for MK-7252
Panel
Period 1b
Period 2b
Period 3b
Period 4b
Period 5b
Aa
1 mg
6 mg
24 mg
72 mg
108 mg 
Ba
3 mg
12 mg
48 mg
72 mg
162 mg
Ca
120 mgc
240 mgd
360 mgd
540 mgd
120 mg (fed)c,d
a Within each treatment period, 6 subjects will be randomized to receive MK-7252 and 2 subjects to receive 
matching placebo according to a computer-generated allocation schedule.
b The suggested doses may be adjusted downward based on evaluation of safety, tolerability, PK and/or PD data 
observed in previous treatment periods.
c The assigned treatment for Panel C Periods 1 and 5 (fasted/fed) will be the same, such that the same subjects will 
receive active drug or matching placebo in both treatment periods.  Panel C Period 5 may be replaced with a 
fasting daily dose not exceeding 540 mg.
d Daily dose may be divided into two doses. See study flowcharts (for Panel C only).
The shaded area represents a PK pause after Panel B in Period 2, after Panel A in Period 4 and after Panel C in 
Period 1 and Period 3; PK samples up to Panel B Period 2 will be reviewed prior to dosing for Panel A Period 3, 
PK samples up to Panel A Period 4 will be reviewed prior to dosing Panel B Period 4, PK samples up to Panel C 
Period 1 will be reviewed prior to dosing Panel C Period 2 and PK samples up to Panel C Period 3 will be 
reviewed prior to dosing in Panel C Period 4.
3.0 OBJECTIVE(S) & HYPOTHESIS(ES)
Primary Objective(s) & Hypothesis(es)
3.1
1. Objective:  To evaluate the safety and tolerability of single ascending dose
administration of MK-7252 in healthy men and women of non-childbearing potential 
(WONCBP).
Secondary Objective(s) & Hypothesis(es)
3.2
1. Objective:  To obtain preliminary plasma PK data including area under the curve 
(AUC0-∞, AUC0-24hr, AUC0-12hr, AUClast), maximal concentration (Cmax), C12hr 
and C24hr postdose, time to reach maximal concentration (Tmax), and apparent terminal 
half-life (t½) following oral administration of single doses of MK-7252.
Hypothesis:  The geometric mean Ctrough at 12 hr postdose (C12hr) meets or exceeds 
100 nM after single dose administration of MK-7252 at a dose that is sufficiently well 
tolerated to continue development for the treatment of cancer. 
2. Objective: To evaluate hemodynamic changes of MK-7252 given as single doses on 
peripheral blood pressure (BP) (systolic and diastolic) and heart rate in healthy men and 
WONCBP.
3. Objective (Panel C only): To compare the effects of a high-fat breakfast on the plasma 
PK of MK-7252 to those in the fasted state after administration of a single oral dose of 
MK-7252 in healthy men and WONCBP.  
 
 
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Estimation:  The plasma AUC0-∞, AUC0-12hr and Cmax resulting from a single oral 
dose of MK-7252 following a standard breakfast will be estimated and compared to that 
observed with the identical dose level administered in the fasted state.
Exploratory Objectives
3.3
1.
 
 
  
2. Objective:
To
explore urinary excretion of MK-7252 following single dose 
administration in in healthy men and WONCBP.
3. Objective: To explore the relationship between genetic variation and response to the 
treatment administered, and mechanisms of disease.  Variation across the human genome 
may be analyzed for association with clinical data collected in this study.
4.0 BACKGROUND & RATIONALE
Background
4.1
Refer to the Investigator’s Brochure (IB) for detailed background information on MK-7252.
Pharmaceutical and Therapeutic Background
4.1.1
MK-7252 is a potent, selective small molecule antagonist of the human adenosine receptor 
subtype 2A (A2a). 
 
 
 
  
 
Although immunotherapies (including Keytruda) have been shown to be efficacious in 
treating multiple malignancies, evidence suggests that malignant cells are able to utilize 
multiple pathways to achieve immune escape, contributing to the lack of response or 
resistance to T cell immune checkpoint inhibitors. Along with IDO, arginase, TGFβ, etc., 
adenosine and its receptors represent a key pathway contributing to the immune suppressive 
environment in tumors, allowing tumors to escape from immune responses [1].
Adenosine is an important natural mediator of immune suppression to avoid collateral tissue 
damage during inflammatory conditions such as infection and wound healing [2].  Under 
normal physiologic conditions, extracellular release of adenosine is balanced by rapid 
cellular uptake thus maintained at very low levels.  In contrast, in a tumor microenvironment, 
aberrant cancer cell growth and hypoxic conditions produce and actively sustain high levels 
of adenosine levels and extracellular adenosine triphosphate (ATP) [3]. Therefore, an 
adenosine rich tumor microenvironment (the “adenosine halo”) represents a major barrier for 
effective tumor immunotherapy and needs to be overcome to achieve more effective and 
broader clinical efficacy.
 
 
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Adenosine signaling through A2a receptors expressed on a variety of immune cell subsets 
and endothelial cells has been established as the major pathway in suppressing T cell-
mediated cytotoxic activity, proliferation, activation and priming [4].   Levels of extracellular 
adenosine are also increased by the catabolism of extracellular ATP and adenosine 
diphosphate by the tandem activity of the ectonucleotidases CD-39 and CD-73.  One of the 
signature features of the solid tumor environment is hypoxia.  In response to hypoxia-induced 
HIF-1 generation in tumors and inflamed tissues, CD-39 and CD-73 are up regulated on 
endothelial, stromal and some solid tumor cells, and on several subsets of immune cells 
(including Tregs, CD-8+ T cells, and B cells) [5]. Adenosine/A2aR signaling on endothelial 
cells upregulates vascular endothelia growth factor (VEGF) production and leads to 
angiogenesis which directly promotes cancer cell proliferation and tumor metastasis. 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
Pre-clinical and Clinical Trials
4.1.2
Refer to the IB for detailed pre-clinical information on MK-7252.  As this is the First-in-
Human (FIH) study for MK-7252, there is no clinical trial information related to this 
molecule besides the initial doses given described in section 4.1.3.  Clinical experiences with 
other A2a Receptor antagonists are summarized in the IB.
Ongoing Clinical Trials
4.1.3
In the current single ascending dose study (Protocol 001), the preliminary plasma exposure of 
MK-7252 was reviewed, along with safety and tolerability data.  The interim PK analysis 
after oral administration of 1, 3, 6, 12, 24, 48, 72, 108 and 162 mg single doses (shown in
Table 2), demonstrated that MK-7252 was rapidly absorbed with a median Tmax of 0.75-1.0 
hours.  Concentrations declined in a monophasic pattern at lower doses but appear to be 
exhibiting a biphasic decline at the 162 mg dose.  The apparent terminal half-life could not 
be calculated following the 1 mg and 3 mg doses due to insufficient terminal phase data.  
 
 
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However, the geometric mean t½ ranged from 1.29 to 5.97 hours following the 6 mg to 162 
mg doses.  All C24hr samples were below the limit of quantitation (BLQ) following 1 to 72 
mg doses.  The geometric C24hr at 108 and 162 mg was 3.91 and 9.69 nM, respectively and 
geometric C12hr at 108 mg and 162 mg was 26.1 and 28,2 nM, respectively.   Exposure 
increases were approximately dose proportional.
Table 2
Summary 
Pharmacokinetic 
Parameter 
Values 
for 
MK-7252 
Following 
Administration of Single Oral 1 to 162 mg Doses to Healthy Fasted Subjects 
(Preliminary Results)
Dose 
(mg)
Tmax1 
(hr)
Cmax2
(nM)
AUC0-122
(nM*hr)
AUC0-242
(nM*hr)
t1/22
(hr)
AUC0-
inf2
(nM*hr)
C122
(nM)
C242
(nM)
1
1.0 
(0.5-1.0)
20.8 
(29.7)
48.4
(45.6)
48.4
(45.6)
--3
--3
--4
--4
3
0.75
(0.5-1.0)
50.2
(38.9)
113
(58.8)
113
(58.8)
--3
--3
--4
--4
6
0.75
(0.5-1.0)
120
(37.6)
275
(40.4)
275
(40.4)
1.29
(12.2)
273
(47.3)
--4
--4
12
1.0
(0.5-1.0)
213
(75.7)
541
(83.0)
541
(83.0)
1.34
(15.0)
723
(20.5)
--4
--4
24
1.0
(0.5-1.0)
474
(39.1)
1250
(37.9)
1260
(38.6)
1.60
(19.9)
1260
(37.9)
2.73
(60.9)
5
--4
48
0.75
(0.5-1.0)
742
(69.1)
1830
(72.7)
1840
(73.5)
1.35
(9.93)
1840
(72.7)
--6
--4
72
Panel 
A/B 
Combined
1.0
(0.5-2.0)
1690
(39.9)
4450
(47.2)
4510
(47.3)
1.67
(41.8)
4480
(47.1)
10.1
(78.5)
--4
108
0.75
(0.5-1.0)
2430
(30.4)
6800
(35.8)
7030
(36.7)
3.09
(81.1)
7080
(37.6)
26.1
(132)
3.91
(239)
5
162
0.75
(0.5-1.0)
3020
(58.5)
8350
(79.8)
8620
(80.0)
5.97
(92.2)
8870
(76.6)
28.2
(138)
9.69
(209)
5
1median (min-max);
2geometric mean (%CVGM)
3insufficient data to report;
4all values were BLQ (2.74nM);
5BLQ values replaced with 1/2 LLOQ (1.37nM) to enable GM calculation
6greater than half of the values were BLQ;
 
 
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MK-7252-001 Preliminary Safety and Tolerability
Preliminary interim safety summary revealed that single oral administration of 1, 3, 6, 12, 24, 
48, 72, 108 and 162 mg doses of MK-7252 or placebo was generally well tolerated. 
Orthostatic tachycardia was noted following the 12 mg and 48 mg doses, which was 
considered to be not drug-related at the time. However, palpitations noted following the 
24 mg and 72 mg doses was considered drug-related at the time. Moreover, modest transient 
increases in systolic blood pressure (5-20 mmHg), diastolic blood pressure (5-12 mmHg),
and increases in heart rate (<10 bpm) have been observed at doses up to 162 mg.  Of note, 
one subject at the 72 mg dose, showed across a 2-hr interval, a mean increase in systolic 
blood pressure of 33 mmHg (semi-recumbent), and a mean increase in heart rate of 49 bpm
(semi-recumbent). There were modest elevations of the diastolic BP (mean semi-recumbent 
DBP increase of 12 mmHg).  This subject reported dizziness upon standing at 4 hr post-dose,
but otherwise reported no other symptoms.  Based on these observations, the subject was 
discontinued and the 72 mg dose was repeated in the next dosing period.  Moreover, upon 
review of the safety and tolerability data to date, hemodynamic stopping criteria was added 
(Appendix 12.8) and modification to the original dose escalation plan in Period 5 was made. 
There were no additional subjects with systolic blood pressure increases of >30 mmHg 
and/or HR increase of >30 bpm in the repeated 72 mg dose panel, or at the 108 mg and 
162 mg dose. Thus no additional subjects were discontinued.  No other clinically significant 
abnormalities were noted in routine blood chemistry, ECG, vital signs, physical exam, and 
laboratory adverse experiences. There have been no serious adverse events (AEs). Most AEs 
have been categorized as either mild to moderate intensity, with exception of one AE 
(headache) categorized as severe. Based on the blinded review of AEs, there were no dose-
related increases in the frequency of AEs. Adverse experiences reported to date (April 30, 
2018) are provided in Table 3.
 
 
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Table 3
Subjects with Adverse Events (Incidence >0% in One or More Treatment Group)
  
MK-7252 1 mg / 
PBO
MK-7252 3 mg / 
PBO   
MK-7252 6 mg / 
PBO    
MK-7252 12 mg 
/ PBO  
MK-7252 24 mg 
/ PBO  
MK-7252 48 mg 
/ PBO  
MK-7252 72 mg 
/ PBO  
  
n 
(%)
n 
(%)
n 
(%)
n 
(%)
n 
(%)
n 
(%)
n 
(%)
Subjects in population
8
8
8
8
8
8
16
   With one or more adverse  events              
3
(37.5)
6
(75.0)
5
(62.5)
7
(87.5)
6
(75.0)
6
(75.0)
10
(62.5)
   With no adverse events                               
5
(62.5)
2
(25.0)
3
(37.5)
1
(12.5)
2
(25.0)
2
(25.0)
6
(37.5)
Cardiac disorders
0
(0.0)
0
(0.0)
0
(0.0)
1
(12.5)
1
(12.5)
2
(25.0)
2
(12.5)
   Heart rate increased
0
(0.0)
0
(0.0)
0
(0.0)
0
(0.0)
0
(0.0)
0
(0.0)
0
(0.0)
   Palpitations
0
(0.0)
0
(0.0)
0
(0.0)
0
(0.0)
1
(12.5)
0
(0.0)
2
(12.5)
   Postural orthostatic tachycardia    
syndrome
0
(0.0)
0
(0.0)
0
(0.0)
1
(12.5)
0
(0.0)
2
(25.0)
0
(0.0)
Ear and labyrinth disorders                       
0
(0.0)
0
(0.0)
1
(12.5)
0
(0.0)
0
(0.0)
0
(0.0)
0
(0.0)
   Cerumen impaction
0
(0.0)
0
(0.0)
1
(12.5)
0
(0.0)
0
(0.0)
0
(0.0)
0
(0.0)
Eye disorders
0
(0.0)
1
(12.5)
0
(0.0)
1
(12.5)
0
(0.0)
0
(0.0)
1
(6.3)
   Eye irritation
0
(0.0)
0
(0.0)
0
(0.0)
0
(0.0)
0
(0.0)
0
(0.0)
1
(6.3)
   Photophobia
0
(0.0)
1
(12.5)
0
(0.0)
1
(12.5)
0
(0.0)
0
(0.0)
0
(0.0)
   Visual field defect
0
(0.0)
0
(0.0)
0
(0.0)
1
(12.5)
0
(0.0)
0
(0.0)
0
(0.0)
Gastrointestinal disorders                           
1
(12.5)
1
(12.5)
1
(12.5)
3
(37.5)
1
(12.5)
1
(12.5)
0
(0.0)
   Abdominal discomfort
1
(12.5)
0
(0.0)
0
(0.0)
0
(0.0)
0
(0.0)
0
(0.0)
0
(0.0)
   Abdominal pain
0
(0.0)
0
(0.0)
0
(0.0)
0
(0.0)
0
(0.0)
1
(12.5)
0
(0.0)
   Diarrhoea
1
(12.5)
0
(0.0)
1
(12.5)
0
(0.0)
0
(0.0)
0
(0.0)
0
(0.0)
   Epigastric discomfort
0
(0.0)
0
(0.0)
0
(0.0)
0
(0.0)
0
(0.0)
0
(0.0)
0
(0.0)
   Nausea                                                        
0
(0.0)
1
(12.5)
0
(0.0)
3
(37.5)
1
(12.5)
0
(0.0)
0
(0.0)
   Vomiting
0
(0.0)
1
(12.5)
0
(0.0)
0
(0.0)
0
(0.0)
0
(0.0)
0
(0.0)
General Disorders And Administration 
Site Conditions                       
1
(12.5)
1
(12.5)
0
(0.0)
1
(12.5)
1
(12.5)
3
(37.5)
4
(25.0)
   Catheter site hematoma
0
(0.0)
1
(12.5)
0
(0.0)
0
(0.0)
0
(0.0)
0
(0.0)
0
(0.0)
   Catheter site pain
0
(0.0)
0
(0.0)
0
(0.0)
1
(12.5)
0
(0.0)
0
(0.0)
0
(0.0)
   Chest discomfort
0
(0.0)
0
(0.0)
0
(0.0)
0
(0.0)
0
(0.0)
1
(12.5)
0
(0.0)
   Dermatitis contact
0
(0.0)
1
(12.5)
0
(0.0)
0
(0.0)
0
(0.0)
1
(12.5)
0
(0.0)
   Fatigue                                                        
1
(12.5)
0
(0.0)
0
(0.0)
0
(0.0)
0
(0.0)
0
(0.0)
1
(6.3)
   Feeling of body temperature change
0
(0.0)
0
(0.0)
0
(0.0)
0
(0.0)
1
(12.5)
2
(25.0)
1
(6.3)
   Pain in extremity 
0
(0.0)
0
(0.0)
0
(0.0)
0
(0.0)
0
(0.0)
0
(0.0)
2
(12.5)
 
 
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MK-7252 108 mg 
/ PBO
MK-7252 162 
mg / PBO   
Total 
  
n 
(%)
n 
(%)
n 
(%)
Subjects in population
8
8
16
   With one or more adverse  events              
6
(75.0)
5
(62.5)
16
(100.0)
   With no adverse events                               
2
(25.0)
3
(37.5)
0
(0.0)
Cardiac disorders
0
(0.0)
0
(0.0)
4
(25.0)
   Heart rate increased
0
(0.0)
1
(12.5)
1
(6.3)
   Palpitations
0
(0.0)
0
(0.0)
3
(18.8)
   Postural 
orthostatic 
tachycardia 
syndrome
0
(0.0)
0
(0.0)
2
(12.5)
Ear and labyrinth disorders                       
0
(0.0)
0
(0.0)
1
(6.3)
   Cerumen impaction
0
(0.0)
0
(0.0)
1
(6.3)
Eye disorders
0
(0.0)
0
(0.0)
3
(18.8)
   Eye irritation
0
(0.0)
0
(0.0)
1
(6.3)
   Photophobia
0
(0.0)
0
(0.0)
2
(12.5)
   Visual field defect
0
(0.0)
0
(0.0)
1
(6.3)
Gastrointestinal disorders                           
0
(0.0)
2
(25.0)
7
(43.8)
   Abdominal discomfort
0
(0.0)
0
(0.0)
1
(6.3)
   Abdominal pain
0
(0.0)
0
(0.0)
1
(6.3)
   Diarrhoea
0
(0.0)
0
(0.0)
2
(12.5)
   Epigastric discomfort
0
(0.0)
1
(12.5)
1
(6.3)
   Nausea                                                        
0
(0.0)
0
(0.0)
5
(31.3)
   Vomiting
0
(0.0)
1
(12.5)
1
(6.3)
General Disorders And Administration 
Site Conditions                       
3
(37.5)
1
(12.5)
10
(62.5)
   Catheter site hematoma
0
(0.0)
0
(0.0)
1
(6.3)
   Catheter site pain
0
(0.0)
0
(0.0)
1
(6.3)
   Chest discomfort
0
(0.0)
0
(0.0)
1
(6.3)
   Dermatitis contact
3
(37.5)
0
(0.0)
5
(31.3)
   Fatigue                                                        
0
(0.0)
1
(12.5)
2
(12.5)
   Feeling of body temperature change
0
(0.0)
0
(0.0)
3
(18.8)
   Pain in extremity 
0
(0.0)
0
(0.0)
2
(12.5)
 
 
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MK-7252 1 mg / 
PBO
MK-7252 3 mg / 
PBO   
MK-7252 6 mg / 
PBO    
MK-7252 12 mg 
/ PBO  
MK-7252 24 mg 
/ PBO  
MK-7252 48 mg 
/ PBO  
MK-7252 72 mg / 
PBO  
  
n 
(%)
n 
(%)
n 
(%)
n 
(%)
n 
(%)
n 
(%)
n 
(%)
Infections And Infestations                         
0
(0.0)
0
(0.0)
1
(12.5)
0
(0.0)
0
(0.0)
1
(12.5)
2
(12.5)
   Cystitis                                                        
0
(0.0)
0
(0.0)
1
(12.5)
0
(0.0)
0
(0.0)
0
(0.0)
0
(0.0)
   Nasopharyngitis
0
(0.0)
0
(0.0)
0
(0.0)
0
(0.0)
0
(0.0)
1
(12.5)
0
(0.0)
   Oral herpes
0
(0.0)
0
(0.0)
0
(0.0)
0
(0.0)
0
(0.0)
0
(0.0)
1
(6.3)
   Sinusitis
0
(0.0)
0
(0.0)
0
(0.0)
0
(0.0)
0
(0.0)
0
(0.0)
1
(6.3)
   Vulvovaginitis
0
(0.0)
0
(0.0)
1
(12.5)
0
(0.0)
0
(0.0)
0
(0.0)
0
(0.0)
Injury, poisoning and procedural 
complications
0
(0.0)
0
(0.0)
0
(0.0)
0
(0.0)
0
(0.0)
0
(0.0)
1
(6.3)
   Ligament sprain
0
(0.0)
0
(0.0)
0
(0.0)
0
(0.0)
0
(0.0)
0
(0.0)
1
(6.3)
Musculoskeletal and connective tissue 
disorders
0
(0.0)
1
(12.5)
1
(12.5)
1
(12.5)
1
(12.5)
2
(25.0)
7
(43.8)
   Arthralgia
0
(0.0)
0
(0.0)
0
(0.0)
0
(0.0)
0
(0.0)
1
(12.5)
0
(0.0)
   Back pain
0
(0.0)
1
(12.5)
0
(0.0)
0
(0.0)
0
(0.0)
0
(0.0)
2
(12.5)
   Muscle contusion
0
(0.0)
0
(0.0)
1
(12.5)
0
(0.0)
0
(0.0)
0
(0.0)
0
(0.0)
   Muscle spasms
0
(0.0)
0
(0.0)
0
(0.0)
0
(0.0)
1
(12.5)
0
(0.0)
2
(12.5)
   Muscle twitching
0
(0.0)
0
(0.0)
0
(0.0)
0
(0.0)
0
(0.0)
0
(0.0)
1
(6.3)
   Musculoskeletal pain
0
(0.0)
0
(0.0)
0
(0.0)
1
(12.5)
0
(0.0)
0
(0.0)
2
(12.5)
   Musculoskeletal stiffness
0
(0.0)
0
(0.0)
0
(0.0)
0
(0.0)
0
(0.0)
0
(0.0)
1
(6.3)
   Myofascial pain syndrome
0
(0.0)
0
(0.0)
0
(0.0)
0
(0.0)
0
(0.0)
0
(0.0)
1
(6.3)
   Neck pain
0
(0.0)
0
(0.0)
0
(0.0)
0
(0.0)
0
(0.0)
1
(12.5)
1
(6.3)
   Trismus
0
(0.0)
0
(0.0)
0
(0.0)
0
(0.0)
0
(0.0)
0
(0.0)
1
(6.3)
Nervous system disorders
1
(12.5)
5
(62.5)
3
(37.5)
7
(87.5)
2
(25.0)
1
(12.5)
1
(6.3)
   Dizziness
0
(0.0)
0
(0.0)
1
(12.5)
2
(25.0)
0
(0.0)
1
(12.5)
0
(0.0)
   Dizziness postural
0
(0.0)
0
(0.0)
0
(0.0)
0
(0.0)
0
(0.0)
0
(0.0)
1
(6.3)
   Dysgeusia
0
(0.0)
0
(0.0)
0
(0.0)
1
(12.5)
0
(0.0)
0
(0.0)
0
(0.0)
   Headache
1
(12.5)
4
(50.0)
3
(37.5)
3
(37.5)
2
(25.0)
0
(0.0)
1
(6.3)
   Paresthesia
0
(0.0)
0
(0.0)
0
(0.0)
0
(0.0)
0
(0.0)
0
(0.0)
1
(6.3)
   Presyncope
0
(0.0)
1
(12.5)
0
(0.0)
1
(12.5)
0
(0.0)
0
(0.0)
0
(0.0)
   Sensory loss
0
(0.0)
0
(0.0)
0
(0.0)
1
(12.5)
0
(0.0)
0
(0.0)
0
(0.0)
Psychiatric disorders
0
(0.0)
0
(0.0)
0
(0.0)
0
(0.0)
0
(0.0)
0
(0.0)
0
(0.0)
   Irritability
0
(0.0)
0
(0.0)
0
(0.0)
0
(0.0)
0
(0.0)
0
(0.0)
0
(0.0)
 
 
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MK-7252 108 mg 
/ PBO
MK-7252 162 
mg / PBO   
Total 
  
n 
(%)
n 
(%)
n 
(%)
Infections And Infestations                         
0
(0.0)
0
(0.0)
4
(25.0)
   Cystitis                                                        
0
(0.0)
0
(0.0)
1
(6.3)
   Nasopharyngitis
0
(0.0)
0
(0.0)
1
(6.3)
   Oral herpes
0
(0.0)
0
(0.0)
1
(6.3)
   Sinusitis
0
(0.0)
0
(0.0)
1
(6.3)
   Vulvovaginitis
0
(0.0)
0
(0.0)
1
(6.3)
Injury, 
poisoning 
and 
procedural 
complications
0
(0.0)
0
(0.0)
1
(6.3)
   Ligament sprain
0
(0.0)
0
(0.0)
1
(6.3)
Musculoskeletal and connective tissue 
disorders
0
(0.0)
1
(12.5)
11
(68.8)
   Arthralgia
0
(0.0)
1
(12.5)
2
(12.5)
   Back pain
0
(0.0)
0
(0.0)
2
(12.5)
   Muscle contusion
0
(0.0)
0
(0.0)
1
(6.3)
   Muscle spasms
0
(0.0)
0
(0.0)
3
(18.8)
   Muscle twitching
0
(0.0)
0
(0.0)
1
(6.3)
   Musculoskeletal pain
0
(0.0)
0
(0.0)
3
(18.8)
   Musculoskeletal stiffness
0
(0.0)
0
(0.0)
1
(6.3)
   Myofascial pain syndrome
0
(0.0)
0
(0.0)
1
(6.3)
   Neck pain
0
(0.0)
0
(0.0)
2
(12.5)
   Trismus
0
(0.0)
0
(0.0)
1
(6.3)
Nervous system disorders
2
(25.0)
5
(62.5)
12
(75.0)
   Dizziness
0
(0.0)
0
(0.0)
4
(6.3)
   Dizziness postural
0
(0.0)
1
(12.5)
2
(12.5)
   Dysgeusia
0
(0.0)
1
(12.5)
1
(6.3)
   Headache
2
(25.0)
3
(37.5)
11
(68.8)
   Paresthesia
0
(0.0)
1
(12.5)
2
(12.5)
   Presyncope
0
(0.0)
0
(0.0)
2
(12.5)
   Sensory loss
0
(0.0)
0
(0.0)
1
(6.3)
Psychiatric disorders
0
(0.0)
0
(0.0)
1
(12.5)
   Irritability
0
(0.0)
1
(12.5)
1
(12.5)
 
 
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MK-7252 1 mg / 
PBO
MK-7252 3 mg / 
PBO   
MK-7252 6 mg / 
PBO    
MK-7252 12 mg 
/ PBO  
MK-7252 24 mg 
/ PBO  
MK-7252 48 mg 
/ PBO  
MK-7252 72 mg 
/ PBO  
  
n 
(%)
n 
(%)
n 
(%)
n 
(%)
n 
(%)
n 
(%)
n 
(%)
Respiratory, thoracic and mediastinal 
disorders
2
(25.0)
0
(0.0)
2
(25.0)
1
(12.5)
4
(50.0)
0
(0.0)
2
(12.5)
   Cough
0
(0.0)
0
(0.0)
0
(0.0)
0
(0.0)
0
(0.0)
0
(0.0)
1
(6.3)
   Mouth swelling
0
(0.0)
0
(0.0)
0
(0.0)
0
(0.0)
0
(0.0)
0
(0.0)
1
(6.3)
   Mucosal pain
0
(0.0)
0
(0.0)
0
(0.0)
0
(0.0)
0
(0.0)
0
(0.0)
0
(0.0)
   Nasal congestion
0
(0.0)
0
(0.0)
2
(12.5)
1
(12.5)
1
(25.0)
0
(0.0)
0
(0.0)
   Oropharyngeal pain
0
(0.0)
0
(0.0)
1
(12.5)
0
(0.0)
1
(12.5)
0
(0.0)
0
(0.0)
   Throat irritation
2
(25.0)
0
(0.0)
0
(0.0)
0
(0.0)
0
(0.0)
0
(0.0)
0
(0.0)
   Throat tightness
0
(0.0)
0
(0.0)
0
(0.0)
0
(0.0)
1
(12.5)
0
(0.0)
0
(0.0)
Skin and subcutaneous tissue disorders
0
(0.0)
1
(12.5)
0
(0.0)
0
(0.0)
0
(0.0)
0
(0.0)
2
(12.5)
   Cold sweat
0
(0.0)
1
(12.5)
0
(0.0)
0
(0.0)
0
(0.0)
0
(0.0)
0
(0.0)
   Dry skin
0
(0.0)
0
(0.0)
0
(0.0)
0
(0.0)
0
(0.0)
0
(0.0)
1
(6.3)
   Ecchymosis
0
(0.0)
0
(0.0)
0
(0.0)
0
(0.0)
0
(0.0)
0
(0.0)
0
(0.0)
   Erythema
0
(0.0)
0
(0.0)
0
(0.0)
0
(0.0)
0
(0.0)
0
(0.0)
1
(6.3)
Vascular Disorders
0
(0.0)
0
(0.0)
0
(0.0)
0
(0.0)
0
(0.0)
0
(0.0)
1
(6.3)
Peripheral coldness
0
(0.0)
0
(0.0)
0
(0.0)
0
(0.0)
0
(0.0)
0
(0.0)
1
(6.3)
 
 
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MK-7252 108 mg 
/ PBO
MK-7252 162 
mg / PBO   
Total 
  
n 
(%)
n 
(%)
n 
(%)
Respiratory, thoracic and mediastinal 
disorders
1
(12.5)
1
(12.5)
9
(56.3)
   Cough
0
(0.0)
0
(0.0)
1
(6.3)
   Mouth swelling
0
(0.0)
0
(0.0)
1
(6.3)
   Mucosal pain
0
(0.0)
1
(12.5)
1
(6.3)
   Nasal congestion
1
(12.5)
0
(0.0)
5
(31.3)
   Oropharyngeal pain
0
(0.0)
0
(0.0)
2
(12.5)
   Throat irritation
0
(0.0)
0
(0.0)
2
(12.5)
   Throat tightness
0
(0.0)
0
(0.0)
1
(6.3)
Skin and subcutaneous tissue disorders
1
(12.5)
1
(12.5)
5
(31.3)
   Cold sweat
0
(0.0)
0
(0.0)
1
(6.3)
   Dry skin
1
(12.5)
0
(0.0)
2
(12.5)
   Ecchymosis
0
(0.0)
1
(12.5)
1
(6.3)
   Erythema
0
(0.0)
0
(0.0)
1
(6.3)
Vascular Disorders
0
(0.0)
0
(0.0)
1
(6.3)
Peripheral coldness
0
(0.0)
0
(0.0)
1
(6.3)
 
 
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Rationale
4.2
Rationale for the Trial and Selected Subject Population
4.2.1
This First-in-Human (FIH) study is being conducted to evaluate safety, tolerability, PK and 
PD of MK-7252 after administration of single oral doses in healthy men and WONCBP 
subjects. Reproductive toxicity studies have yet to be conducted thus WONCBP subjects will 
be included in this study.
Rationale for Dose Selection/Regimen/Modification
4.2.2
As this is a Phase I assessment of MK-7252 in humans, and the PK, PD and safety profiles of 
the compound are still being evaluated,  modifications to the dose or dosing regimen may be 
required to achieve the scientific goals of the trial objectives and/or to ensure appropriate 
safety monitoring of the trial subjects.  Details of allowed modifications are provided in 
Section 7.1.5.6 - Trial Design/Dosing/Procedures Modifications Permitted within Protocol 
Parameter.
The primary objective of this study is to assess the safety and tolerability profile of MK-7252
after single dose administration in healthy subjects to support the current clinical 
development of MK-7252.  
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
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Dosing with food (Panel C Period 5) may be replaced with a fasting dose and will not exceed
the maximum daily dose of 540 mg.  
Rationale for the Use of Placebo
4.2.2.1
The primary objective of this study is to evaluate the safety and tolerability of MK-7252.  A 
matching placebo control trial will facilitate an unbiased assessment of safety and 
tolerability.  Because subjects are healthy adults and will not receive clinical benefit from 
MK-7252, an A2a receptor antagonist, an active comparator, is not justified.
Starting Dose for This Trial
4.2.2.2
As recommended by the ICH guideline M3(R2) on non-clinical safety studies for the conduct 
of human clinical trials and marketing authorization for pharmaceuticals (2009), the 
calculation of the first starting dose in human subjects is based on no-observed adverse effect 
level (NOAEL) determined in nonclinical safety studies performed in the most sensitive and 
relevant animal species adjusted with allometric factors to calculate the Human Equivalent 
Dose (HED).
The administration of MK-7252 to humans is supported by preclinical toxicology studies 
outlined in the IB.  One-month good laboratory practice (GLP) repeat dose toxicity studies 
were conducted in both rats and dogs. The NOAEL of the sensitive species was the mid-dose 
tested at 20mg/kg in the dog (with AUC0-24hr of 64.7 µM*hr and Cmax of 13.6 µM).
For MK-7252, a dog NOAEL of 20 mg/kg/day supports the first starting dose of  66 mg 
(with default safety factor of 1/10th), assuming 60 kg human using the following calculation, 
where 1.8 is the conversion factor from the dog dose in mg/kg to HED in mg/kg:
HED = 20 mg/kg/day ÷ 1.8 = 11.11 mg/kg ÷ 10 = 1.11mg/kg x 60kg = 66 mg.
 
adenosine is associated with multiple signaling pathways that are ubiquitously expressed in 
immune system and is a known vasodilator.  
 
 
 
 
 
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A starting dose of 1 mg is proposed for this study (with a predicted human AUC0-24hr of 
approximately 0.24 µM*hr). 
 
 
Maximum Dose/Exposure for This Trial
4.2.2.3
As described above, the initial target dose for efficacy was projected to be 128 mg MK-7252 
BID, which was expected to achieve steady state human exposure of AUC0-12hr: 32.1 
(28.7 – 35.8) µM.hr, and Cmax: 5.39 (4.72 – 6.10) µM.  However, review of interim human 
PK data up to 162 mg, suggested that human exposures were considerably lower than initial 
projections because the rate of elimination seems to be faster than anticipated. Therefore, in 
order to achieve exposures closer to the target exposure for efficacy, the maximum dose 
proposed for Panel C is 540 mg in this amendment.  
 
 
As recommended by the EMA Guideline on strategies to identify and mitigate risks for first-
in-human and early clinical trials with investigational medicinal products (2017), the 
maximum exposure in humans should be predefined and justified based on all available non-
clinical and clinical data, including PD, PK and findings in toxicity studies and exposures at 
the expected therapeutic dose range.
Current projections of exposure are based on population modeling of measurable PK data up
to 162 mg.
However, uncertainty exists about the characterization of a relatively flat 
terminal phase, since it was seen only at the highest doses tested to date (108 mg and 
162 mg). To better characterize the terminal elimination rate at higher doses, the maximum 
dose (in this amendment) has been increased to 540 mg and two additional PK sampling time
points (at 14 hr and 32 hr postdose) have been added.  At the maximum single dose proposed 
(540 mg), the currently projected AUC0-24hr of ~29.4 µM*hr, and Cmax ~8.7 µM, are 
expected to be approximately 2-fold and 1.5-fold below for AUC and Cmax of the dog 
NOAEL levels (at 20mg/kg) AUC0-24hr and Cmax of 64.7µM*hr and 13.6 µM, 
respectively.
Four (4) interim PK pauses are included in this trial: (1) following Panel B Period 2; (2) 
following Panel A Period 4 and two PK pauses in Panel C: (3) following Period 1 and (4) 
following Period 3. The first PK pause, after Panel C Period 1, will confirm that exposures in 
Panel C subjects are consistent with interim PK data from Panels A and B.   Available PK 
data will be reviewed to ensure that subsequent doses administered are not projected to 
exceed the NOAEL AUC and Cmax levels determined from preclinical toxicology studies.
The ascending-dose study design and interim available PK data ensure that human exposure 
levels will be reviewed along with safety and tolerability from previous dose levels before 
escalating to dose levels that would approach dog NOAEL dose. If the interim PK data
reveals that subsequent doses may produce exposures that would exceed the dog NOAEL 
exposure, then doses will be adjusted downward or subsequent dosing periods may be 
 
 
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eliminated.   Dose escalation decisions will be communicated to the site via an administrative 
letter, and safety will be monitored throughout the study by repeated clinical and laboratory 
evaluations.
Rationale for Dose Interval and Trial Design
4.2.2.4
MK-7252, an adenosine 2a receptor antagonist, is not considered a compound with a high 
degree of uncertainty to the potential for risk of harm to volunteers according to the 
publication "Guideline on Strategies to Identify and Mitigate Risks for First-in-Human 
Clinical Trials with Investigational Medicinal Products" (European Medicine Agency 
guidance released July 2017).  The degree of uncertainty was determined by careful 
evaluation of the following: mode of action of MK-7252, presence or absence of biomarkers, 
the nature of the target, the relevance of available animal models and/or findings in non-
clinical safety studies, and the study population. Furthermore, MK-7252 acts via a well-
established mechanism. Safety assessment toxicity trials and ancillary pharmacology trials 
with MK-7252 provide no contraindications to the initiation of clinical trials in people with 
this compound via the oral route. Monitorable dose-limiting toxicities were observed 
(hemodynamic changes) in a 7-day rat and ascending-dose dog toxicity trials and substantial 
preclinical safety margins were obtained over initial human doses.
The trial design includes 2 alternating ascending dose panels (Panels A and B) and one 
ascending dose Panel C, of 8 subjects each, 6 subjects randomized to active treatment and 2 
to placebo in a balanced design across periods.  For each panel in each period, all 8 subjects 
are planned to be administered MK-7252 or matching placebo on the same day in spaced 
time intervals by Phase I Clinical Research standards for compounds not considered to have a
high degree of uncertainty related to the potential of harm to participants. The dosing 
regimen was determined based on the following: the presence of preclinical safety margins 
for MK-7252, the inclusion of extensive safety monitoring in the clinic, and the fact that 
MK-7252 is not considered a compound with a high potential for risk of harm.  There will be 
frequent, careful assessments of adverse events throughout the postdose period prior to 
administering the next dose level.  This recommendation is in keeping with the projected 
safety profile and the ability of the Phase I unit to monitor each subject closely.  Other 
modifications to the dosing and/or clinical procedure, currently outlined in the protocol, may 
be required to achieve the scientific goals of the study objectives and/or to ensure appropriate 
safety monitoring of the study subjects.
There will be a 7-day washout between doses for any given subject. Based on initial PK 
results with a terminal t1/2 of 1.3 to 6 hours, this 7-day washout is sufficient to ensure 
appropriate elimination of MK-7252 before the following dose period.
The study will also include four pre-specified PK breaks (after Panel B Period 2; after Panel 
A Period 4 and after Panel C Periods 1 and 3.  This will provide an estimation of 
exposure/concentration during the study and further guide subsequent conduct of the study. 
 
 
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Rationale for Endpoints
4.2.3
Efficacy Endpoints
4.2.3.1
No efficacy endpoints will be obtained in this study.
Safety Endpoints
4.2.3.2
This will be the first introduction of MK-7252 into humans.  It is anticipated that oral 
administration of MK-7252 will be well-tolerated in humans based on preclinical safety and 
toxicology testing in rats and dogs; and based on experience with another A2aR antagonist, 
preladenant.
The safety and tolerability of MK-7252 will be monitored by standard means including 
clinical assessments of AEs, repeated physical examinations, targeted neurologic 
examination, monitoring vital signs, 12-lead ECGs, and standard laboratory safety tests 
(including hematology, chemistry, and urinalysis).  The time points for safety data collection 
are based on the projected PK of MK-7252.
Adenosine is known to be a vasodilator, and antagonism of the A2a receptor by MK-7252 is 
expected to affect hemodynamic changes (e.g., BP changes observed in both in clinical trials 
with another A2aR antagonist, preladenant and in dog studies with MK-7252). 
 
 
 
 
 
 
 
Thus blood pressure will be 
monitored throughout study as outlined in the protocol.
Pharmacokinetic Endpoints
4.2.3.3
The systemic pharmacokinetics of MK-7252 will be characterized following single dose 
administration of MK-7252.  The primary PK endpoints will include AUC0-12hr, AUC0-
24hr, AUC0-∞, Cmax, C12hr and C24hr, Tmax, and apparent terminal t½ following single 
oral dose administration of MK-7252.  Plasma samples will be analyzed at specified times 
for the determination of MK-7252 as specified in the Study Flow Chart (Section 6.0).  These 
procedures may also be performed at various unscheduled time points, if deemed clinically
appropriate. This study is planned to include an assessment of plasma PK of MK-7252 in 
fasted and fed conditions in Panel C; to evaluate the potential for a food effect (high fat) on 
exposure.
To evaluate the renal excretion of MK-7252, urine will also be collected for determination of 
MK-7252 concentrations following single dose administration.  If data permits, urinary PK 
 
 
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values (amount recovered [Ae], fraction of dose recovered [fe], and renal clearance [Clr]) 
will be calculated.
Pharmacodynamic Endpoints
4.2.3.4
 
 
 
Planned Exploratory Biomarker Research
4.2.3.5
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Planned Genetic Analysis
Understanding genetic determinants of drug response and the molecular basis of disease 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 and/or disease. If genetic variation is found to predict efficacy or adverse events, 
the data might inform optimal use of therapies in the patient population. Knowledge of the 
molecular basis of disease contributes to the development of novel biomarkers and the 
identification of new drug targets. This research contributes to understanding molecular basis 
of disease and the genetic determinants of efficacy and safety associated with the treatments 
in this study.
 
 
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Future Biomedical Research
4.2.3.6
The Sponsor will conduct Future Biomedical Research on specimens consented for future 
biomedical research during this clinical trial.  This research may include genetic analyses 
(DNA), gene expression profiling (RNA), proteomics, metabolomics (serum, plasma) and/or 
the measurement of other analytes, depending on which specimens are consented for future 
biomedical research.
Such research is for biomarker testing to address emergent questions not described elsewhere 
in the protocol (as part of the main trial) and will only be conducted on specimens from 
appropriately consented subjects. The objective of collecting/retaining specimens for Future 
Biomedical Research is to explore and identify biomarkers that inform the scientific 
understanding of diseases and/or their therapeutic treatments. The overarching goal is to use 
such information to develop safer, more effective drugs/vaccines, and/or to ensure that 
subjects receive the correct dose of the correct drug/vaccine at the correct time.  The details
of this Future Biomedical Research sub-trial are presented in Section 12.2 – Collection and 
Management of Specimens for Future Biomedical Research.
Benefit/Risk
4.3
Subjects in early clinical trials generally cannot expect to receive direct benefit from 
treatment during participation as these clinical trials are designed to provide information 
about the safety and pharmacokinetics of an investigational medicine.
Additional details regarding specific benefits and risks for subjects participating in this 
clinical trial may be found in the accompanying IB and Informed Consent documents.
5.0 METHODOLOGY
Entry Criteria
5.1
Diagnosis/Condition for Entry into the Trial
5.1.1
Healthy men and women of non-childbearing potential between the ages of 18 and 50 years 
(inclusive) 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:
1. Provide written informed consent for the trial, including for Future Biomedical 
Research.
2. Be male or female of non-childbearing potential 18 to 50 years of age at the pre-trial 
(screening) visit; further:
a.
If postmenopausal female: subject is without menses for at least 1 year and has a 
documented follicle stimulating hormone (FSH) level in the postmenopausal 
range at pre-trial (screening) - OR -
 
 
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b. If surgically sterile female: subject is status post hysterectomy, oophorectomy or 
tubal ligation.
NOTE: These procedures must be confirmed with medical records.  In the 
absence of documentation, hysterectomy may be confirmed by pelvic exam or if 
necessary by ultrasound; oophorectomy may be confirmed by hormone levels, 
particularly FSH in the post-menopausal range, but tubal ligation subjects without 
records should be excluded.  Information must be captured appropriately within 
the site’s source documents.
3. Have a Body Mass Index (BMI) between 18.5 and 32 kg/m2, inclusive. BMI = weight 
(kg)/height (m)2.
4. While in semi-recumbent position, have a systolic blood pressure (SBP) ≤140 mmHg 
and diastolic blood pressure (DBP) ≤90 mm Hg and a respiratory rate (RR) ≤20 
breath/min at the pre-trial (screening) visit and prior to randomization in triplicate; 
mean values from triplicate measurements will be used; if mean value is out of range, 
repeat triplicate measurement may be taken and mean value of subsequent triplicate 
may be used.
5. Be judged to be in good health based on medical history, physical examination, vital 
sign measurements and ECG performed prior to randomization. Appendix section 12.5 
provides a table of 12-Lead Electrocardiogram Abnormality Criteria.
6. Be judged to be in good health based on laboratory safety tests (Section 7.1.3.1) 
obtained at the screening visit and at screening 2.  Appendix section 12.4 provides an 
algorithm for the assessment of out-of-range laboratory values.
a.
Liver Function Tests including aspartate aminotransferase (AST), alanine 
aminotransferase (ALT) direct bilirubin, and alkaline phosphatase must be equal 
to or below the upper limit of normal before the subject can considered eligible 
for randomization.
7. Be a non-smoker and/or has not used nicotine or nicotine-containing products (e.g., 
nicotine patch) for at least approximately 3 months.
8. Be willing to comply with the trial restrictions (see Section 5.7 for a complete 
summary of trial restrictions).
Subject Exclusion Criteria
5.1.3
The subject must be excluded from participating in the trial if the subject:
1. Is under the age of legal consent.
2. Is mentally or legally incapacitated, has significant emotional problems at the time of 
pretrial (screening) visit or expected during the conduct of the trial or has a history of 
clinically significant psychiatric disorder of the last 5 years. Subjects who have had 
situational depression may be enrolled in the trial at the discretion of the investigator.
 
 
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3. Has a history of clinically significant endocrine, gastrointestinal, cardiovascular, 
hematological, hepatic, immunological, renal, respiratory, genitourinary or major 
neurological (including stroke and chronic seizures) abnormalities or diseases.  
Subjects with a history of uncomplicated kidney stones, as defined as spontaneous 
passage and no recurrence in the last 5 years, or childhood asthma may be enrolled in 
the trial at the discretion of the investigator.
4. Has a history of liver disease (chronic hepatitis, cirrhosis, etc.).
5. Has a history of cancer (malignancy).
Exceptions: (1) Subjects with adequately treated non-melanomatous skin carcinoma 
or carcinoma in situ of the cervix may participate in the trial; (2) Subjects with other 
malignancies which have been successfully treated ≥10 years prior to the pretrial 
(screening) visit where, in the judgment of both the investigator and treating 
physician, appropriate follow-up has revealed no evidence of recurrence from the 
time of treatment through the time of the pretrial (screening) visit (except those 
cancers identified at the beginning of exclusion criterion 5); or, (3) Subjects, who, in 
the opinion of the trial investigator, are highly unlikely to sustain a recurrence for the 
duration of the trial.  
6. Has a history of significant multiple and/or severe allergies (e.g. food, drug, latex 
allergy), or has had an anaphylactic reaction or significant intolerability (i.e. systemic 
allergic reaction) to prescription or non-prescription drugs or food. 
7. Is positive for hepatitis B surface antigen, hepatitis C antibodies or HIV.
8. Had major surgery, donated or lost 1 unit of blood (approximately 500 mL) within 
4 weeks prior to the pretrial (screening) visit. 
9. Has participated in another investigational trial within 4 weeks (or 5 half-lives), 
whichever is greater, prior to the pretrial (screening) visit.  The window will be 
derived from the date of the last visit in the previous trial. 
10. Has QTc interval ≥470 msec (for males) and ≥480 msec (for females).
11. Has taken during the 5 days prior to start of study treatment a Proton Pump Inhibitor
(PPI).
12. Is unable to refrain from or anticipates the use of any medication, including 
prescription and non-prescription drugs or herbal remedies beginning approximately 
2 weeks (or 5 half-lives) prior to administration of the initial dose of trial drug, 
throughout the trial (including washout intervals between treatment periods), until the 
post-trial visit.  There may be certain medications that are permitted, see Section 5.5.
13. Consumes greater than 3 glasses of alcoholic beverages (1 glass is approximately 
equivalent to: beer [354 mL/12 ounces], wine [118 mL/4 ounces], or distilled spirits 
[29.5 mL/1 ounce]) per day.  Subjects that consume 4 glasses of alcoholic beverages 
per day may be enrolled at the discretion of the investigator.
 
 
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14. Consumes excessive amounts, defined as greater than 6 servings (1 serving is 
approximately equivalent to 120 mg of caffeine) of coffee, tea, cola, energy-drinks, or 
other caffeinated beverages per day.
15. Is a regular user of cannabis, any illicit drugs or has a history of drug (including 
alcohol) abuse within approximately 1 year. Subjects must have a negative UDS prior 
to randomization.
16. Is any concern by the investigator regarding the safe participation of the subject in the 
trial or for any other reasons the investigator considers the subject inappropriate for 
participation in the trial.
17. Is or has an immediate family member (e.g., spouse, parent/legal guardian, sibling or 
child) who is investigational site or Sponsor staff directly involved with this trial.
Trial Treatment(s)
5.2
The treatments to be used in this trial are outlined below in Table 4.
Table 4
Trial Treatment
Drug
Dose/Potency
Dose 
Frequency
Route of 
Administration
Regimen
/Treatment Period
Use
MK-7252
Panel A or B: 
1, 3, 6, 12, 
24, 48, 72, 
108, and 162
mg 
Panel C: 120
(fasted and 
fed), 240, 360
and 540
(doses in all 
panels may 
be adjusted 
downward)
Potencies: 
1mg/mL and 
20 mg/mL
Single dose 
in each 
period 
Oral
Day 1 in Periods 1, 
2, 3, 4 or 5
Experimental
Placebo
N/A
Single dose 
in each 
period 
Oral
Day 1 in Periods 1, 
2, 3, 4 or 5
Placebo-
control 
Trial treatment should begin on the day of treatment allocation/randomization or as close as 
possible to the date on which the subject is allocated/assigned.
 
 
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The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of trial 
treatments in accordance with the protocol and any applicable laws and regulations.
Dose Selection/Modification
5.2.1
Dose Selection (Preparation)
5.2.1.1
The rationale for selection of doses to be used in this trial is provided in Section 4.0 –
Background & Rationale.  Specific calculations or evaluations required to be performed in 
order to administer the proper dose to each subject are outlined in a separate document 
provided by the Sponsor.
Dose Modification (Escalation)
5.2.1.2
All dose escalation decisions will be made jointly by the investigator and the Sponsor. Each 
dose escalation decision will occur after at least 6 evaluable participants have completed the 
previous dose level (subjects will be randomized to receive MK-7252 or placebo in a 3:1 
ratio, respectively. Given that the compound has no significant toxicology findings in the 
dose range to be studied, dose escalation decisions can be made based on 6 evaluable 
subjects (minimum of 4 subjects on active study drug). Dose escalation decisions will be
based on key safety variables including vital signs, 12-lead ECG, laboratory safety tests, 
targeted neurological examination and adverse events from the previous dose levels up to at 
least 24 hours (or longer depending on the compound). Pharmacokinetic and 
pharmacodynamic data may be included in the dose escalation decisions.  See Background & 
Rationale - Section 4.0.
If, as judged by the Sponsor and investigator, the safety and tolerability data do not justify 
dose escalation, the dose will not be increased as planned. Instead, subjects may:
●
receive the same dose level to further explore safety and tolerability at that level;
●
receive a lower dose of the trial drug;
●
receive the same or lower dose as a divided dose; or
●
receive a lower dose with or without food.
Or, dosing may be stopped. Subject discontinuation criteria are outlined in Section 5.8.
Prior to each treatment, the clinical and laboratory safety parameters from the previous dose 
level will be reviewed by the investigator and discussed with the Sponsor to permit a 
decision on whether to advance to the next higher dose level.  No dose escalation will occur 
without the joint agreement of the investigator and the Sponsor.
Timing of Dose Administration
5.2.2
All doses of MK-7252 or matching placebo will be prepared and dosed per the instructions 
outlined in the Method of Preparation Document.
 
 
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In each treatment period, subjects will receive a single dose (or divided doses without 
exceeding the maximum daily dose as indicated per period in Panel C only) of MK-7252 or 
matching placebo as an oral suspension.  Each on-site formulation (OSF) oral suspension 
dose should be administered with a water volume that brings the total ingested volume to 
approximately 240 mL (approximate to the nearest 10 mL).  For example, if the OSF 
suspension volume dosed is 10 mL, the water volume to follow dosing would be 230 mL.  
Trial Blinding 
5.2.3
A double-blinding technique will be used.  MK-7252 and placebo will be prepared and/or 
dispensed in a blinded fashion by an unblinded pharmacist or qualified trial site personnel. 
The subject and the investigator who is involved in the MK-7252 and placebo administration 
or clinical evaluation of the subjects are unaware of the group assignments.
See Section 7.1.4.2, Blinding/Unblinding, for a description of the method of unblinding a 
subject during the trial, should such action be warranted.
Randomization or Treatment Allocation
5.3
Subjects will be assigned randomly according to a computer-generated allocation schedule.
The sample allocation schedules are shown below in Table 5.  In Panels A and B, the 
allocation schedule from the original protocol (001-00) will be used for active or placebo 
assignment, however the protocol clarification letter (PCL) issued after each dose escalation 
meeting will provide the dose.
 
 
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Table 5
Sample Allocation Schedule 
Subjects a
Period 1b
Period 2b
Period 3b
Period 4b
Period 5b
Panel A
n=2
n=2
n=2
n=2
Placebo
1 mg
1 mg
1 mg
6 mg
Placebo
6 mg
6 mg
24 mg
24 mg
Placebo
24 mg
72 mg
72 mg
72 mg
Placebo
108 mg 
108 mg 
Placebo
108 mg 
Panel B
n=2
n=2
n=2
n=2
Placebo
3 mg
3 mg
3 mg
12 mg
Placebo
12 mg
12 mg
48 mg
48 mg
Placebo
48 mg
72 mg
72 mg
72 mg
Placebo
162 mg
162 mg
Placebo
162 mg
Panel C
n=2
n=2
n=2
n=2
Placeboc
120 mgc
120 mgc
120 mgc
240 mg d
Placebo d
240 mg d
240 mg d
360 mg d
360 mg d
Placebod
360 mg d
540 mg d
540  mg d
540 mg d
Placebo d
Placeboc,d
120 mg fedc,d
120 mg fedc,d
120 mg fedc,d
a Within each treatment period, 6 subjects will be randomized to receive MK-7252 and 2 subjects to 
receive matching placebo according to a computer-generated allocation schedule.
b The suggested doses may be adjusted downward based on evaluation of safety, tolerability, PK and/or 
PD data observed in previous treatment periods.
c The assigned treatment for Panel C Periods 1 and 5 (fasted/fed) will be the same, such that the same 
subjects will receive active drug or matching placebo in both treatment periods.  Panel C Period 5 may 
be replaced with a fasting daily dose not exceeding 540 mg. 
d Daily dose may be divided into two doses.  See study flowcharts (for Panel C only).
The shaded area represents a PK pause after Panel B Period 2, after Panel A Period 4 and after Panel C 
Period 1 and after Panel C Period 3; PK samples up to Panel B Period 2 will be reviewed prior to dosing 
for Panel A Period 3, PK samples up to Panel A Period 4 will be reviewed prior to dosing Panel B 
Period 4, PK samples up to Panel C Period 1 will be reviewed prior to dosing for Panel C Period 2 and PK 
samples up to Panel C Period 3 will be reviewed prior to dosing for Panel C Period 4.
Stratification
5.4
No stratification based on age, sex or other characteristics will be used in this trial.
Concomitant Medications/Vaccinations (Allowed & Prohibited)
5.5
If a subject does not discontinue all prior medications within 14 days or 5 half-lives of the 
first dose of trial medication, he/she may be included in the study if the investigator can 
rationalize that the specific use of a prior medication is not clinically relevant within the 
context of the trial.
Concurrent use of any prescription or non-prescription medication, or concurrent vaccination,
during the course of the trial (i.e., after randomization or treatment allocation) must first be 
discussed between the investigator and Sponsor prior to administration, unless appropriate 
 
 
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medical care necessitates that therapy or vaccination should begin before the investigator and 
Sponsor can consult.  The subject will be allowed to continue in the trial if both the Sponsor 
and the investigator agree.
Paracetamol/acetaminophen may be used for minor ailments without prior consultation with 
the Sponsor.
Rescue Medications & Supportive Care
5.6
No rescue or supportive medications are specified to be used in this trial.
Diet/Activity/Other Considerations
5.7
Diet and Fruit Juice Restrictions
5.7.1
Diet
5.7.1.1
Fasting requirements for trial procedures, such as but not limited to laboratory safety 
evaluations, are specified in Section 7.1.
In each treatment period (except the fed panel), subjects will fast from all food and drinks, 
except water, for at least 8 hours prior to the dose administration.  Subjects will fast from all 
food and drinks except water between trial drug administration and the first scheduled meal.  
Meals and snack(s) will be provided by the investigator at time points indicated in the trial 
flowchart.  Subjects will fast from all food and drinks except water between meals and 
snacks.  The caloric content and composition of meals will be the same in each treatment 
period, with the exception that a standard high-fat breakfast will be provided prior to trial 
drug administration for the fed panel.  After the 24-hour postdose procedures have been 
completed, subsequent meals and snacks will be unrestricted in caloric content, composition 
and timing. 
Water will be provided during trial drug administration.  Water will be restricted 1 hour prior 
to and 1 hour after trial drug administration.  Each OSF oral suspension dose should be 
administered with a water volume that brings the total ingested volume to approximately 240 
mL (approximate to the nearest 10 mL). For example, if the OSF volume dosed is 100 mL, 
the water volume to follow dosing would be 140 mL.
In treatment Period 5 of Panel C, approximately 30 minutes prior to trial drug administration, 
subjects will begin to consume a standard high-fat breakfast.  The contents of the standard 
high-fat breakfast are listed in Table 6.  
 
 
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Table 6
Contents of the Standard, High-Fat Breakfast
2 fried or scrambled eggs
2 strips bacon or 60 g feta cheese (for vegetarian)
2 slices toast with 2 pats of butter
4 oz (113 g) hash browns (fried potato)
240 mL whole milk
The nutritional content of the high-fat breakfast is as follows:
Total fat = 55.6 g
Total carbohydrates = 55 g
Total protein = 31.1 g
Total calories (for non-vegetarian, i.e. bacon) = 500.4 in fat, 220 in carbohydrates, and 124.4 
in protein.
Total calories (for vegetarian, i.e. feta cheese) = ~513 in fat, ~236 in carbohydrates, and ~148
in protein.
The exact meal contents may be substituted with agreement between Sponsor and 
investigator, and must be documented in an administrative letter.
This breakfast should be consumed in its entirety within approximately 20 minutes.  The start 
and stop time of the breakfast will be recorded.  Within approximately 10 minutes after 
consuming the breakfast, subjects will be administered trial drug as indicated in Section 5.2.
Instructions on whether to take MK-7252 with or without food and/or drink may be modified 
during the trial based on newly available data.
Fruit Juice Restrictions
5.7.1.2
Subjects will refrain from the consumption of grapefruit juice, grapefruits and grapefruit 
products beginning approximately 2 weeks prior to administration of the initial dose of trial 
drug, throughout the trial (including the washout interval between treatment periods) and 
until the post-trial visit.  
Subject also will refrain from the consumption of all fruit juices 24 hours prior to and after 
trial drug administration.  All other days during the trial, consumption of fruits and fruit 
juices (except for grapefruit, grapefruit juices, and grapefruit products) is allowed.
 
 
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Alcohol, Caffeine, Tobacco, Activity
5.7.2
Alcohol Restrictions
5.7.2.1
Subjects will refrain from consumption of alcohol 24 hours prior to the pre- and post-trial 
visits and from 24 hours prior to and after trial drug administration in each treatment period.  
At all other times, alcohol consumption is limited to no more than approximately 3 alcoholic 
beverages or equivalent (1 glass is approximately equivalent to: beer [354 mL/12 ounces], 
wine [118 mL/4 ounces], or distilled spirits [29.5 mL/1 ounce]) per day.
Caffeine Restrictions 
5.7.2.2
Subjects will refrain from consumption of caffeinated beverages or xanthine containing 
products from 12 hours prior to the pre- and post-trial visits and from 12 hours prior to and 
after trial drug administration and prior to the 48 hour and 72 hour postdose procedures in 
each treatment period.  At all other times, caffeinated beverages or xanthine-containing 
products will be limited to no more than 6 units per day amounts (>6 units: 1 unit=120 mg of 
caffeine).
Smoking Restrictions
5.7.2.3
Smoking and/or the use of nicotine/nicotine containing products is not permitted during the 
trial.
Activity Restrictions
5.7.2.4
Subjects will avoid unaccustomed strenuous physical activity (i.e., weight lifting, running, 
bicycling, etc.) from the pre-trial (screening) visit until administration of the initial dose of 
trial drug, throughout the trial (including washout intervals between treatment periods) and 
until the post-trial visit.
Contraception
5.7.3
Male subjects with female partner(s) of child-bearing potential must agree to use a medically 
acceptable method of contraception during the trial and for 90 days after the last dose of trial 
drug. Males should use a condom. Female partners must additionally use one of the 
following methods if they are not pregnant: hormonal contraception, intra-uterine device, 
diaphragm, or cervical cap. If their partner is pregnant, males must agree to use a condom 
and no additional method of contraception is required for the pregnant partner. Male subjects 
must also agree to not donate sperm during the study and for a period of 90 days after the last 
dose of study drug.
Other: Sun Exposure
5.7.4
MK-7252 absorbs light in the UV-VIS range, and phototoxicity testing for MK-7252 has not 
yet been conducted. Therefore prolonged exposure to sunlight should be avoided.  Subject 
must minimize sunlight exposure on the skin from 24hr prior to first dosing until the post-
 
 
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trial visit.  Subjects should also refrain from activities, including doing sports in the sun, 
tanning lamp exposure, or any other occupational, recreational or incidental sunlight 
exposure.  Subjects should apply a sunscreen with minimum SPF 50 or wear a long-sleeve 
shirt, long pants, and hats to block sunlight.  All subjects should use the same sunscreen.  
Subjects will also be instructed to not change any of their other personal care products 
including cosmetics, cleansers or lotion during the course of the study.
Stopping rules:
5.7.5
The following stopping rules will be employed during the conduct of this trial.
If any of the below stopping rules are met, the trial will be paused and no further dosing will
occur until the Sponsor has reviewed the totality of data available. In order to continue the
trial (upon joint agreement with the Sponsor and investigator), a substantial amendment will
be submitted for approval.
1. An individual participant reports a Serious Adverse Event considered related to the 
study drug by the investigator.
2. Two (2) or more participants within a Panel (at the same dose level) report Severe 
Non-Serious Adverse Events considered related to the study drug by the investigator.
If any of the below stopping rules are met, subsequent higher doses will be lowered based
upon joint agreement of the Sponsor and investigator in order for the trial to continue.
Panel Wide:  Should the emerging PK (mean) data indicate that the maximum clinical 
exposure (Cmax or AUC), as defined in Section 4.2 will be exceeded, subsequent higher 
doses will be adjusted based upon joint agreement of the Sponsor and investigator.
Individual:  Hemodynamic changes that exceed the pre-specified limitations (see Appendix 
12.8)
Subject Withdrawal/Discontinuation Criteria
5.8
Discontinuation of Treatment
5.8.1
Discontinuation of treatment does not represent withdrawal from the trial.
As certain data on clinical events beyond treatment discontinuation may be important to the 
study, they must be collected through the subject’s last scheduled follow-up, even if the 
subject has discontinued treatment.  Therefore, all subjects who discontinue trial treatment
prior to completion of the treatment period will still continue to participate in the trial as 
specified 
in 
Section 
6.0 
-
Trial 
Flow 
Chart 
and 
Section 
7.1.4.1 
–
Withdrawal/Discontinuation, or if available, Protocol Clarification Letter.
Subjects may discontinue treatment at any time for any reason or be dropped from treatment
at the discretion of the investigator should any untoward effect occur.  In addition, a subject 
may be discontinued from treatment by the investigator or the Sponsor if treatment is 
 
 
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inappropriate, the trial plan is violated, or for administrative and/or other safety reasons.  
Specific details regarding procedures to be performed at treatment discontinuation are 
provided in Section 7.1.4 – Other Procedures.
A subject must be discontinued from treatment but continue to be monitored in the trial for 
any of the following reasons:
◦
The subject or subject’s legally acceptable representative requests to discontinue 
treatment.
◦
The subject’s treatment assignment has been unblinded by the investigator or Merck 
subsidiary. 
◦
The subject has a medical condition or personal circumstance which, in the opinion of the 
investigator and/or Sponsor, placed the subject at unnecessary risk from continued 
administration of study drug.
◦
The subject has findings on targeted neurologic examination (including assessment of 
mental status, motor function (muscle strength, coordination and gait) that in the opinion 
of the investigator and/or Sponsor, places the subject at unnecessary risk with continued 
administration of study drug.
◦
The subject has a positive urine drug screen at any time during the course of the trial, 
confirmed upon rechecks.
◦
The subject meets hemodynamic stopping criteria per Appendix 12.8.
For subjects who are discontinued from treatment, all applicable discontinuation activities 
will be performed according to Section 7.1.4.1 – Withdrawal/Discontinuation, or if available, 
Protocol Clarification Letter.
Discontinuation from treatment is “permanent.” Once a subject is discontinued, he/she shall 
not be allowed to restart treatment.
Withdrawal from the Trial
5.8.2
A subject must be withdrawn from the trial if the subject or subject’s legally acceptable 
representative withdraws consent from the trial.
If a subject withdraws from the study, they will no longer receive treatment or be followed at 
scheduled protocol visits.
Specific details regarding procedures to be performed at the time of withdrawal from the trial 
including the procedures to be performed should a subject repeatedly fail to return for 
scheduled visits and/or if the study site is unable to contact the subject, as well as specific 
details regarding withdrawal from Future Biomedical Research are outlined in Section 7.1.4 
– Other Procedures.
 
 
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Subject Replacement Strategy
5.9
If a subject discontinues from trial treatment or withdraws from the trial, a replacement 
subject may be enrolled if deemed appropriate by the investigator and Sponsor.  The 
replacement subject will generally receive the same treatment or treatment sequence (as 
appropriate) as the subject being replaced. The replacement subject will be assigned a unique 
treatment/randomization number. The trial site should contact the Sponsor for the 
replacement subject’s treatment/randomization number.
The replacement subject may begin dosing at the subsequent dose level for that panel, based 
on investigator and Sponsor review and discussion.
Beginning and End of the Trial
5.10
The overall trial begins when the first subject signs the informed consent form.  The overall 
trial ends when the last subject completes the last study-related phone-call or visit, withdraws 
from the trial or is lost to follow-up (i.e. the subject is unable to be contacted by the 
investigator).
A trial may be paused during review of newly available preclinical/clinical safety, 
pharmacokinetic, pharmacodynamic, efficacy or biologic data or other items of interest, prior 
to a final decision on continuation or termination of the trial.  It may be necessary to keep the 
trial open for gathering/reviewing of additional supportive data to optimally complete the 
objective(s) of the trial.  If necessary, the appropriate amendment(s) to the protocol and/or 
appropriate communication(s) will be generated.  If the decision has been made to end the 
study following this review period, the study end will be defined as the date of the Sponsor 
decision and this end of study date supersedes the definitions outlined above. The Competent 
Authority(ies) and Institutional Review Board(s)/Independent Ethics Committee(s) 
[IRB(s)/IEC(s)] will be apprised of the maximum duration of the trial beyond the last subject 
out and the justification for keeping the trial open.
Clinical Criteria for Early Trial Termination
5.11
There are no pre-specified criteria for terminating the trial early.
A primary objective of this early Phase I trial is to identify the maximum safe and well-
tolerated dose and/or dosing regimen that achieve pharmacokinetic, pharmacodynamic and/or 
biologic targets in humans based on preclinical or early clinical data.  Therefore, it is possible 
that trial subjects may not receive all doses specified in the protocol if this objective is 
achieved at lesser dose levels in this trial.  This would not be defined as early termination of 
the trial, but rather an earlier than anticipated achievement of the trial objective(s).  If a 
finding (e.g., pharmacokinetic, pharmacodynamic, efficacy, biologic targets, etc.) from 
another preclinical or clinical trial using the trial treatment(s), comparator(s), drug(s) of the 
same class, or methodology(ies) used in this trial, results in the trial(s) or program being 
stopped for non-safety reasons, this also does not meet the definition of early trial 
termination.
 
 
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Early trial termination is defined as a permanent discontinuation of the trial due to 
unanticipated concerns of safety to the trial subjects arising from clinical or preclinical trials 
with the trial treatment(s), comparator(s), drug(s) of the same class or methodology(ies) used 
in this trial.
 
 
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6.0 TRIAL FLOW CHART
Procedures for Panels A and B
Scheduled Time
Hours/Days – All Periods
D1
D2 D3 D4
Screening 1
Screening 2a
Predose
0
0.25 0.5
1
2
4
8
10 12
24
48
72
Post-trialr
Administrative Procedures
Informed Consent
X
Informed Consent for Future Biomedical Research
X
Inclusion/Exclusion Criteriab
X
X
Xc
Subject Identification Card
X
Xc
Medical History
X
X
X
Concomitant Medication Review
X------------------------------------------------------------------------------------------------------X
Assignment of Screening Number
X
Assignment of Randomization Number
Xc
Clinic Procedures/Assessments
Full Physical Examination
X
Xd
X
X
Targeted Neurological Examination
X
Xd
X
X
Height
X
Weighte
X
X
X
12-Lead Electrocardiogramf
X
X
X X X
X
X
X
X
X
X
Vital Signs (heart rate, blood pressure)g
X
X
X X X
X
X
X
X
X
X
Orthostatic Vital Signs (heart rate, blood pressure)g
X
X
X
X
Vital Signs (respiratory rate, oral/tympanic temperature)h
X
X
X
X
Standard Mealsi
X--------X
MK-7252/Placebo Administrationj
X
Taste Assessment Questionnairek
X
 
 
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Procedures for Panels A and B
Scheduled Time
Hours/Days – All Periods
D1
D2 D3 D4
Screening 1
Screening 2a
Predose
0
0.25 0.5
1
2
4
8
10 12
24
48
72
Post-trialr
Adverse Events Monitoring
X-----------------------------------------------------------------------------------------------------X
Laboratory Procedures/Assessments
Laboratory Safety Testsl ( Hematology, Urinalysis and Serum Chemistry)
X
X
Xd
X
X
FSH (if applicable)
X
Urine/Blood Drug Screenm
X
X
HIV/Hepatitis Screen (per site SOP)
X
Blood for Genetic Analysisn
X
Pharmacokinetics Evaluations
Blood for Plasma MK-7252 Assayo
X
X
X
X X X
X
X
X
X
X
X
Urine for Urinary MK-7252 Assayp
X
X------------------------------------------X
Pharmacodynamic Evaluations
 
 
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a
If screening 1 occurs within 72hrs prior to the initial dose of trial drug, screening 2 is not required.
b
Review of inclusion/exclusion criteria will occur at Screening and after predose procedures (if applicable) in Period 1 only.
c
These predose procedures are only applicable to Period 1.
d
Physical examination, targeted neurological exam and safety labs can be conducted/collected on admission within 24 hours prior to dosing.
e 
Weight will be measured after 8 hours of fasting, with shoes and jacket off.
f
In all treatment periods, all ECGs will be obtained in triplicate and the mean of QTcF will be calculated. There should be ~1-2 minute intervals between ECG 
measurements. Predose ECGs will be obtained in triplicate at least 1-2 minutes apart within 3 hours prior to dosing of trial drug.
g  All semi-recumbent HR and BP measurements will be done in triplicate at least a 1-2 minutes interval between measurements.  Predose measurements can be performed 
within 3 hours prior to dosing. Subjects should be resting in the semi-recumbent position for at least 10 minutes prior to obtaining HR and BP. At pre-specified time points, 
following measurements of the semi-recumbent HR and BP, subjects assume a standing position for approximately 2 minutes and then orthostatic HR and BP will be 
obtained. 
Refer to Appendix 12.8, which provides guidance on hemodynamic monitoring and stopping criteria should a subject have an increase in HR or BP.
h
RR taken at screening and predose will be done in triplicate with at least a 1-2 minute interval between measurements. Predose measurements will be performed within 3 
hours prior to dosing.  For all other time points, a single measurement will be obtained.
i  
Standardized meals will be provided at ~ 4 hours (lunch) and ~10 hours (dinner) postdose. A snack will be offered at ~ 7 and ~13 hours postdose. After the 24 hr. postdose 
procedures have completed, subsequent meal and snacks will be unrestricted in terms of caloric content, composition, and timing.
j
MK-7252 or placebo will be  administered fasted unless otherwise specified in the protocol 
k
The taste assessment questionnaire should to be administered immediately after dosing and 10 min postdose at the dose level/panel anticipated to receive the highest dose 
only.
l
Safety laboratory samples will be collected after at least an 8-hour fast.
m
The drug screen at Screening is mandatory; any additional drug screens are conducted per site SOP. Predose drug screen can be conducted within 24 hours prior to dosing.
n
This sample should be drawn once only after randomization for planned analysis of the association between genetic variants in DNA and drug response. This sample will 
not be collected at the site if there is either a local law or regulation prohibiting collection, or if the IRB/IEC does not approve the collection of the sample for these 
purposes. If the sample is collected, leftover extracted DNA will be stored for future biomedical research if the subject signs the FBR consent. If the planned genetic 
analysis is not approved, but FBR is approved and consent is given, this sample will be collected for the purpose of FBR.  
o
Leftover main study plasma will be stored for future biomedical research.
p
Urine for Urinary MK-7252 Assay will be collected only in Panel B Period 2 and Panel B Period 5 at predose and at the following intervals postdose: 0-4, 4-8, 8-12, and 
12-24 hrs.
q 
 
r
Post-trial visit should occur approximately 14 days postdose. If the visit occurs prior to 14 days postdose, a phone call should be made to follow up on potential AEs.
 
 
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Procedures for Panel C (QD Dosing)
Scheduled Time
                                                 Hours/Days – All Periods
D1
D2
D3
D4
Screening 
1
Screening 
2a
Pre-dose
0
0.25
0.5
1
2
4
8
10
12
14
24
32
48
72
Post-trialr
Administrative Procedures
Informed Consent
X
Informed Consent for Future Biomedical Research
X
Inclusion/Exclusion Criteriab
X
X
Xc
Subject Identification Card
X
Xc
Medical History
X
X
X
Concomitant Medication Review
X----------------------------------------------------------------------------------------------------------------------------------------------X
Assignment of Screening Number
X
Assignment of Randomization Number
Xc
Clinic Procedures/Assessments
Full Physical Examination
X
Xd
X
X
Targeted Neurological Examination
X
Xd
X
X
Height
X
Weighte
X
X
X
12-Lead Electrocardiogramf
X
X
X
X
X
X
X
X
X
X
X
Vital Signs (heart rate, blood pressure)g
X
X
X
X
X
X
X
X
X
X
X
Orthostatic Vital Signs (heart rate, blood pressure)g
X
X
X
X
Vital Signs (respiratory rate, oral/tympanic 
temperature)h
X
X
X
X
Standard Mealsi
X-------------X
Standard High-Fat Meal for Fed Periodj
X
MK-7252/Placebo Administrationk
X
Adverse Events Monitoring
X----------------------------------------------------------------------------------------------------------------------------------------------X
 
 
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Procedures for Panel C (QD Dosing)
Scheduled Time
                                                 Hours/Days – All Periods
D1
D2
D3
D4
Screening 
1
Screening 
2a
Pre-dose
0
0.25
0.5
1
2
4
8
10
12
14
24
32
48
72
Post-trialr
Laboratory Procedures/Assessments
Laboratory Safety Testsl ( Hematology, Urinalysis 
and Serum Chemistry)
X
X
Xd
X
X
FSH (if applicable)
X
Urine/Blood Drug Screenm
X
X
HIV/Hepatitis Screen (per site SOP)
X
Blood for Genetic Analysisn
X
Pharmacokinetics Evaluations
Blood for Plasma MK-7252 Assayo
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urine for Urinary MK-7252 Assayp
X
X-------------------------------------------------------------------X
 
 
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a. If screening 1 occurs within 72hrs prior to the initial dose of trial drug, screening 2 is not required.
b. Review of inclusion/exclusion criteria will occur at Screening and after predose procedures (if applicable) in Period 1 only.
c. These pre-dose procedures are only applicable to Period 1.
d. Physical examination, targeted neurological exam and safety labs can be conducted/collected on admission within 24 hours prior to dosing.
e. Weight will be measured after 8 hours of fasting, with shoes and jacket off.
f. In all treatment periods, all ECGs will be obtained in triplicate and the mean of QTcF will be calculated. There should be ~1-2 minute intervals between ECG measurements. 
Predose ECGs will be obtained in triplicate at least 1-2 minutes apart within 3 hours prior to dosing of trial drug..
g. All semi-recumbent HR and BP measurements will be done in triplicate at least a 1-2 minutes interval between measurements.  Predose measurements can be performed 
within 3 hours prior to dosing. Subjects should be resting in the semi-recumbent position for at least 10 minutes prior to obtaining HR and BP. At pre-specified time points, 
following measurements of the semi-recumbent HR and BP, subjects assume a standing position for approximately 2 minutes and then orthostatic HR and BP will be 
obtained. 
Refer to Appendix 12.8, which provides guidance on hemodynamic monitoring and stopping criteria should a subject have an increase in HR or BP.
h. RR taken at screening and predose will be done in triplicate with at least a 1-2 minute interval between measurements. Predose measurements will be performed within 3 hours 
prior to dosing.  For all other timepoints, a single measurement will be obtained.
i. Standardized meals will be provided at ~ 4 hours (lunch) and ~10 hours (dinner) post dose. A snack will be offered at ~ 7 and ~13 hours post dose. After the 24 h post dose 
procedures have completed, subsequent meal and snacks will be unrestricted in terms of caloric content, composition, and timing.
j. A standard high-fat breakfast is to be administered 30 minutes prior to dosing for the fed period.
k. MK-7252 or placebo will be  administered fasted unless otherwise specified in the protocol 
l. Safety laboratory samples will be collected after at least an 8-hour fast.
m. The drug screen at Screening is mandatory; any additional drug screens are conducted per site SOP. Predose drug screen can be conducted within 24 hours prior to dosing.
n. This sample should be drawn once only after randomization for planned analysis of the association between genetic variants in DNA and drug response. This sample will not 
be collected at the site if there is either a local law or regulation prohibiting collection, or if the IRB/IEC does not approve the collection of the sample for these purposes. If 
the sample is collected, leftover extracted DNA will be stored for future biomedical research if the subject signs the FBR consent. If the planned genetic analysis is not 
approved, but FBR is approved and consent is given, this sample will be collected for the purpose of FBR.  
o. Leftover main study plasma will be stored for future biomedical research.
p. Urine for Urinary MK-7252 Assay will be collected only in Period 2 and Period 4 at pre-dose and at the following intervals post-dose: 0-4, 4-8, 8-12, and 12-24 hrs.
q.
r. Post-trial visit should occur approximately 14 days postdose. If the visit occurs prior to 14 days postdose, a phone call should be made to follow up on potential AEs.
 
 
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Procedures for Panel C (BID Dosing)
Scheduled Time
Hours/Days – All Applicable Periods
D1
D2
D3
Pre-dose
0
0.5
1
2
3
4
4.5
5
6
8
12
14
24
32
48
Post-trialm
Administrative Procedures
Medical History
X
Concomitant Medication Review
   X--------------------------------------------------------------------------------------------------------------------------------------X
Clinic Procedures/Assessments
Full Physical Examination
Xa
X
X
Targeted Neurological Examination
Xa
X
X
Weightb
X
X
12-Lead Electrocardiogramc
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital Signs (heart rate, blood pressure)d
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Orthostatic Vital Signs (heart rate, blood pressure)d
X
X
X
Vital Signs (respiratory rate, oral/tympanic 
temperature)e
X
X
X
Standard Mealsf
X-------------------------------------------------X
MK-7252/Placebo Administrationg
X
X
Adverse Events Monitoring
X-------------------------------------------------------------------------------------------------------------------------------X
Laboratory Procedures/Assessments
Laboratory Safety Testsh ( Hematology, Urinalysis and 
Serum Chemistry)
Xa
X
X
Urine/Blood Drug Screen
Xa
Blood for Genetic Analysisi(only applicable if sample 
not drawn in Period 1)
X
 
 
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Procedures for Panel C (BID Dosing)
Scheduled Time
Hours/Days – All Applicable Periods
D1
D2
D3
Pre-dose
0
0.5
1
2
3
4
4.5
5
6
8
12
14
24
32
48
Post-trialm
Pharmacokinetics Evaluations
Blood for Plasma MK-7252 Assayj
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urine for Urinary MK-7252 Assayk
X
X-------------------------------------------------------------------------------------X
a. Physical examination, targeted neurological exam, safety labs and drug screen can be conducted/collected on admission within 24 hours prior to dosing.
b. Weight will be measured after 8 hours of fasting, with shoes and jacket off.
c. In all treatment periods, all ECGs will be obtained in triplicate and the mean of QTcF will be calculated. There should be ~1-2 minute intervals between ECG 
measurements. Predose ECGs will be obtained in triplicate at least 1-2 minutes apart within 3 hours prior to dosing of trial drug..
d. All semi-recumbent HR and BP measurements will be done in triplicate at least a 1-2 minutes interval between measurements.  Predose measurements can be performed 
within 3 hours prior to dosing. Subjects should be resting in the semi-recumbent position for at least 10 minutes prior to obtaining HR and BP. At pre-specified time points, 
following measurements of the semi-recumbent HR and BP, subjects assume a standing position for approximately 2 minutes and then orthostatic HR and BP will be 
obtained. 
Refer to Appendix 12.8, which provides guidance on hemodynamic monitoring and stopping criteria should a subject have an increase in HR or BP.
e. RR taken predose will be done in triplicate with at least a 1-2 minute interval between measurements and within 3 hours prior to dosing.  For all other timepoints, a single 
measurement will be obtained.
f. Standardized meals will be provided at ~ 3 hours (lunch) and ~10 hours (dinner) post dose. A snack will be offered at ~ 7 and ~13 hours post dose. After the 24 h post dose 
procedures have completed, subsequent meal and snacks will be unrestricted in terms of caloric content, composition, and timing.
g. MK-7252 or placebo will be  administered fasted unless otherwise specified in the protocol 
h. Safety laboratory samples will be collected after at least an 8-hour fast.
i.
This sample should be drawn once only after randomization for planned analysis of the association between genetic variants in DNA and drug response. This sample will 
not be collected at the site if there is either a local law or regulation prohibiting collection, or if the IRB/IEC does not approve the collection of the sample for these 
purposes. If the sample is collected, leftover extracted DNA will be stored for future biomedical research if the subject signs the FBR consent. If the planned genetic 
analysis is not approved, but FBR is approved and consent is given, this sample will be collected for the purpose of FBR.    
j. Leftover main study plasma will be stored for future biomedical research.
k. Urine for Urinary MK-7252 Assay will be collected only in Period 2 and Period 4 at pre-dose and at the following intervals post-dose: 0-4, 4-8, 8-12, and 12-24 hrs.
l.
m. Post-trial visit should occur approximately 14 days postdose. If the visit occurs prior to 14 days postdose, a phone call should be made to follow up on potential AEs.
 
 
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7.0 TRIAL PROCEDURES
Trial Procedures
7.1
The Trial Flow Chart - Section 6.0 summarizes the trial procedures to be performed at each 
visit.  Individual trial procedures are described in detail below.  It may be necessary to 
perform these procedures at unscheduled time points if deemed clinically necessary by the 
investigator.
Furthermore, additional evaluations/testing may be deemed necessary by the investigator and 
or the Sponsor for reasons related to subject safety. In some cases, such evaluation/testing 
may be potentially sensitive in nature (e.g., HIV, Hepatitis C, etc.), and thus local regulations 
may require that additional informed consent be obtained from the subject.  In these cases, 
such evaluations/testing will be performed in accordance with those regulations.
Administrative Procedures
7.1.1
Informed Consent
7.1.1.1
The investigator or qualified designee must obtain documented consent from each potential 
subject or each subject’s legally acceptable representative prior to participating in a clinical
trial or Future Biomedical Research. If there are changes to the subject’s status during the 
trial (e.g., health or age of majority requirements), the investigator or qualified designee must 
ensure the appropriate consent is in place. 
7.1.1.1.1 General Informed Consent
Consent must be documented by the subject’s dated signature or by the subject’s legally 
acceptable representative’s dated signature on a consent form along with the dated signature 
of the person conducting the consent discussion. 
A copy of the signed and dated consent form should be given to the subject before 
participation in the trial.
The initial informed consent form, any subsequent revised written informed consent form 
and any written information provided to the subject must receive the IRB/ERC’s 
approval/favorable opinion in advance of use.  The subject or his/her legally acceptable 
representative should be informed in a timely manner if new information becomes available 
that may be relevant to the subject’s willingness to continue participation in the trial.  The 
communication of this information will be provided and documented via a revised consent 
form or addendum to the original consent form that captures the subject’s dated signature or 
by the subject’s legally acceptable representative’s dated signature.
Specifics about a trial and the trial population will be added to the consent form template at 
the protocol level.  
 
 
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The informed consent will adhere to IRB/IEC 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.
Inclusion/Exclusion Criteria
7.1.1.2
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee 
to ensure that the subject qualifies for the trial.
Subject Identification Card
7.1.1.3
All subjects will be given a Subject Identification Card identifying them as participants in a 
research trial. The card will contain trial site contact information (including direct telephone 
numbers) to be utilized in the event of an emergency. The investigator or qualified designee 
will provide the subject with a Subject Identification Card immediately after the subject 
provides written informed consent. At the time of treatment allocation/randomization, site 
personnel will add the treatment/randomization number to the Subject Identification Card.
Medical History
7.1.1.4
A medical history will be obtained by the investigator or qualified designee.
Prior and Concomitant Medications Review
7.1.1.5
7.1.1.5.1 Prior Medications
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the subject 
within14 days (or 5 half-lives) before first dose of trial medication.
7.1.1.5.2 Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the subject 
during the trial.
Assignment of Screening Number
7.1.1.6
All consented subjects will be given a unique screening number that will be used to identify 
the subject for all procedures that occur prior to randomization or treatment allocation.  Each 
subject will be assigned only one screening number.  Screening numbers must not be re-used 
for different subjects.
 
 
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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.  
Assignment of Treatment/Randomization Number
7.1.1.7
All eligible subjects will be randomly allocated and will receive a treatment/randomization 
number.  The treatment/randomization number identifies the subject for all procedures 
occurring after randomization.  Once a treatment/randomization number is assigned to a 
subject, it can never be re-assigned to another subject.
A single subject cannot be assigned more than 1 treatment/randomization number.
Trial Compliance (Medication)
7.1.1.8
Administration of trial medication will be witnessed by the investigator and/or trial staff.  
The date and time of administration as well as volume will also be recorded.  Please refer to 
the Method of Preparation Document regarding study drug preparation and administration.
Clinical Procedures/Assessments
7.1.2
Physical Examination
7.1.2.1
The physical exam assessments will be defined and conducted per the site SOP.
Targeted Neurological Examination
7.1.2.2
Please refer to the Appendix section 12.7 for details about the targeted neurological 
examination.  When applicable, targeted neurological examination assessments should be 
performed after all other pre-specified 4hr and 24hr procedures at the same time point 
(including vital sign measurements).
Body Weight and Height
7.1.2.3
Body height and weight will be obtained with the subjects shoes off, jacket or coat removed.
Body Mass Index (BMI)
7.1.2.4
Body mass index equals a person's weight in kilograms divided by height in meters squared. 
(BMI=kg/m2).  Body weight and height will be obtained with the subjects shoes off, jacket or 
coat removed.
 
 
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12-Lead ECG
7.1.2.5
Special care must be taken for proper lead placement by qualified personnel. Skin should be 
clean and dry prior to lead placement.  Subjects may need to be shaved to ensure proper lead 
placement.  Female subjects may need to remove their bra.
Lead placement should be rechecked in cases where unexpected ECG findings are noted.
Subjects should be resting in the semi-recumbent position for at least 10 minutes prior to 
each ECG measurement.  Subject position during safety ECG collection should be consistent 
throughout the study.
The correction formula to be used for QTc is Fridericia.
If repeat ECGs are required the clinical site will decide whether to leave the electrodes in 
place or mark the position of the electrodes for subsequent ECGs.  To mark the position of 
the electrodes, 12-lead electrode sites will be marked on the skin of each subject with an 
ECG skin marker pen to ensure reproducible electrode placement.
In all treatment periods, all ECGs will be obtained in triplicate and the mean of QTcF will be 
calculated. There should be ~1-2 minute intervals between ECG measurements. Predose
ECGs will be obtained in triplicate at least 1-2 minutes apart within 3 hours prior to dosing of 
trial drug.  The mean of these measurements will be used as the baseline to calculate change 
from baseline for safety evaluations (and for rechecks, if needed).  The investigator may 
perform additional ECGs for safety at other times if deemed necessary.
During each treatment period, if a subject demonstrates an increase in mean QTcF interval 
≥60 msec compared with mean predose baseline measurement, the ECG will be repeated 
twice within 5 minutes.  The mean value of the QTcF interval from the 5 ECGs will represent 
the value at that time point.  If the mean QTcF interval increase from baseline for any 
postdose time point is ≥60 msec, the subject will continue to be monitored by repeat safety 
12-lead ECGs every 15 minutes for at least 1 hour or until the QTcF is within 60 msec of 
baseline.  If prolongation of the QTcF interval ≥60 msec persists, a consultation with a study 
cardiologist may be appropriate and the Sponsor should be notified.
If the QTcF interval is ≥500 msec, the Sponsor should be notified and the safety ECGs 
should be reviewed by a cardiologist. The subject should be telemetry-monitored (until the 
QTcF is <500 msec) or should be considered for transfer to a location where closer 
monitoring and definitive care (e.g., a Cardiac or Intensive Care Unit) is available.
If the subject has unstable hemodynamics, or has any clinically significant dysrhythmias 
noted on telemetry, the subject should be immediately transferred to an acute care setting for 
definitive therapy.  
If prolongation of the QTcF is noted, concomitant medications that prolong QTcF should be 
held until the QTcF is within 60 msec of baseline and the QTcF is <500 msec.
 
 
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A study cardiologist should be arranged by the Principal Investigator to be available as 
needed to review safety ECG tracings with abnormalities.
Vital Sign Measurements (Heart Rate and Blood Pressure)
7.1.2.6
Subjects should be resting in a semi-recumbent position for at least 10 minutes prior to 
having vital sign measurements obtained.  Semi-recumbent vital signs will include HR and 
BP.  The correct size of the blood pressure cuff and the correct positioning on the subjects' 
arm is essential to increase the accuracy of BP measurements. 
All HR and BP measurements are to be obtained using a validated, semi-automated 
oscillometric device supplied by the investigator.  The same type of device (model) is to be 
used for all subjects throughout the study.  Preferentially, the same machine is to be used on 
the same subject throughout the study.  The oscillometric device model name and assigned 
number should be recorded in the source document for each subject.  Additionally, the arm 
used to obtain the BP measurements should be recorded in the source documents.  Ideally, 
the same arm will be used for these measurements for each subject throughout the study.  
At all predose and postdose timepoints in each period, HR and BP triplicate measurements 
will be obtained at least ~1-2 minutes apart.  The mean predose measurements in each 
period, taken 3 hours before dosing, will be used as the baseline for the purpose of safety 
monitoring by the site during the trial.
Orthostatic vital signs (HR and BP) will also be obtained.  Subjects should be semi-
recumbent for at least 10 minutes and then stand upright for 2 minutes prior to measurement 
of orthostatic vital signs.
Subjects will continue to rest semi-recumbent from dosing until 4 hours postdose except to 
stand for the measurement of orthostatic vital signs or other trial related procedure (if 
needed).
Refer to Appendix 12.8, which provides guidance on hemodynamic monitoring and stopping 
criteria should a subject have an increase in HR or BP.
Respiratory Rate Assessment
7.1.2.7
Respiratory rate will be counted as per site’s SOP. Respiratory rate taken at screening and
predose will be done in triplicate with at least 1 to 2 minute interval between measurements 
and predose measurements will be performed within 3 hours prior to dosing.  Subject should 
be resting in a semi-recumbent position for at least 10 minutes prior to measurement.  All 
other measurements will be single measurements.
Body Temperature
7.1.2.8
The same method must be used for all body temperature measurements for each individual 
subject and should be the same for all subjects.
 
 
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Taste Assessment Questionnaire
7.1.2.9
A taste assessment questionnaire will be implemented in this trial to assist with the 
development of future formulations of MK-7252.  A panel of subjects (anticipated to be 
Panel B) will be given this questionnaire immediately after dosing and at 10 minutes 
postdose in Period 5 or the highest dose period.
In order to prevent potential study unblinding, the questionnaire will be administered and 
reviewed by clinical staff members not involved with safety evaluations.  Subjects will be 
asked to individually complete their questionnaires and not discuss/share their responses with 
one another.  An example of the taste questionnaire is in Appendix section 12.6 and 
additional information is provided in the Study Operations Manual.
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 Section 12.3.
Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis)
7.1.3.1
Laboratory tests for hematology, chemistry and urinalysis are specified in Table 7.
 
 
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Table 7
Laboratory Tests
Hematology
Chemistry
Urinalysis
Other
Hematocrit
Albumin
Blood (RBC, WBC)
Follicle Stimulating 
Hormone (FSH) in 
WONCBP*
Hemoglobin
Alkaline phosphatase
Glucose
Hepatitis B surface 
antigen
Platelet count
Alanine aminotransferase 
(ALT)
Protein
Hepatitis C antibodies
WBC: total and 
differentials 
including:
Absolute 
Neutrophils
Absolute 
Lymphocytes
Absolute 
Monocytes
Absolute 
Eosinophils
Absolute 
Basophils
Aspartate aminotransferase 
(AST)
Specific gravity 
HIV 
RBC
Bicarbonate
Microscopic exam, if 
abnormal results are 
noted
Urine Drug Screen
Calcium
Chloride
Creatinine
Glucose
Phosphorus
Potassium
Sodium
Total Bilirubin  
Direct Bilirubin, if total 
bilirubin is elevated above the 
upper limit of normal
Total protein
Ureum
*Only collected at prestudy 
 
 
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Laboratory safety tests will be performed after at least an 8-hour fast.  Predose laboratory 
procedures can be conducted up to 24 hours prior to dosing.
Pharmacokinetic/Pharmacodynamic Evaluations
7.1.3.2
The decision as to which plasma and/or urine samples collected will be assayed for 
evaluation of PK/PD will be collaboratively determined by the Department of Quantitative 
Pharmacology and Pharmacometrics (QP2) and the appropriate department within Early-
Stage Development, (e.g., samples at lower doses may not be assayed if samples at higher 
doses reveal undetectable drug concentrations).  If indicated, these samples may also be 
assayed and/or pooled for assay in an exploratory manner for metabolites and/or additional 
pharmacodynamic markers.
Blood Collection for Plasma MK-7252
7.1.3.3
Sample collection, storage and shipment instructions for plasma samples will be provided in 
the Study Operations Manual.  
Urine Collection for Urinary MK-7252
7.1.3.4
Sample collection, storage and shipment instructions for urine samples will be provided in 
the Study Operations Manual.
 
 
 
 
 
 
Planned Genetic Analysis Sample Collection
7.1.3.6
Sample collection, storage and shipment instructions for Planned Genetic Analysis samples 
will be provided in the Study Operations Manual.
Future Biomedical Research Samples
7.1.3.7
The following specimens are to be obtained as part of Future Biomedical Research:
•
DNA for future research
•
Leftover main study plasma samples from MK-7252 stored for future research
 
 
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Other Procedures
7.1.4
Withdrawal/Discontinuation
7.1.4.1
The investigator or trial coordinator must notify the Sponsor when a subject has been 
discontinued/withdrawn from the trial and/or treatment.  If a subject discontinues for any 
reason at any time during the course of the trial and/or treatment, the subject may be asked to 
return to the clinic (or be contacted) for a post-trial visit (approximately 14 days after the last 
dose of trial drug is given) to have the applicable procedures conducted.  However, the 
investigator may decide to perform the post-trial procedures at the time of discontinuation or 
as soon as possible after discontinuation.  If the post-trial visit occurs prior to 14 days after 
the last dose of trial drug is given, the investigator should perform a follow-up phone call 14 
days after the last dose of trial drug to determine if any adverse events have occurred since 
the post-trial clinic visit.  Any adverse events which are present at the time of 
discontinuation/withdrawal should be followed in accordance with the safety requirements 
outlined in Section 7.2 - Assessing and Recording Adverse Events.
7.1.4.1.1 Withdrawal From Future Biomedical Research
Subjects may withdraw their consent for Future Biomedical Research.  Subjects may 
withdraw consent at any time by contacting the principal investigator for the main trial.  If 
medical records for the main trial are still available, the investigator will contact the Sponsor 
using the designated mailbox (clinical.specimen.management@merck.com).  Subsequently, 
the subject's consent for Future Biomedical Research will be withdrawn.  A letter will be sent 
from the Sponsor to the investigator confirming the withdrawal. It is the responsibility of the 
investigator to inform the subject of completion of withdrawal.  Any analyses in progress at 
the time of request for withdrawal or already performed prior to the request being received 
by the Sponsor will continue to be used as part of the overall research trial data and results.  
No new analyses would be generated after the request is received.
In the event that the medical records for the main trial are no longer available (e.g., if the 
investigator is no longer required by regulatory authorities to retain the main trial records) or 
the specimens have been completely anonymized, there will no longer be a link between the 
subject’s personal information and their specimens.  In this situation, the request for 
specimen withdrawal cannot be processed.
7.1.4.1.2 Lost to Follow-up
If a subject fails to return to the clinic for a required study visit and/or if the site is unable to 
contact the subject, the following procedures are to be performed:
•
The site must attempt to contact the subject and reschedule the missed visit.  If the 
subject is contacted, the subject should be counseled on the importance of maintaining 
the protocol-specified visit schedule.
 
 
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•
The investigator or designee must make every effort to regain contact with the subject at 
each missed visit (e.g. phone calls and/or a certified letter to the subject’s last known 
mailing address or locally equivalent methods). These contact attempts should be 
documented in the subject’s medical record.
•
Note:  A subject is not considered lost to follow up until the last scheduled visit for the 
individual subject.  The amount of missing data for the subject will be managed via the 
pre-specified statistical data handling and analysis guidelines.
Subject Blinding/Unblinding
7.1.4.2
Supplies will be provided with random code/disclosure envelopes or lists containing drug 
disclosure information. The Sponsor will provide one sealed envelope to the investigator for 
each treatment/randomization number and for each interval identifier (e.g., treatment period 
or visit).
Random code/disclosure envelopes or lists must be received by a designated person at the 
trial site and kept in a secured location to which only the investigator and delegate(s) have 
access.  The random code/disclosure envelopes or lists should be opened only in the case of 
an emergency. Drug identification information is to be unblinded ONLY in the event that this 
is required for subject safety. Subjects whose treatment assignment has been unblinded by 
the investigator/delegate and/or non-study treating physician must be discontinued from 
study drug, but should continue to be monitored in the trial.
Treatment identification information is to be unmasked ONLY if necessary for the welfare of 
the subject.  Every effort should be made not to unblind the subject unless necessary. 
In the event that unblinding has occurred, the circumstances around the unblinding (e.g., 
date, reason and person performing the unblinding) must be documented promptly, and the 
Sponsor Clinical Director notified as soon as possible. Only the principal investigator or 
delegate and the respective subject’s code should be unblinded. Other trial site personnel and 
Sponsor personnel directly associated with the conduct of the trial should not be unblinded.
At the end of the trial, random code/disclosure envelopes or lists and unblinding logs are to 
be returned to the Sponsor or designee.
Domiciling
7.1.4.3
Subjects will report to the clinical research unit (CRU) the evening prior to the scheduled day 
of trial drug administration in each treatment period remain in the unit until 24 hours 
postdose. At the discretion of the investigator, subjects may be requested to remain in the 
CRU longer.
Calibration of Critical Equipment
7.1.4.4
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 
 
 
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information about inclusion/exclusion criteria and/or safety or efficacy parameters shall be 
suitably calibrated and maintained to ensure that the data obtained is reliable and/or 
reproducible.  Documentation of equipment calibration must be retained as source 
documentation at the trial site.
Critical Equipment for this trial includes:
•
Equipment for taking vital signs
•
12-Lead ECG
•
Freezers used for PK and PD assay samples
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.
Screening
7.1.5.1
Approximately 4 weeks prior to treatment allocation/randomization, potential subjects will 
be evaluated to determine that they fulfill the entry requirements as set forth in Section 5.1.
Subjects may be rescreened after consultation with the Sponsor. Rescreening should include 
all screening procedures listed in the protocol flow chart, including consent review. Rescreen 
procedures cannot be conducted the day prior to treatment allocation/randomization if there 
are Day -1 procedures planned per protocol.
Treatment Period Visit
7.1.5.2
In each treatment period, subjects will report to the CRU prior to the scheduled day of dosing 
or time as specified by the investigator.  Subjects will fast from all food and drink, except for 
water, for at least 8 hours prior to trial drug administration. Subjects in the designated fed 
cohort (e.g. Period 5 of Panel C) will consume a standard high-fat meal (refer to Section 5.7)
30 minutes prior to trial drug administration. At all other visits, subjects will report to the 
CRU the evening prior to or the morning of the scheduled procedure.  Subjects are not 
required to have fasted prior to the scheduled visits following 24 hours postdose.
Critical Procedures Based on Trial Objectives: Timing of Procedure 
7.1.5.3
For this trial, the blood sample for MK-7252 is the critical procedure. 
At any postdose timepoint, the blood sample for MK-7252 needs to be collected as close to 
the exact timepoint as possible.  All other procedures should be completed as close to the 
prescribed/scheduled time as possible. Trial procedures can be performed prior or after the 
prescribed/scheduled time.  
 
 
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The order of priority can be changed during the trial with joint agreement of the investigator 
and the Sponsor Clinical Director.  
Any nonscheduled procedures required for urgent evaluation of safety concerns take 
precedence over all routine scheduled procedures. 
The following variance in procedure collection times will be permitted.
•
PK Collection as outlined in Table 8 and Table 9 below.
Table 8
PK (Blood) Collection Windows (QD Dosing)
PK/PD collection
PK /PD Collection Window
0 to <1 hr
5 min
1 to <24 hr
15 min
24 to <48 hr
60 min
≥48 hr
2 hr
Table 9
PK (Blood) Collection Windows (BID Dosing)
PK/PD collection
PK /PD Collection Window
0 to <5 hr
5 min
5 to <24 hr
15 min
24 to <48 hr
60 min
≥48 hr
2 hr
•
Urine PK Collection as outlined in Table 10 below.
Table 10
PK (Urine) Collection Windows
Urine PK collection
Urine PK Collection Window
0 to <24 hr
15 min
≥24 hr
60 min
 
 
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•
Predose standard safety evaluations:  
•
Vital signs (including weight) and ECG 3 hrs. prior to dosing; 
•
Laboratory safety tests (including drug screen) and physical and targeted neurological 
exam 24 hrs. prior to dosing.
•
Postdose standard safety evaluations (vital signs including weight, ECG, blood laboratory 
safety tests, physical exam, targeted neurological exam) as outlined in Table 11 below.
•
Postdose urine laboratory safety tests: 3 hrs.
Table 11
Scheduled Time Collection Windows
Scheduled Time
Collection Window
0 to <1 hr
15 min
1 to <24 hr
30 min
24 to <48 hr
60 min
>48 hr
2 hrs
Trial Design/Dosing/Procedures Modifications Permitted within Protocol 
7.1.5.4
Parameters
This is a Phase I assessment of MK-7252 in humans, and the PK, PD and safety profiles of 
the compound is still being elucidated.  This protocol is written with some flexibility to 
accommodate the inherent dynamic nature of Phase I clinical trials.  Modifications to the 
dose, dosing regimen and/or clinical or laboratory procedures currently outlined below may 
be required to achieve the scientific goals of the trial objectives and/or to ensure appropriate 
safety monitoring of the trial subjects.  
As such, some alterations from the currently outlined dose and/or dosing regimen may be 
permitted based on newly available data, but the maximum daily dose may not exceed those 
currently outlined in the protocol.
•
Repeat of or decrease in the dose of the trial drug administered in any given period/panel
•
Interchange of doses between panels
•
Entire period(s) or panel(s) may be omitted
•
Adjustment of the dosing interval (e.g., divided doses [BID to QD, QD to BID, TID or 
vice versa])
 
 
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•
Lengthening of the wash-out period between doses
•
Remove a planned pharmacokinetic pause if agreed by Sponsor and investigator if no 
further increases in total daily dose
•
Addition of pharmacokinetic pause
•
Instructions to take trial drug with or without food or drink may also be modified based 
on newly available data
•
Modification of the fed period to dosing in the fasted state or elimination of the fed 
period.
•
Taste assessment questionnaire may be administered in an earlier treatment period in the 
event that the highest planned dose level is not reached (e.g. due to safety signals etc.)
•
Modification of the PK/PD sample processing and shipping details based on newly 
available data
•
Modification of urine sample collection to another panel or period.
•
The pharmacokinetic/pharmacodynamic sampling scheme currently outlined in the protocol 
may be modified during the trial based on newly available pharmacokinetic or 
pharmacodynamic data (e.g., to obtain data closer to the time of peak plasma concentrations).  
If indicated, these collected samples may also be assayed in an exploratory manner for 
metabolites and/or additional pharmacodynamic markers.
Up to additional 50 mL (NOTE:  Never more than 50 mL) of blood may be drawn for safety, 
pharmacokinetic, and/or pharmacodynamic analyses.  The total blood volume withdrawn 
from any single subject will not exceed the maximum allowable volume during his/her 
participation in the entire trial (Appendix section 12.3). 
The timing of procedures for assessment of safety procedures (e.g., vital signs, ECG, safety 
laboratory tests, etc.) currently outlined in the protocol may be modified during the trial 
based on newly available safety, tolerability, pharmacokinetic or pharmacodynamic data 
(e.g., to obtain data closer to the time of peak plasma concentrations).  Additional laboratory 
safety tests may be added to blood samples previously drawn to obtain additional safety 
information (e.g., adding creatinine kinase to serum chemistry panel that was already drawn. 
These changes will not increase the number of trial procedures for a given subject during 
his/her participation in the entire trial. 
 
 
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It is understood that the current trial may employ some or none of the alterations described 
above.  Any alteration made to this protocol to meet the trial objectives must be detailed by 
the Sponsor in a letter to the Trial File and forwarded to the investigator for retention.  The 
letter may be forwarded to the IRB/IEC at the discretion of the investigator.
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.
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.
For randomized subjects only, all adverse events that occur after the consent form is signed 
but before treatment allocation/randomization must be reported by investigator if they 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).
 
 
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Definition of an Overdose for This Protocol and Reporting of Overdose to the 
7.2.1
Sponsor
The subject has taken (accidentally or intentionally) any drug administered as part of the 
protocol and exceeding the dose as prescribed by the protocol. It is up to the investigator or 
the reporting physician to decide whether a dose is to be considered an overdose, in 
consultation with the Sponsor.
If an adverse event(s) is associated with (“results from”) the overdose of Sponsor's product or 
vaccine, the adverse event(s) is reported as a serious adverse event, even if no other 
seriousness criteria are met.
If a dose of Sponsor's product or vaccine meeting the protocol definition of overdose is taken 
without any associated clinical symptoms or abnormal laboratory results, the overdose is 
reported as a non-serious Event of Clinical Interest (ECI), using the terminology “accidental 
or intentional overdose without adverse effect.”
All reports of overdose with and without an adverse event must be reported by the 
investigator within 24 hours to the Sponsor either by electronic media or paper. Electronic 
reporting procedures can be found in the EDC data entry guidelines. Paper reporting 
procedures can be found in the Investigator Trial File Binder (or equivalent).
Reporting of Pregnancy and Lactation to the Sponsor
7.2.2
Although pregnancy and lactation are not considered adverse events, it is the responsibility of 
investigators or their designees to report any pregnancy or lactation in a subject 
(spontaneously reported to them) that occurs during the trial.
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).
 
 
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Immediate Reporting of Adverse Events to the Sponsor
7.2.3
Serious Adverse Events
7.2.3.1
A serious adverse event is any adverse event occurring at any dose or during any use of 
Sponsor's product that:
●
Results in death;
●
Is life threatening;
●
Results in persistent or significant disability/incapacity;
●
Results in or prolongs an existing inpatient hospitalization;
●
Is a congenital anomaly/birth defect;
●
Is an other important medical event.
Note: In addition to the above criteria, adverse events meeting either of the below criteria, 
although not serious per ICH definition, are reportable to the Sponsor in the same timeframe 
as SAEs to meet certain local requirements. Therefore, these events are considered serious by 
the Sponsor for collection purposes.
●
Is a cancer;
●
Is associated with an overdose.
Refer to Table 12 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 
investigator at any time outside of the time period specified in the previous paragraph also 
must be reported immediately to the Sponsor.
 
 
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All subjects with serious adverse events must be followed up for outcome.
Events of Clinical Interest
7.2.3.2
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI) and must be reported to the Sponsor.
For the time period beginning when
the consent form is signed until treatment 
allocation/randomization, any ECI, or follow up to an ECI, that occurs to any subject must be 
reported within 24 hours to the Sponsor if it causes the subject to be excluded from the trial, 
or is the result of a protocol-specified intervention, including but not limited to washout or 
discontinuation of usual therapy, diet, placebo treatment or a procedure.
For the time period beginning at treatment allocation/randomization through 14 days 
following cessation of treatment, any ECI, or follow up to an ECI, whether or not related to 
the Sponsor’s product, must be reported within 24 hours to the Sponsor, either by electronic 
media or paper.  Electronic reporting procedures can be found in the EDC data entry 
guidelines.  Paper reporting procedures can be found in the Investigator Trial File Binder (or 
equivalent).
Events of clinical interest for this trial include:
1. an overdose of Sponsor's product, as defined in Section 7.2.1 - Definition of an Overdose 
for This Protocol and Reporting of Overdose to the Sponsor, that is not associated with 
clinical symptoms or abnormal laboratory results. 
2. an elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of 
normal and an elevated total bilirubin lab value that is greater than or equal to 2X the 
upper limit of normal and, at the same time, an alkaline phosphatase lab value that is less 
than 2X the upper limit of normal, as determined by way of protocol-specified laboratory 
testing or unscheduled laboratory testing.*
*Note:  These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that must trigger 
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).
It may also be appropriate to conduct additional evaluation for an underlying etiology in 
the setting of abnormalities of liver blood tests including AST, ALT, bilirubin, and 
alkaline phosphatase that do not meet the criteria noted above. In these cases, the decision 
to proceed with additional evaluation will be made through consultation between the 
study investigators and the Sponsor Clinical Director. However, abnormalities of liver 
blood tests that do not meet the criteria noted above are not ECIs for this trial.
   
 
 
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Evaluating Adverse Events
7.2.4
An investigator who is a qualified physician will evaluate all adverse events with respect to 
the elements outlined in Table 12. The investigator’s assessment of causality is required for 
each adverse event.  Refer to Table 12 for instructions in evaluating adverse events.
 
 
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Table 12
Evaluating Adverse Events
Maximum
Mild
awareness of sign or symptom, but easily tolerated  (for pediatric trials, awareness of symptom, but easily tolerated)
Intensity
Moderate
discomfort enough to cause interference with usual activity (for pediatric trials, definitely acting like something is wrong)
Severe
incapacitating with inability to work or do usual activity (for pediatric trials, extremely distressed or unable to do usual activities)
Seriousness
A serious adverse event (AE) is any adverse event occurring at any dose or during any use of Sponsor's product that:
†Results in death; or
†Is life threatening; or places the subject, in the view of the investigator, at immediate risk of death from the event as it occurred [Note: This does not include an 
adverse event that, had it occurred in a more severe form, might have caused death.]; or
†Results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to conduct normal life functions); or
†Results in or prolongs an existing inpatient hospitalization (hospitalization is defined as an inpatient admission, regardless of length of stay, even if the 
hospitalization is a precautionary measure for continued observation.  (Note: Hospitalization for an elective procedure to treat a pre-existing condition that has not 
worsened is not a serious adverse event.  A pre-existing condition is a clinical condition that is diagnosed prior to the use of a Merck product and is documented in the 
patient’s medical history.); or
†Is a congenital anomaly/birth defect  (in offspring of subject taking the product regardless of time to diagnosis); or
Is a cancer (although not serious per ICH definition, is reportable to the Sponsor within 24 hours to meet certain local requirements); or
Is associated with an overdose (whether accidental or intentional).  Any adverse event associated with an overdose is considered a serious adverse event for 
collection purposes. An overdose that is not associated with an adverse event is considered a non-serious event of clinical interest and must be reported within 24 
hours.
Other important medical events that may not result in death, not be life threatening, or not require hospitalization may be considered a serious adverse event when, 
based upon appropriate medical judgment, the event may jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes listed 
previously (designated above by a †).
Duration
Record the start and stop dates of the adverse event.  If less than 1 day, indicate the appropriate length of time and units
Action taken 
Did the adverse event cause the Sponsor's product to be discontinued?
 
 
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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
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.
 
 
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Record one of the following:
Use the following scale of criteria as guidance (not all criteria must be present to be indicative of a Sponsor's product relationship).
Yes, 
there 
is 
a 
reasonable 
possibility of Sponsor's product 
relationship.
There is evidence of exposure to the Sponsor's product.  The temporal sequence of the AE onset relative to the administration of the Sponsor's 
product is reasonable.  The AE is more likely explained by the Sponsor's product than by another cause. 
No, there is not a reasonable 
possibility of Sponsor's product 
relationship
Subject did not receive the Sponsor's product OR temporal sequence of the AE onset relative to administration of the Sponsor's product is not 
reasonable OR the AE is more likely explained by another cause than the Sponsor’s product.  (Also entered for a subject with overdose without 
an associated AE.)
 
 
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Sponsor Responsibility for Reporting Adverse Events
7.2.5
All Adverse Events will be reported to regulatory authorities, IRB/IECs and investigators in 
accordance with all applicable global laws and regulations, i.e., per ICH Topic E6 (R1) 
Guidelines for Good Clinical Practice.
8.0 STATISTICAL ANALYSIS PLAN
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).
Statistical Methods
8.1.1
Safety 
Summary statistics and plots will be generated for raw laboratory safety tests, ECGs, and 
vital signs as well as for change from baseline, as deemed clinically appropriate.  Depending 
on the safety parameter, the difference from baseline will either be computed on the original 
scale (raw change from baseline) or on the log scale and back-transformed for reporting 
(percent change from baseline).
Pharmacokinetics 
Model-based PK summary: Separately for each PK parameter, individual values of [AUC0-
∞, AUC0-24hr, AUC0-12hr, AUClast, Cmax , C12hr  and C24hr postdose, Tmax and t½] at 
each fasted and fed dose level will be natural log-transformed and evaluated with a linear 
mixed effects model containing a fixed effect for treatment and a random effect for subject. 
Kenward and Roger's method will be used to calculate the denominator degrees of freedom 
for the fixed effects.  Ninety-five percent confidence intervals for the least squares means for 
each treatment will be constructed on the natural log scale and will reference a t-distribution. 
Exponentiating the least-squares means and lower and upper limits of these confidence 
intervals will yield estimates for the population geometric means and confidence intervals 
about the geometric means on the original scale.
Food effect: The effect of food on MK-7252 will be estimated by obtaining the geometric 
mean ratio (fed/fasted) and 90% confidence interval for [AUC0-∞, AUC0-12hr and Cmax] at 
the dose level administered in both the fasted and fed state, using the previously-defined 
model.
Target PK level: The secondary hypothesis that the geometric mean C12hr of MK-7252
exceeds 100 nM at 1 or more well-tolerated fasted doses will be tested using the previously-
defined linear mixed effects model and the following stepwise procedure. At the highest safe 
and well-tolerated fasted dose, a 2-sided 90% confidence interval for the geometric mean of 
C12hr will be constructed.  The hypothesis will be supported (i.e., the true geometric mean 
C12hr exceeds 100 nM at this dose level) if the lower limit of this 90% confidence interval 
(equivalent to the lower limit of a one-sided 95% confidence interval) is greater than 100 nM. 
 
 
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If the hypothesis is supported in the previous step, then the same procedure will be applied to 
the next lowest safe and well-tolerated fasted dose.  The procedure continues in this stepwise 
fashion until the lower limit of the 90% confidence interval at a particular dose fails to 
exceed 100 nM (i.e. the true geometric mean C12hr fails to exceed 100 nM at this, and all 
lower doses). For estimation purposes, 90% confidence intervals will also be constructed for 
all doses at which the true geometric mean C12hr fails to exceed 100 nM.
Power
8.1.2
Pharmacokinetics: Since this will be the first administration of MK-7252 to humans, no 
variability estimates for PK are available from which to estimate power or precision.
A sample size of 6 subjects on active dose and 2 on placebo per panel per treatment period is 
considered to be adequate to address the primary objectives of the study.
Responsibility for Analyses/In-House Blinding
8.2
The statistical analysis of the data obtained from this study will be conducted by, or under the 
direct auspices of the Early Clinical Development Statistics Department in collaboration with 
the Quantitative Pharmacology and Pharmacometrics Department and Translational 
Pharmacology Department of the Sponsor.
If, after the study has begun, changes are made to the statistical analysis plan stated below, 
then these deviations to the plan will be listed, along with an explanation as to why they 
occurred, in the Clinical Study Report.
Objective(s) & Hypotheses/Estimation
8.3
Primary
1. Objective:  To evaluate the safety and tolerability of single ascending dose 
administration of MK-7252 in healthy men and women of non-childbearing potential 
(WONCBP).
Secondary
1. Objective:  To obtain preliminary plasma pharmacokinetic data including area under the 
curve (AUC0-∞, AUC0-24hr, AUC0-12hr, AUClast), maximal concentration (Cmax), 
C12hr and C24hr postdose, time to reach maximal concentration (Tmax), and apparent 
terminal half-life (t½) following oral administration of single doses of MK-7252.
Hypothesis:  The geometric mean Ctrough at 12 hr postdose (C12hr) meets or exceeds 
100 nM after single dose administration of MK-7252 at a dose that is sufficiently well 
tolerated to continue development for the treatment of cancer.
2. Objective: To evaluate the hemodynamic changes of MK-7252 given as single doses on 
peripheral BP (systolic and diastolic) and heart rate in healthy men and WONCBP.
 
 
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3. Objective (Panel C only): To compare the effects of a high-fat breakfast on the plasma 
pharmacokinetics of MK-7252 to those in the fasted state after administration of a single 
oral dose of MK-7252 in in healthy males and WONCBP.
Estimation:  The plasma AUC0-∞, AUC0-12hr and Cmax resulting from a single oral 
dose of MK-7252 following a standard breakfast will be estimated and compared to that 
observed with the identical dose level administered in the fasted state.
Exploratory
1.
 
 
2. Objective:
To
explore urinary excretion of MK-7252 following single dose 
administration in in healthy men and WONCBP.
3. Objective: To explore the relationship between genetic variation and response to the 
treatment administered, and mechanisms of disease.  Variation across the human genome 
may be analyzed for association with clinical data collected in this study.
Analysis Endpoints
8.4
Primary Endpoints
Safety: Primary safety endpoints will include all types of adverse experiences, in addition to 
laboratory safety tests, ECGs, and vital signs. [For changes from baseline analyses, baseline 
is defined as Day 1 Predose]
Secondary Endpoints (Pharmacokinetic)
1. Pharmacokinetics: The pharmacokinetic variables of interest for MK-7252 are AUC0-∞, 
AUC0-24hr, AUC0-12hr, AUClast, Cmax, Ctrough (12 hrs. and 24 hrs. postdose), Tmax 
and t½.  
2. Peripheral BP (systolic and diastolic)
Exploratory Endpoints:
1.
2. Urine excretion of MK-7252 is of secondary interest.
Analysis Populations
8.5
The following populations are defined for the analysis and reporting of data.  All subjects 
will be reported, and their data analyzed, according to the treatment(s) they actually received. 
 
 
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All Subjects as Treated (AST): The All Subjects as Treated Population consists of all subjects 
who received at least one dose of treatment.  This population will be used for assessments of 
safety and tolerability.
Per-Protocol (PP): The Per-Protocol Population consists of the set of data generated by the 
subset of subjects who comply with the protocol sufficiently to ensure that these data will be 
likely to exhibit the effects of treatment, according to the underlying scientific model. 
Compliance covers such considerations as exposure to treatment, availability of 
measurements and absence of major protocol deviations.  Major protocol deviations will be 
identified to the extent possible prior to unblinding by individuals responsible for data 
collection/compliance, and its analysis and interpretation.  Any subjects or data values 
excluded from analysis will be identified, along with their reason for exclusion, in the CSR.  
At the end of the study, all subjects who are compliant with the study procedure as 
aforementioned and have available data from at least one treatment will be included in the 
Per-Protocol dataset. This population will be used for the PK and PD analyses.
Statistical Methods
8.6
Safety 
Summary statistics and plots will be generated for raw laboratory safety tests, ECGs, and/or 
vital signs as well as for change from baseline, as deemed clinically appropriate.  Depending 
on the safety parameter, the difference from baseline will either be computed on the original 
scale (raw change from baseline) or on the log scale and back-transformed for reporting 
(percent change from baseline). 
Pharmacokinetics
Model-Based PK Summary 
Separately for each PK parameter, individual values of [AUC0-∞, AUC0-24hr, AUC0-12hr, 
AUClast, Cmax, Ctrough (12 hrs. and 24 hrs. postdose), Tmax and t½] at each fasted and fed 
dose level will be natural log-transformed and evaluated with a linear mixed effects model 
containing a fixed effect for treatment and a random effect for subject. Kenward and Roger's 
method will be used to calculate the denominator degrees of freedom for the fixed effects.  
Ninety-five percent confidence intervals for the least squares means for each treatment will 
be constructed on the natural log scale and will reference the t-distribution. Exponentiating 
the least-squares means and lower and upper limits of these confidence intervals will yield 
estimates for the population geometric means and confidence intervals about the geometric 
means on the original scale.
If BID dosing is implemented in Panel C, a slightly different model than described above for 
selected PK parameters may be utilized.
 
 
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Food Effect 
The effect of food on MK-7252 will be estimated by obtaining the geometric mean ratio 
(fed/fasted) and 90% confidence interval for [AUC0-∞, AUC0-12hr and Cmax] at the dose 
level administered in both the fasted and fed state, using the previously-described linear 
mixed effects model.
Target PK Level 
The secondary hypothesis that the geometric mean Ctrough at 12 hr. postdose (C12hr) of 
MK-7252 exceeds 100 nM at one or more well-tolerated fasted doses will be tested using the 
previously-described linear mixed effects model and the following stepwise procedure. At 
the highest safe and well-tolerated fasted dose, a 2-sided 90% confidence interval for the 
geometric mean of C12hr will be constructed.  The hypothesis will be supported (i.e., the true 
geometric mean C12hr exceeds 100 nM at this dose level) if the lower limit of this 90% 
confidence interval (equivalent to the lower bound of a one-sided 95% confidence interval) is 
greater than 100 nM. If the hypothesis is supported in the previous step, then the same 
procedure will be applied to the next lowest safe and well-tolerated fasted dose.  The 
procedure continues in this stepwise fashion until the lower limit of the 90% confidence 
interval at a particular dose fails to exceed 100 nM (i.e. the true geometric mean C12hr fails 
to exceed 100 nM at this, and all lower doses). For estimation purposes, 90% confidence 
intervals will also be constructed for all doses at which the true geometric mean C12hr fails 
to exceed 100 nM.
Dose Proportionality
An exploratory analysis will be conducted to preliminarily assess dose proportionality of 
MK-7252 [AUC0-∞, Cmax, Ctrough (12 hrs. and 24 hrs. postdose)] in the fasted state. 
Separately for each PK parameter, the potential effects of panel will be first explored using a 
linear mixed effect model with ln(dose), panel, and ln(dose) by panel interaction as fixed 
effects and subject within panel as a random effect. If the ln(dose) by panel interaction is 
found to be statistically significant at the 0.05 significance level, the slope will be estimated 
separately for each panel, and a plot containing observed PK data vs. dose and an estimated 
regression line on the raw scale will be provided separately for each panel, together with a 
95% Schéffe confidence band for the regression line. If the interaction term is not statistically 
significant, then it will be dropped from the above full model, and the main panel effect will 
be tested for statistical significance at the 0.05 level. If the panel effect is statistically 
significant, then the final model will include ln(dose) as a covariate, panel as a fixed effect 
and subject within panel as a random effect; otherwise, the final model will include ln(dose) 
as a covariate and subject within panel as a random effect. In both cases, an overall slope will 
be estimated across both panels. In the former case, a plot containing observed PK data vs. 
dose and an estimated regression line on the raw scale will be provided separately for each 
panel, together with a 95% Schéffe confidence band for the regression line. In the latter case, 
a plot of the observed PK data versus dose will be provided along with an overall estimated 
regression line on the raw scale and a 95% Schéffe confidence band. 
 
 
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Descriptive Statistics 
Individual values will be listed for each PK parameter by treatment, and the following (non-
model-based) descriptive statistics will be provided: N (number of subjects with non-missing 
data), arithmetic mean, standard deviation, arithmetic  percent CV (calculated as 100 x 
standard deviation/arithmetic mean), median, minimum, maximum, geometric mean, and 
geometric percent CV (calculated as  100 x sqrt(exp(s2) - 1), where s2 is the observed 
variance on the natural log-scale).
Pharmacodynamics
PK-PD
The relationship between plasma concentrations 
 peripheral BP
(systolic and diastolic) and HR will be explored graphically. Upon visual inspection, 
additional model-based analysis may be employed to further explore the PK/PD relationship.
QTc Analysis
If multiple QT measurements are taken at a single time point, then the average of the 
multiple measurements will be calculated prior to any further analysis. Fridericia’s correction 
to QT (QTcF = QT^( RR1/3)) will be made in order to correct for HR. The appropriateness 
of the correction factor (i.e., 1/3) will be assessed via a linear mixed effects model with QTcF 
as the response variable and RR interval as a covariate and subject as a random effect, using 
data from the placebo treatment and the predose measurements of the active treatments.  A 
slope estimate close to zero would indicate that Fridericia's correction provides an adequate 
correction to the original QT data; otherwise, an appropriate transformation on RR will be 
further explored.
The predose value in each treatment period will serve as baseline for calculating individual 
change from baseline at each time point in that period.  Observed plasma concentrations and
observed QTcF change from baseline will be used to investigate the relationship between 
QTcF and plasma MK-7252 concentrations (placebo data will also be used in this 
assessment, with the plasma concentration of MK-7252 set to 0). Scatter plots of QTcF 
change from baseline versus corresponding time-matched MK-7252 concentration will be 
provided.
The QTcF change from baseline will be further evaluated using a linear mixed effects model 
with fixed effects for treatment and time point and continuous effects for QTcF baseline and 
plasma concentration.  A double compound symmetry covariance structure will be assumed. 
The highest ‘safe’ drug concentration (C_safe), defined as the highest drug concentration 
whose upper limit of 2-sided 90% confidence interval (equivalent to a 1-sided upper 95% 
confidence limit) of ΔΔQTcF (placebo- baseline- adjusted) less than 10 milliseconds (ms), 
will be reported. An estimate of the expected mean effect and 90% confidence interval of 
 
 
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ΔΔQTcF will also be computed at the observed geometric mean Cmax for each MK-7252 
dose of interest.  
The adequacy of the above models and covariance structure will be assessed, and other
models (e.g., nonlinear, delayed effect, additional random effect on slope) may be explored if 
needed.
Additionally, a bootstrap based 2-sided 90% confidence interval for the ΔΔQTcF at the 
observed geometric mean Cmax for each MK-7252 dose of interest will be obtained using a 
bias corrected nonparametric bootstrap procedure with 3000 replicates and subject as unit of 
resampling. The geometric mean Cmax for each MK-7252 dose of interest will be 
determined for each replicate. The estimated ΔΔQTcF at the observed geometric mean Cmax 
will be determined from each of the replicates using the above linear mixed effects model. 
The bootstrap-based 2-sided 90% confidence interval at the observed geometric mean Cmax 
will be obtained as the 5% quartile and 95% quartile of the distribution of estimated ΔΔQTcF 
at the observed geometric mean Cmax from 3000 replicates.
General
For all analyses, data will be examined for departures from the assumptions of the statistical 
model(s) as appropriate; e.g., heteroscedasticity, non-normality of the error terms.  
Distribution-free methods may be used if a serious departure from the assumptions of the 
models(s) is observed, or suitable data transformations may be applied.
Multiplicity
8.7
No multiplicity adjustment is needed given the estimation purpose of this trial.
Sample Size and Power Calculations
8.8
Pharmacokinetics: Since this will be the first administration of MK-7252 to humans, no 
variability estimates for PK are available from which to estimate power or precision.
A sample size of 6 subjects on active dose and 2 on placebo per panel in each treatment 
period is considered to be adequate to address the primary objectives of the study. 
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.
 
 
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Clinical Supplies will be provided by the Sponsor as summarized in Table 13. The on-site 
formulation of MK-7252 and an identically appearing placebo will be prepared and packaged 
at the clinical study site.
Clinical supplies will be packaged to support enrollment and replacement subjects as 
required.  When a replacement subject is required, the Sponsor or designee needs to be 
contacted prior to dosing the replacement supplies.
Table 13
Product Descriptions
Product Name & Potency
Dosage Form
MK-7252 (1 mg/mL)
Powder for oral suspension 
(1 mg/mL)
MK-7252 (20 mg/mL)
Powder for oral suspension 
(20 mg/mL)
Packaging and Labeling Information
9.2
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements.
Subjects will receive doses of MK-7252 provided in syringes covered with blinding label, 
dispensed by an unblinded pharmacist from clinical supplies. No kitting is required.  Clinical 
supplies will be affixed with a clinical label in accordance with regulatory requirements.
Clinical Supplies Disclosure
9.3
This trial is blinded but supplies are provided open label; therefore, an unblinded pharmacist 
or qualified trial site personnel will be used to blind supplies. Treatment identity (name, 
strength or potency) is included in the label text; random code/disclosure envelopes or lists 
are provided.
Supplies    will be provided with random code/disclosure envelopes or lists containing drug 
disclosure information. The Sponsor will provide one sealed envelope to the investigator for 
each treatment/randomization number per treatment period.
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.
Storage and Handling Requirements
9.4
Clinical supplies must be stored in a secure, limited-access location under the storage 
conditions specified on the label.  
Receipt and dispensing of trial medication must be recorded by an authorized person at the 
trial site.
Clinical supplies may not be used for any purpose other than that stated in the protocol.
 
 
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Discard/Destruction/Returns and Reconciliation
9.5
The investigator is responsible for keeping accurate records of the clinical supplies received 
from the Sponsor or designee, the amount dispensed to and returned by the subjects and the 
amount remaining at the conclusion of the trial. For all trial sites, the local country Sponsor 
personnel or designee will provide appropriate documentation that must be completed for 
drug accountability and return, or local discard and destruction if appropriate.  Where local 
discard and destruction is appropriate, the investigator is responsible for ensuring that a local 
discard/destruction procedure is documented.
10.0 ADMINISTRATIVE AND REGULATORY DETAILS
Confidentiality
10.1
Confidentiality of Data
10.1.1
By signing this protocol, the investigator affirms to the Sponsor that information furnished to 
the investigator by the Sponsor will be maintained in confidence, and such information will 
be divulged to the institutional review board, ethics review committee (IRB/ERC) or similar 
or expert committee; affiliated institution and employees, only under an appropriate 
understanding of confidentiality with such board or committee, affiliated institution and 
employees.  Data generated by this trial will be considered confidential by the investigator, 
except to the extent that it is included in a publication as provided in the Publications section 
of this protocol.
Confidentiality of Subject Records
10.1.2
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/ERC, or regulatory authority representatives may consult and/or copy trial documents in 
order to verify worksheet/case report form data.  By signing the consent form, the subject 
agrees to this process.  If trial documents will be photocopied during the process of verifying 
worksheet/case report form information, the subject will be identified by unique code only; 
full names/initials will be masked prior to transmission to the Sponsor.
By signing this protocol, the investigator agrees to treat all subject data used and disclosed in 
connection with this trial in accordance with all applicable privacy laws, rules and 
regulations.
Confidentiality of Investigator Information
10.1.3
By signing this protocol, the investigator recognizes that certain personal identifying 
information with respect to the investigator, and all subinvestigators and trial site personnel, 
may be used and disclosed for trial management purposes, as part of a regulatory 
submissions, and as required by law.  This information may include:
1. name, address, telephone number and e-mail address;
2. hospital or clinic address and telephone number;
 
 
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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 that reviews and 
approves this trial.  The Sponsor is also required to document that each IRB/IEC meets 
regulatory and ICH GCP requirements by requesting and maintaining records of the names 
and qualifications of the IRB/IEC members and to make these records available for 
regulatory agency review upon request by those agencies.
Compliance with Financial Disclosure Requirements
10.2
Financial Disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54).  It is the 
Sponsor's responsibility to determine, based on these regulations, whether a request for 
Financial Disclosure information is required.  It is the investigator's/subinvestigator's 
responsibility to comply with any such request.  
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21 
CFR Part 54, to provide his/her financial interests in and/or arrangements with the Sponsor to 
allow for the submission of complete and accurate certification and disclosure statements.  
The investigator/subinvestigator(s) further agree to provide this information on a 
Certification/Disclosure Form, commonly known as a financial disclosure form, provided by 
the Sponsor. The investigator/subinvestigator(s) also consent to the transmission of this 
information to the Sponsor in the United States for these purposes.  This may involve the 
transmission of information to countries that do not have laws protecting personal data.
Compliance with Law, Audit and Debarment
10.3
By signing this protocol, the investigator agrees to conduct the trial in an efficient and 
diligent manner and in conformance with this protocol; generally accepted standards of Good 
Clinical Practice (e.g., International Conference on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human Use Good Clinical Practice: 
Consolidated Guideline and other generally accepted standards of good clinical practice); and 
 
 
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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/IEC 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 
when documents may be destroyed.  The Sponsor will determine the minimum retention 
period and upon request, will provide guidance to the investigator when documents no longer 
need to be retained.  The Sponsor also recognizes that documents may need to be retained for 
 
 
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a longer period if required by local regulatory requirements. All trial documents shall be 
made available if required by relevant regulatory authorities. The investigator must consult 
with and obtain written approval by the Sponsor prior to destroying trial and/or subject files.  
ICH Good Clinical Practice guidelines recommend that the investigator inform the subject’s 
primary physician about the subject’s participation in the trial if the subject has a primary 
physician and if the subject agrees to the primary physician being informed.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this trial.
Persons debarred from conducting or working on clinical trials by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s trials.  The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the trial is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
In the event the Sponsor prematurely terminates a particular trial site, the Sponsor will 
promptly notify that trial site’s IRB/IEC.
According to European legislation, a Sponsor must designate an overall coordinating 
investigator for a multi-center trial (including multinational).  When more than one trial site 
is open in an EU country, Merck, as the Sponsor, will designate, per country, a national 
principal coordinator (Protocol CI), responsible for coordinating the work of the principal 
investigators at the different trial sites in that Member State, according to national 
regulations.  For a single-center trial, the Protocol CI is the principal investigator.  In 
addition, the Sponsor must designate a principal or coordinating investigator to review the 
trial report that summarizes the trial results and confirm that, to the best of his/her 
knowledge, the report accurately describes the conduct and results of the trial [Clinical Study 
Report (CSR) CI].  The Sponsor may consider one or more factors in the selection of the 
individual to serve as the Protocol CI and or CSR CI (e.g., availability of the Protocol/CSR 
CI during the anticipated review process, thorough understanding of clinical trial methods, 
appropriate enrollment of subject cohort, timely achievement of trial milestones).  The 
Protocol CI must be a participating trial investigator.
Compliance with Trial Registration and Results Posting Requirements
10.4
Under the terms of the Food and Drug Administration Amendments Act (FDAAA) of 2007 
and the European Medicines Agency (EMA) clinical trial Directive 2001/20/EC, the Sponsor 
of the trial is solely responsible for determining whether the trial and its results are subject to 
the 
requirements 
for 
submission 
to 
http://www.clinicaltrials.gov, 
www.clinicaltrialsregister.eu or other local registries.  Merck, as Sponsor of this trial, will 
review this protocol and submit the information necessary to fulfill these requirements. 
Merck entries are not limited to FDAAA or the EMA clinical trial directive mandated trials.  
Information posted will allow subjects to identify potentially appropriate trials for their 
disease conditions and pursue participation by calling a central contact number for further 
information on appropriate trial locations and trial site contact information.  
 
 
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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 accurac y 
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 
 
 
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allow the journal, if it so desires, to post on its website the key sections of the protocol that 
are relevant to evaluating the trial, specifically those sections describing the trial objectives 
and hypotheses, the subject inclusion and exclusion criteria, the trial design and procedures, 
the efficacy and safety measures, the statistical analysis plan, and any amendments relating to 
those sections.  The Sponsor reserves the right to redact proprietary information.
For multicenter trials, subsequent to the multicenter publication (or after public disclosure of 
the results online at www.clinicaltrials.gov if a multicenter manuscript is not planned), an 
investigator and his/her colleagues may publish their data independently.  In most cases, 
publication of individual trial site data does not add value to complete multicenter results, 
due to statistical concerns.  In rare cases, publication of single trial site data prior to the main 
paper may be of value.  Limitations of single trial site observations in a multicenter trial 
should always be described in such a manuscript.
Authorship credit should be based on 1) substantial contributions to conception and design, 
or acquisition of data, or analysis and interpretation of data; 2) drafting the article or revising 
it critically for important intellectual content; and 3) final approval of the version to be 
published. Authors must meet conditions 1, 2 and 3.  Significant contributions to trial 
execution may also be taken into account to determine authorship, provided that 
contributions have also been made to all three of the preceding authorship criteria.  Although 
publication planning may begin before conducting the trial, final decisions on authorship and 
the order of authors’ names will be made based on participation and actual contributions to 
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]
Smyth MJ, Ngiow SF, Ribas A, Teng MW. Combination cancer 
immunotherapies tailored to the tumour microenvironment. Nat Rev Clin Oncol. 
2016 Mar;13(3):143-58.
[2]
Bours MJ, Swennen EL, Di Virgilio F, Cronstein BN, Dagnelie PC. Adenosine 
5'-triphosphate and adenosine as endogenous signaling molecules in immunity 
and inflammation. Pharmacol Ther. 2006 Nov;112(2):358-404.
[3]
Hatfield SM, Sitkovsky M. A2A adenosine receptor antagonists to weaken the 
hypoxia-HIF-1α driven immunosuppression and improve immunotherapies of 
cancer. Curr Opin Pharmacol. 2016 Aug;29:90-6.
[4]
Linnemann C, Schildberg FA, Schurich A, Diehl L, Hegenbarth SI, Endl E, et al. 
Adenosine regulates CD8 T-cell priming by inhibition of membrane-proximal 
T-cell receptor signalling. Immunology. 2009 Sep;128(1 Suppl):e728-37.
[5]
Leone RD, Lo YC, Powell JD. A2aR antagonists: Next generation checkpoint 
blockade for cancer immunotherapy. Comput Struct Biotechnol J. 2015 
Apr 8;13:265-72.
[6]
Mittal D, Young A, Stannard K, Yong M, Teng MW, Allard B, et al. 
Antimetastatic effects of blocking PD-1 and the adenosine A2A receptor. Cancer 
Res. 2014 Jul 15;74(14):3652-8.
[7]
Willingham S, Ho P, Leone R, Piccione E, Choy C,  Hotson A, et al. The 
adenosine A2A receptor antagonist CPI-444 blocks adenosine-mediated T-cell 
suppression and exhibits antitumor activity alone and in combination with anti-
PD-1 and anti-PD-L1. Poster session presented at: 107th Annual Meeting of the 
American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA.
[8]
Hotson A, Willingham S, Ho P, Choy C, Laport G, McCaffery I, et al. CPI-444: 
a potent and selective inhibitor of adenosine 2A receptor (A2AR) induces anti-
tumor responses alone and in combination with anti-PD-L1 [abstract]. Journal for 
ImmunoTherapy of Cancer. 2016 Nov; 04(1):120. Abstract no. P-212.
 
 
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12.0 APPENDICES
Merck Code of Conduct for Clinical Trials
12.1
Merck*
Code of Conduct for Clinical Trials
I.
Introduction
A. Purpose
Merck, through its subsidiaries, conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, implementing, conducting, analyzing and reporting these trials in 
compliance with the highest ethical and scientific standards. Protection of subject safety is the overriding concern in 
the design of clinical trials. In all cases, Merck clinical trials will be conducted in compliance with local and/or 
national regulations and in accordance with the ethical principles that have their origin in the Declaration of Helsinki. 
B. Scope
Such standards shall be endorsed for all clinical interventional investigations sponsored by Merck irrespective of the 
party (parties) employed for their execution (e.g., contract research organizations, collaborative research efforts). This 
Code is not intended to apply to trials which are observational in nature, or which are retrospective. Further, this Code 
does not apply to investigator-initiated trials which are not under the control of Merck.
II. Scientific Issues
A. Trial Conduct
1. Trial Design
Except for pilot or estimation trials, clinical trial protocols will be hypothesis-driven to assess safety, efficacy 
and/or pharmacokinetic or pharmacodynamic indices of Merck or comparator products.  Alternatively, Merck may 
conduct outcomes research trials, trials to assess or validate various endpoint measures, or trials to determine 
subject preferences, etc.  
The design (i.e., subject population, duration, statistical power) must be adequate to address the specific purpose 
of the trial.  Research subjects must meet protocol entry criteria to be enrolled in the trial. 
2. Site Selection
Merck selects investigative sites based on medical expertise, access to appropriate subjects, adequacy of facilities 
and staff, previous performance in Merck trials, as well as budgetary considerations.  Prior to trial initiation, sites 
are evaluated by Merck personnel to assess the ability to successfully conduct the trial.
3. Site Monitoring/Scientific Integrity
Trial sites are monitored to assess compliance with the trial protocol and general principles of Good Clinical 
Practice.  Merck reviews clinical data for accuracy, completeness and consistency. Data are verified versus source 
documentation according to standard operating procedures.  Per Merck policies and procedures, if fraud, 
misconduct or serious GCP-non-Compliance are suspected, the issues are promptly investigated. When necessary, 
the clinical site will be closed, the responsible regulatory authorities and ethics review committees notified and 
data disclosed accordingly. 
B. Publication and Authorship
To the extent scientifically appropriate, Merck seeks to publish the results of trials it conducts.  Some early phase or 
pilot trials are intended to be hypothesis-generating rather than hypothesis testing.  In such cases, publication of 
results may not be appropriate since the trial may be underpowered and the analyses complicated by statistical issues 
of multiplicity.
Merck’s policy on authorship is consistent with the requirements outlined in the ICH-Good Clinical Practice 
guidelines. In summary, authorship should reflect significant contribution to the design and conduct of the trial, 
performance or interpretation of the analysis, and/or writing of the manuscript.  All named authors must be able to 
defend the trial results and conclusions.  Merck funding of a trial will be acknowledged in publications. 
 
 
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III. Subject Protection
A. IRB/ERC review
All clinical trials will be reviewed and approved by an independent IRB/ERC before being initiated at each site.  
Significant changes or revisions to the protocol will be approved by the IRB/ERC prior to implementation, except that 
changes required urgently to protect subject safety and well-being may be enacted in anticipation of IRB/ERC 
approval. For each site, the IRB/ERC and Merck will approve the subject informed consent form. 
B. Safety
The guiding principle in decision-making in clinical trials is that subject welfare is of primary importance.  Potential 
subjects will be informed of the risks and benefits of, as well as alternatives to, trial participation. At a minimum, trial 
designs will take into account the local standard of care.  Subjects are never denied access to appropriate medical care 
based on participation in a Merck clinical trial. 
All participation in Merck clinical trials is voluntary.  Subjects are enrolled only after providing informed consent for 
participation.  Subjects may withdraw from a Merck trial at any time, without any influence on their access to, or 
receipt of, medical care that may otherwise be available to them.
C. Confidentiality
Merck is committed to safeguarding subject confidentiality, to the greatest extent possible. Unless required by law, 
only the investigator, Sponsor (or representative) and/or regulatory authorities will have access to confidential medical 
records that might identify the research subject by name.  
D. Genomic Research
Genomic Research will only be conducted in accordance with informed consent and/or as specifically authorized by 
an Ethics Committee.
IV. Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive.  It is Merck’s policy to compensate investigators (or the sponsoring 
institution) in a fair manner for the work performed in support of Merck trials.  Merck does not pay incentives to 
enroll subjects in its trials.  However, when enrollment is particularly challenging, additional payments may be made 
to compensate for the time spent in extra recruiting efforts.
Merck does not pay for subject referrals.  However, Merck may compensate referring physicians for time spent on 
chart review to identify potentially eligible subjects.
B. Clinical Research Funding 
Informed consent forms will disclose that the trial is sponsored by Merck, and that the investigator or sponsoring 
institution is being paid or provided a grant for performing the trial.  However, the local IRB/ERC may wish to alter 
the wording of the disclosure statement to be consistent with financial practices at that institution.  As noted above, 
publications resulting from Merck trials will indicate Merck as a source of funding.
C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (e.g., to scientific meetings, investigator meetings, etc.) will be 
consistent with local guidelines and practices including, in the U.S., those established by the American Medical 
Association (AMA). 
V. Investigator Commitment
Investigators will be expected to review Merck’s Code of Conduct as an appendix to the trial protocol, and in signing 
the protocol, agree to support these ethical and scientific standards.
* In this document, "Merck" refers to Merck Sharp & Dohme Corp. and Schering Corporation, each of which is a 
subsidiary of Merck & Co., Inc.  Merck is known as MSD outside of the United States and Canada.  As warranted by 
context, Merck also includes affiliates and subsidiaries of Merck & Co., Inc."
 
 
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Collection and Management of Specimens for Future Biomedical Research
12.2
1. Definitions
a.
Biomarker:  A biological molecule found in blood, other body fluids, or tissues that is a 
sign of a normal or abnormal process or of a condition or disease.  A biomarker may be 
used to see how well the body responds to a treatment for a disease or condition.1
b. Pharmacogenomics:  The investigation of variations of DNA and RNA characteristics as 
related to drug/vaccine response.2
c.
Pharmacogenetics:  A subset of pharmacogenomics, pharmacogenetics is the influence of 
variations in DNA sequence on drug/vaccine response.2
d. DNA:  Deoxyribonucleic acid.
e.
RNA:  Ribonucleic acid.
2. Scope of Future Biomedical Research
The specimens consented and/or collected in this trial as outlined in Section 7.1.3.7 –
Future Biomedical Research Samples will be used in various experiments to understand:
o
The biology of how drugs/vaccines work
o
Biomarkers responsible for how a drug/vaccine enters and is removed by the body
o
Other pathways drugs/vaccines may interact with
o
The biology of disease
The specimen(s) may be used for future assay development and/or drug/vaccine 
development.
It is now well recognized that information obtained from studying and testing clinical 
specimens offers unique opportunities to enhance our understanding of how individuals 
respond to drugs/vaccines, enhance our understanding of human disease and ultimately 
improve public health through development of novel treatments targeted to populations 
with the greatest need.  All specimens will be used by the Sponsor or those working for 
or with the Sponsor.
3. Summary of Procedures for Future Biomedical Research
a.
Subjects for Enrollment
All subjects enrolled in the clinical trial will be considered for enrollment in the
Future Biomedical Research sub-trial.
b. Informed Consent
Informed consent for specimens (i.e., DNA, RNA, protein, etc.) will be obtained 
during screening for protocol enrollment from all subjects or legal guardians, at a trial 
visit by the investigator or his or her designate.  Informed consent for Future 
Biomedical Research should be presented to the subjects on the visit designated in the 
 
 
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trial flow chart.  If delayed, present consent at next possible Subject Visit.  Consent 
forms signed by the subject will be kept at the clinical trial site under secure storage 
for regulatory reasons.  
A template of each trial site’s approved informed consent will be stored in the 
Sponsor’s clinical document repository.
c.
eCRF Documentation for Future Biomedical Research Specimens
Documentation of subject consent for Future Biomedical Research will be captured in 
the electronic Case Report Forms (eCRFs). Any specimens for which such an 
informed consent cannot be verified will be destroyed.
d. Future Biomedical Research Specimen(s)
Collection of specimens for Future Biomedical Research will be performed as 
outlined in the trial flow chart. In general, if additional blood specimens are being 
collected for Future Biomedical Research, these will usually be obtained at a time 
when the subject is having blood drawn for other trial purposes.
4. Confidential Subject Information for Future Biomedical Research 
In order to optimize the research that can be conducted with Future Biomedical Research 
specimens, it is critical to link subject' clinical information with future test results. In fact 
little or no research can be conducted without connecting the clinical trial data to the 
specimen. The clinical data allow specific analyses to be conducted. Knowing subject 
characteristics like gender, age, medical history and treatment outcomes are critical to 
understanding clinical context of analytical results.
To maintain privacy of information collected from specimens obtained for Future 
Biomedical Research, the Sponsor has developed secure policies and procedures. All 
specimens will be single-coded per ICH E15 guidelines as described below. 
At the clinical trial site, unique codes will be placed on the Future Biomedical Research 
specimens.  This code is a random number which does not contain any personally 
identifying information embedded within it. The link (or key) between subject identifiers 
and this unique code will be held at the trial site.  No personal identifiers will appear on 
the specimen tube.  
5. Biorepository Specimen Usage
Specimens obtained for the Sponsor will be used for analyses using good scientific 
practices.  Analyses utilizing the Future Biomedical Research specimens may be 
performed by the Sponsor, or an additional third party (e.g., a university investigator)
designated by the Sponsor. The investigator conducting the analysis will follow the 
Sponsor’s privacy and confidentiality requirements. Any contracted third party analyses 
will conform to the specific scope of analysis outlined in this sub-trial. Future Biomedical 
Research specimens remaining with the third party after specific analysis is performed 
will be reported to the Sponsor.
 
 
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6. Withdrawal From Future Biomedical Research 
Subjects may withdraw their consent for Future Biomedical Research and ask that their 
biospecimens not be used for Future Biomedical Research.  Subjects may withdraw 
consent at any time by contacting the principal investigator for the main trial. If medical 
records for the main trial are still available, the investigator will contact the Sponsor 
using 
the 
designated 
mailbox 
(clinical.specimen.management@merck.com). 
Subsequently, the subject's specimens will be flagged in the biorepository and restricted 
to main study use only. If specimens were collected from study participants specifically 
for Future Biomedical Research, these specimens will be removed from the biorepository 
and destroyed. Documentation will be sent to the investigator confirming withdrawal 
and/or destruction, if applicable. It is the responsibility of the investigator to inform the 
subject of completion of the withdrawal and/or destruction, if applicable.  Any analyses 
in progress at the time of request for withdrawal/destruction or already performed prior to 
the request being received by the Sponsor will continue to be used as part of the overall 
research trial data and results. No new analyses would be generated after the request is 
received.
In the event that the medical records for the main trial are no longer available (e.g., if the 
investigator is no longer required by regulatory authorities to retain the main trial 
records) or the specimens have been completely anonymized, there will no longer be a 
link between the subject’s personal information and their specimens. In this situation, the 
request for withdrawal of consent and/or destruction cannot be processed.
7. Retention of Specimens 
Future Biomedical Research specimens will be stored in the biorepository for potential 
analysis for up to 20 years from the end of the main study. Specimens may be stored for 
longer if a regulatory or governmental authority has active questions that are being 
answered. In this special circumstance, specimens will be stored until these questions 
have been adequately addressed.
Specimens from the trial site will be shipped to a central laboratory and then shipped to 
the Sponsor-designated biorepository. If a central laboratory is not utilized in a particular 
trial, the trial site will ship directly to the Sponsor-designated biorepository. The 
specimens will be stored under strict supervision in a limited access facility which 
operates to assure the integrity of the specimens.  Specimens will be destroyed according 
to Sponsor policies and procedures and this destruction will be documented in the 
biorepository database.
8. Data Security
Databases containing specimen information and test results are accessible only to the 
authorized Sponsor representatives and the designated trial administrator research 
personnel and/or collaborators. Database user authentication is highly secure, and is 
accomplished using network security policies and practices based on international 
standards to protect against unauthorized access.
 
 
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9. Reporting of Future Biomedical Research Data to Subjects
No information obtained from exploratory laboratory studies will be reported to the 
subject, family, or physicians. Principle reasons not to inform or return results to the 
subject include: Lack of relevance to subject health, limitations of predictive capability, 
and concerns regarding misinterpretation.
If important research findings are discovered, the Sponsor may publish results, present 
results in national meetings, and make results accessible on a public website in order to 
rapidly report this information to doctors and subjects.  Subjects will not be identified by 
name in any published reports about this study or in any other scientific publication or 
presentation.
10. Future Biomedical Research Study Population
Every effort will be made to recruit all subjects diagnosed and treated on Sponsor clinical 
trials for Future Biomedical Research.
11. Risks Versus Benefits of Future Biomedical Research 
For future biomedical research, risks to the subject have been minimized. No additional 
risks to the subject have been identified as no additional specimens are being collected 
for Future Biomedical Research (i.e., only leftover samples are being retained). 
The Sponsor has developed strict security, policies and procedures to address subject data 
privacy concerns.  Data privacy risks are largely limited to rare situations involving 
possible breach of confidentiality.  In this highly unlikely situation there is risk that the 
information, like all medical information, may be misused.
12. Questions
Any questions related to the future biomedical research should be e-mailed directly to 
clinical.specimen.management@merck.com.
13. References
1. National Cancer Institute: http://www.cancer.gov/dictionary/?searchTxt=biomarker
2. International Conference on Harmonization: DEFINITIONS FOR GENOMIC 
BIOMARKERS, PHARMACOGENOMICS, PHARMACOGENETICS, GENOMIC 
DATA 
AND 
SAMPLE 
CODING 
CATEGORIES 
-
E15; 
http://www.ich.org/products/guidelines/efficacy/efficacy-single/article/definitions-
for-genomic-biomarkers-pharmacogenomics-pharmacogenetics-genomic-data-and-
sample-cod.html
3. Industry Pharmacogenomics Working Group. Understanding the Intent, Scope and 
Public Health Benefits of Exploratory Biomarker Research: A Guide for IRBs/IECs 
and Investigational Site Staff. Available at http://i-pwg.org/
4. Industry Pharmacogenomics Working Group. Pharmacogenomics Informational 
Brochure for IRBs/IECs and Investigational Site Staff. Available at http://i-pwg.org/
 
 
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Approximate Blood Volumes Drawn/Collected by Trial Visit and by Sample 
12.3
Types
Panels A and B
Pre-trial
Treatment Periods
Post-trial
Total Collections
mL Per 
Collection
Total mL/ 
Test
Laboratory safety tests
2
2 x 5 Periods
1
13
7.5
97.5
FSH (if applicable)
1
0
0
1
3.5
3.5
HIV/Hepatitis Screen
1
0
0
1
3.5
3.5
Blood for Planned Genetic 
Analysis OR Blood (DNA) 
for Future Biomedical 
Research
1
0
0
1
8.5
8.5
Blood for MK-7252
0
12 x 5 Periods
0
60
4.0
240.0
Total Maximum Blood Volume Per Female Subject†
453.0
Total Maximum Blood Volume Per Male Subject†
449.5
†
If additional pharmacokinetic/pharmacodynamic and/or safety analysis is necessary, additional blood (up to 50 mL) 
may be obtained.  Note: never to exceed 50 mL
Panel C
Pre-trial
Treatment Periods
Post-trial
Total Collections
mL Per 
Collection
Total mL/ 
Test
Laboratory safety tests
2
2 x 5 Periods
1
13
7.5
97.5
FSH (if applicable)
1
0
0
1
3.5
3.5
HIV/Hepatitis Screen
1
0
0
1
3.5
3.5
Blood for Planned Genetic 
Analysis OR Blood (DNA) 
for Future Biomedical 
Research
1
0
0
1
8.5
8.5
Blood for MK-7252
0
14 x 5 Periods
0
70
4.0
280.0
Total Maximum Blood Volume Per Female Subject†
493.0
Total Maximum Blood Volume Per Male Subject†
489.5
†
If additional pharmacokinetic/pharmacodynamic and/or safety analysis is necessary, additional blood (up to 50 mL) 
may be obtained.  Note: never to exceed 50 mL
 
 
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Algorithm for Assessing Out-of-Range Laboratory Values
12.4
For all laboratory values obtained at prestudy (screening) visit and/or predose evaluation:
A. If all protocol-specified laboratory values are normal, the subject may enter the study.
B. If a protocol specified laboratory value is outside of the parameter(s) outlined in the 
inclusion/exclusion criteria (including a repeat if performed), the subject will be excluded 
from the study.
C. If ≥1 protocol-specified laboratory value not specified in the inclusion/exclusion criteria 
is outside the normal range, the following choices are available:
1. The subject may be excluded from the study;
2. The subject may be included in the study if the abnormal value(s) is not clinically 
significant (NCS) (the investigator must annotate the laboratory value “NCS” on the 
laboratory safety test source document).
3. The subject may be included in the study if the abnormality is consistent with a pre-
existing medical condition which is not excluded per protocol (e.g., elevated 
eosinophil count in a subject with asthma or seasonal allergies) the medical condition 
should be annotated on the laboratory report or
4. The abnormal test may be repeated (refer items a. and b. below for continuation of 
algorithm for repeated values).
a.
If the repeat test value is within the normal range, the subject may enter the study.
b. If the repeat test value is still abnormal, the study investigator will evaluate the 
potential subject with a complete history and physical examination, looking 
especially for diseases that could result in the abnormal laboratory value in 
question.  If such diseases can be ruled out, and if the abnormal laboratory value 
is not clinically relevant, then the subject may enter the study.
D. If there is any clinical uncertainty regarding the significance of an abnormal value, the 
subject will be excluded from the study.
 
 
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12-Lead Electrocardiogram Abnormality Criteria
12.5
12-Lead Electrocardiogram Abnormality Criteria
Screen Failure Criteria
 Potentially Significant Post-Randomization 
Findings (clarification on action to take)
RHYTHM
Sinus Tachycardia
110 beats per minute 
(bpm)
HR >110 bpm  and HR increase of ≥ 25 bpm 
from baseline
Sinus Bradycardia
<40 bpm
HR <40 bpm and HR decrease of ≥5 bpm 
from baseline
Sinus Pause/Arrest
>2.0 seconds
>2.0 seconds
Atrial premature complex
1 beat
≥3 beats
Ventricular premature complex
All
≥3 beats
Ectopic Atrial Rhythm 
None
None
Junctional Rhythm
Junctional Rhythm with 
HR <40 bpm
Junctional Rhythm with HR <40 bpm
Idioventricular Rhythm
All
All
Atrial Fibrillation
All
All
Atrial Flutter
All
All
Supraventricular Tachycardia
All
All
Ventricular Tachycardia
All
All
AXIS
Left Axis Deviation
RBBB with Left Anterior 
Hemiblock (LAHB)
New onset LAHB
Right Axis Deviation
RBBB with Left Posterior 
Hemiblock (LPHB)
New onset LPHB
CONDUCTION
1st degree A-V Block
PR ≥230 ms
PR ≥230 ms + increase of 15 ms; or PR 
increase of >25%
2nd degree A-V Block
Mobitz Type II
Mobitz Type II
3rd degree A-V Block
All
All
LBBB   
All
All
RBBB   
RBBB with LAHB/LPHB 
as defined above
New onset RBBB (not including rate-
related)
 
 
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Product:  MK-7252 
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MK-7252-001-03 Final Protocol
13-Jul-2018
Confidential
12-Lead Electrocardiogram Abnormality Criteria
Screen Failure Criteria
 Potentially Significant Post-Randomization 
Findings (clarification on action to take)
Incomplete Right BBB 
(ICRBBB) (QRS<120 ms)
No exclusion
Nothing
Short PR/ Preexcitation syndrome
Delta wave + PR <120 ms
Delta wave + PR <120 ms
Other Intra-ventricular 
Conduction Delay
QRS ≥130 ms
QRS 130 ms + increase of 10 ms
QTc (B or F)
Male
QTc ≥470 ms
QTc ≥500 ms or increase of ≥60 ms from 
baseline
Female
QTc ≥480 ms
QTc ≥500 ms or increase of ≥60 ms from 
baseline
HYPERTROPHY
Atrial abnormalities
Definite evidence of P 
mitrale or P pulmonale
Definite evidence of P mitrale or P 
pulmonale
Ventricular abnormalities
Voltage criteria for LVH 
plus Strain Pattern
Voltage criteria  for LVH plus Strain Pattern
MYOCARDIAL  INFARCTION
Acute or Recent
All
All
Old
All
All
ST/T MORPHOLOGY
ST elevation suggestive of 
Myocardial Injury 
In 2 or more contiguous 
leads
In 2 or more contiguous leads
ST depression suggestive of
Myocardial Ischaemia 
In 2 or more contiguous  
leads
In 2 or more contiguous  leads
T-wave Inversions suggestive of  
Myocardial Ischaemia 
In 2 or more contiguous  
leads
In 2 or more contiguous leads
Non-specific ST-T changes 
(In 2 or more leads)
No exclusion
In 2 or more contiguous leads
PACEMAKER
All
All
Baseline is defined as Predose Day 1
ms=milliseconds, mm=millimeter
 
 
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Product:  MK-7252 
100
Protocol/Amendment No.: 001-03 
MK-7252-001-03 Final Protocol
13-Jul-2018
Confidential
Sample Taste Questionnaire
12.6
Date (DD-MMM-YYYY): __________________ Time (24 hr. clock): _______________
Timepoint (circle one):  
0 minutes postdose (immediately after dosing)
10 minutes postdose
Subject Evaluation 
(The following questions are to be completed by the subject.)
Please answer each question by placing an X in the box of your choice.
1. Does the medication have any taste? 
Yes
No
If No, please skip to question 10.
2. How do you like the taste of the medicine?
Like very much
Like moderately
Like slightly
Neither like nor dislike
Dislike slightly
Dislike moderately
Dislike very much
3. Is the flavor of the medication sweet?
Yes
No
4. Is the flavor of the medication sour?
Yes
No
 
 
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Product:  MK-7252 
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Protocol/Amendment No.: 001-03 
MK-7252-001-03 Final Protocol
13-Jul-2018
Confidential
5. Is the flavor of the medication bitter?
Yes
No
6. Is the flavor of the medication salty?
Yes
No
7. Is the flavor of the medication metallic?
Yes
No
8. Is the flavor of the medication astringent (burning, irritating)?
Yes
No
9. How strong is the taste?
No taste
Mild
Moderate
Strong
Very strong
10. If you feel numbness of your tongue/mouth, how severe is it?
No numbness
Mild
Moderate
Severe
Very severe
 
 
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Product:  MK-7252 
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Protocol/Amendment No.: 001-03 
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13-Jul-2018
Confidential
11. If the study drug were to be prescribed by your doctor, how likely would you be to take 
the medication each day? 
Very likely
Somewhat Likely
A little bit likely
Not at all likely
 
 
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Product:  MK-7252 
103
Protocol/Amendment No.: 001-03 
MK-7252-001-03 Final Protocol
13-Jul-2018
Confidential
Targeted Neurological Examination
12.7
The Targeted Neurological Examination is intended to include evaluations which may best 
demonstrate potential neurological effects of MK-7252.  It includes the following tests:
MODULE 1 – MENTAL STATUS EXAMINATION
A. General Level of Arousal (generally assess general level of alertness, attentiveness,
and concentration throughout the interview. Regarding attentiveness, note evidence of 
impaired attention or concentration. For example difficulty remembering or following 
instructions or distractibility may be signs of inattention)
MODULE 2 – CRANIAL NERVE ASSESSMENT
B.
II, III – Pupil Size and Reactivity
C. III, IV, VI –
Extraocular Movements (range of motion, smooth pursuit, 
saccades, nystagmus
1. Observe for nystagmus during eye movements, increased nystagmus at the end of 
gaze or other oculomotor changes (mild nystagmus at extremes of gaze is normal). 
Note direction of nystagmus
MODULE 3 - MOTOR SYSTEM
B. MuscleStrength
1. Ask the subject to stand up from sitting position without using hands
Grade: NORMAL, IMPAIRED and describe abnormality
MODULE 5 - COORDINATION AND GAIT
D. Gait
1. Ask the volunteer to walk heel-to-toe in a straight line (tandem gait).
Grade: NORMAL or IMPAIRED and describe abnormality
MODULE 6 - SENSORY
A. Light touch sense: cotton wisp on skin of forearms and legs, bilaterally.
 
 
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Product:  MK-7252 
104
Protocol/Amendment No.: 001-03 
MK-7252-001-03 Final Protocol
13-Jul-2018
Confidential
Criteria for Limiting Dose Escalation and /or Discontinuation of Dosing
12.8
Overall dose escalation will be limited by any of the following: (1) completion of scheduled
dose escalation; or (2) agreement between the investigator and Sponsor of unacceptable
safety/tolerability of the administered treatment; or (3) concern based on reasonable evidence
that dose escalation will result in exposures exceeding those corresponding to the NOAEL of
20 mg/kg established in GLP toxicology study in the dogs.
Individual discontinuation criteria are established for safety purposes. If these are achieved at
any point during dosing, no further dose escalation will occur for that individual. 
Hemodynamic Stopping Criteria - Individual Stopping Criteria
During any of the treatment periods, if a particular subject demonstrates a sustained change
(defined below) in any one of the following parameters, that subject will not participate in
additional dose escalation. For assessing change from baseline, mean of triplicate postdose 
values at each timepoint will be compared to the Day 1 mean predose baseline established by 
3 semi-recumbent measurements of heart rate and blood pressure obtained ~1-2 minutes 
apart within 3 hours prior to dosing as per protocol. 
During any of the treatment periods if a particular subject demonstrates change in any one of 
the following parameters lasting ≥ 120 minutes, dose escalation in that subject will be halted
and the subject may be withdrawn from the study or re-challenged at the same dose or at a 
lower dose or divided dose. Subjects that meet criteria listed below will be followed up until 
parameters no longer meet stopping rule criteria. Each subject will individually define his 
limit for continuation.
Heart Rate:

Resting, semi-recumbent HR increase of >30 bpm above the mean predose baseline 
HR.

Resting, semi-recumbent HR >120 bpm

Orthostatic, HR >120 bpm, if associated with symptoms

If an individual exceeds the HR limits as defined above, a 12-lead ECG will be 
performed to confirm sinus rhythm. If the subject is not in sinus rhythm or expert 
input is otherwise indicated, consultation with a cardiologist should occur.
Blood pressure:

Resting, semi-recumbent SBP increase >30 mmHg relative to the mean predose
baseline

Resting, semi-recumbent SBP ≥160 mmHg

Resting, semi-recumbent DBP ≥110 mmHg

In the case of hemodynamic instability, activation of emergency medical services for
cardiac monitoring and definitive care will be implemented.
 
 
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Product:  MK-7252 
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MK-7252-001-03 Final Protocol
13-Jul-2018
Confidential
Definitions for HR and BP
Subjects must be resting and semi-recumbent for at least 10 minutes prior to obtaining any
measurements used to limit dose escalation (except for changes noted while obtaining
orthostatic signs).

Baseline HR and BP: These will be the mean of triplicate values, prior to dosing.

Sustained changes are defined as semi-recumbent changes lasting greater than or 
equal to 120 minutes and orthostatic changes occurring at all measurements over a 12 
hour period.
Guidance for Additional Hemodynamic Monitoring
If any of the resting, semi-recumbent parameters defined above are exceeded, that subject
must remain resting and semi-recumbent for at least the next 120 minutes. During that time,
semi-recumbent BP (systolic and diastolic) will be obtained every 60 minutes (i.e., at 60 and 
120 minutes following).  HR and BP will be measured with the BP device.
Following 120 minutes, if, in the opinion of the investigator, the subject requires further 
observation, the subject will remain resting and semi-recumbent until HR and/or BP return to 
baseline. 
If any of the orthostatic parameters defined above are exceeded, that subject will continue to
have orthostatic assessments according to the schedule of events. Orthostatic re-checks and
additional semi-recumbent assessments can be done at the discretion of the investigator.
 
 
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Product:  MK-7252 
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Protocol/Amendment No.: 001-03 
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13-Jul-2018
Confidential
13.0 SIGNATURES
Sponsor's Representative
13.1
TYPED NAME
TITLE
SIGNATURE
DATE SIGNED
Investigator
13.2
I agree to conduct this clinical trial in accordance with the design outlined in this protocol 
and to abide by all provisions of this protocol (including other manuals and documents 
referenced from this protocol).  I agree to conduct the trial in accordance with generally 
accepted standards of Good Clinical Practice.  I also agree to report all information or data in 
accordance with the protocol and, in particular, I agree to report any serious adverse events 
as defined in Section 7.0 – TRIAL PROCEDURES (Assessing and Recording Adverse 
Events).  I also agree to handle all clinical supplies provided by the Sponsor and collect and 
handle all clinical specimens in accordance with the protocol.  I understand that information 
that identifies me will be used and disclosed as described in the protocol, and that such 
information may be transferred to countries that do not have laws protecting such 
information.  Since the information in this protocol and the referenced Investigator’s 
Brochure is confidential, I understand that its disclosure to any third parties, other than those 
involved in approval, supervision, or conduct of the trial is prohibited.  I will ensure that the 
necessary precautions are taken to protect such information from loss, inadvertent disclosure 
or access by third parties.
TYPED NAME
TITLE
SIGNATURE
DATE SIGNED
 
 
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