Conditions: Acute Cough
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 46
Healthy volunteers: yes

Brief summary:
The purpose of the study is to evaluate the efficacy, safety, and tolerability of gefapixant (MK-7264) in adult participants with induced viral upper respiratory tract infections (URTI).

Detailed description:

Arms:
arm 1: Participants will receive a gefapixant 45 mg tablet twice daily (BID) for 7 days. arm 2: Participants will receive a matching placebo tablet BID for 7 days.

Interventions: intervention 1: Gefapixant intervention 2: Placebo
Intervention descriptions: intervention 1: Gefapixant 45 mg will be administered orally. intervention 2: Placebo tablet matching gefapixant will be administered orally.

Protocol document:
Prot_SAP_000.pdf: 
Official Protocol Title: 
NCT number: 
NCT03569033 
Document Date: 
13-Oct-2017
A Phase 2a, Randomized, Placebo-Controlled Clinical Trial to 
Evaluate the Efficacy, Safety and Tolerability of MK-7264 on Acute 
Cough in Participants with Induced Viral Upper Respiratory Tract 
Infection


Product:  MK-7264 
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Protocol/Amendment No.: 013-00 
MK-7264-013-00 Final Protocol
13-Oct-2017
Confidential
Title Page
THIS PROTOCOL AND ALL OF THE INFORMATION RELATING TO IT ARE 
CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK SHARP & 
DOHME CORP., A SUBSIDIARY OF MERCK & CO., INC., NJ, U.S.A. (MSD).
Protocol Title: A Phase 2a, Randomized, Placebo-Controlled Clinical Trial to Evaluate the 
Efficacy, Safety and Tolerability of MK-7264 on Acute Cough in Participants with Induced 
Viral Upper Respiratory Tract Infection
Protocol Number: 013-00
Compound Number: MK-7264
Sponsor Name and Legal Registered Address: 
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. 
(hereafter referred to as the Sponsor or MSD)
One Merck Drive
P.O. Box 100
Whitehouse Station, New Jersey, 08889-0100, U.S.A.
Regulatory Agency Identifying Number(s):
IND NUMBER:   123007
EudraCT NUMBER: 2017-000472-28
Approval Date:  13-Oct-2017
 
 
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Sponsor Signatory
Typed Name:
Title:
Date
Protocol-specific Sponsor Contact information can be found in the Investigator Trial 
File Binder (or equivalent). 
Investigator Signatory
I agree to conduct this clinical study in accordance with the design outlined in this protocol 
and to abide by all provisions of this protocol.
Typed Name:
Title:
Date
 
 
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Table of Contents
1.
Synopsis.......................................................................................................................11
2.
Schedule of Activities (SoA) ......................................................................................13
3.
Introduction................................................................................................................18
Study Rationale .......................................................................................................19
3.1
Background..............................................................................................................19
3.2
Pharmaceutical and Therapeutic Background .....................................................19
3.2.1
Benefit/Risk Assessment.........................................................................................19
3.3
4.
Objectives/Hypotheses and Endpoints.....................................................................21
5.
Study Design...............................................................................................................22
Overall Design .........................................................................................................22
5.1
Study Diagram .....................................................................................................23
5.1.1
Number of Participants ..........................................................................................25
5.2
Beginning and End of Study Definition ................................................................25
5.3
Clinical Criteria for Early Study Termination .....................................................26
5.3.1
Scientific Rationale for Study Design....................................................................26
5.4
Rationale for Study Design..................................................................................26
5.4.1
Rationale for Cough Challenge in a Subset of Participants .................................27
5.4.2
Rationale for Endpoints .......................................................................................27
5.4.3
Efficacy Endpoints........................................................................................27
5.4.3.1
Safety Endpoints ...........................................................................................29
5.4.3.2
Pharmacokinetic Endpoints ..........................................................................29
5.4.3.3
Planned Exploratory Biomarker Research....................................................29
5.4.3.4
Planned Genetic Analysis ......................................................................29
5.4.3.4.1
Future Biomedical Research.........................................................................30
5.4.3.5
Rationale for the Use of Placebo .........................................................................30
5.4.4
Justification for Dose ..............................................................................................30
5.5
Rationale for Dose Interval and Study Design.....................................................30
5.5.1
6.
Study Population........................................................................................................31
Inclusion Criteria ....................................................................................................31
6.1
 
 
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Exclusion Criteria ...................................................................................................32
6.2
Lifestyle Restrictions...............................................................................................34
6.3
Meals and Dietary Restrictions............................................................................34
6.3.1
Caffeine Alcohol, and Tobacco Restrictions .......................................................34
6.3.2
Activity ................................................................................................................34
6.3.3
Screen Failures ........................................................................................................35
6.4
Participant Replacement Strategy.........................................................................35
6.5
7.
Treatments..................................................................................................................35
Treatments Administered.......................................................................................35
7.1
Dose Modification ...................................................................................................37
7.2
Method of Treatment Assignment.........................................................................37
7.3
Stratification.........................................................................................................37
7.3.1
Blinding....................................................................................................................37
7.4
Preparation/Handling/Storage/Accountability ....................................................38
7.5
Dose Preparation..................................................................................................38
7.5.1
Handling, Storage and Accountability.................................................................38
7.5.2
Treatment Compliance...........................................................................................38
7.6
Concomitant Therapy.............................................................................................39
7.7
Rescue Medications and Supportive Care ...........................................................39
7.7.1
Treatment After the End of the Study ..................................................................39
7.8
Clinical Supplies Disclosure ...................................................................................39
7.9
8.
Discontinuation/Withdrawal Criteria......................................................................39
Discontinuation of Study Treatment .....................................................................39
8.1
Withdrawal from the Study ...................................................................................41
8.2
Lost to Follow Up ....................................................................................................41
8.3
9.
Study Assessments and Procedures..........................................................................41
Administrative and General Procedures ..............................................................42
9.1
Informed Consent.................................................................................................42
9.1.1
General Informed Consent............................................................................42
9.1.1.1
Consent and Collection of Specimens for Future Biomedical 
9.1.1.2
Research........................................................................................................43
Inclusion/Exclusion Criteria ................................................................................43
9.1.2
 
 
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Participant Identification Card.............................................................................43
9.1.3
Medical History ...................................................................................................43
9.1.4
Prior and Concomitant Medications Review .......................................................43
9.1.5
Prior Medications..........................................................................................43
9.1.5.1
Concomitant Medications .............................................................................43
9.1.5.2
Assignment of Screening Number .......................................................................43
9.1.6
Assignment of Treatment/Randomization Number .............................................44
9.1.7
Treatment Administration....................................................................................44
9.1.8
Timing of Dose Administration....................................................................44
9.1.8.1
Discontinuation and Withdrawal .........................................................................44
9.1.9
Withdrawal From Future Biomedical Research ...........................................45
9.1.9.1
Participant Blinding/Unblinding..........................................................................45
9.1.10
Domiciling ...........................................................................................................46
9.1.11
Calibration of Critical Equipment........................................................................46
9.1.12
Other Study Procedures .......................................................................................47
9.1.13
Antibody Titers to Human Rhinovirus Type 16 ...........................................47
9.1.13.1
Ethanol Breath Test.......................................................................................47
9.1.13.2
Urine Cotinine Test.......................................................................................47
9.1.13.3
Nasal Swabs for Human Rhinovirus Polymerase Chain Reaction ...............47
9.1.13.4
Efficacy Assessments...............................................................................................47
9.2
Cough Monitoring – VitaloJAK™ Recording Device ........................................47
9.2.1
Intranasal Administration of Rhinovirus .............................................................48
9.2.2
ATP Cough Challenge (Stage 1 Only).................................................................48
9.2.3
Patient-reported Outcomes...................................................................................49
9.2.4
Cough Severity Diary ...................................................................................49
9.2.4.1
Cough Severity Visual Analog Scale............................................................49
9.2.4.2
Leicester Cough Questionnaire-Acute..........................................................49
9.2.4.3
Wisconsin Upper Respiratory Symptom Survey-24.....................................49
9.2.4.4
Adverse Events (AE), Serious Adverse Events (SAE) and Other 
9.3
Reportable Safety Events .......................................................................................50
Time Period and Frequency for Collecting AE, SAE and Other 
9.3.1
Reportable Safety Event Information ..................................................................50
Method of Detecting AE, SAE and Other Reportable Safety Events ..................52
9.3.2
 
 
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Follow-up of AE, SAE and Other Reportable Safety Event Information............52
9.3.3
Regulatory Reporting Requirements for SAE .....................................................52
9.3.4
Disease-Related Events and/or Disease-Related Outcomes Not 
9.3.5
Qualifying as AEs or SAEs..................................................................................53
Pregnancy and Exposure During Breastfeeding ..................................................53
9.3.6
Events of Clinical Interest (ECI)..........................................................................53
9.3.7
Treatment of Overdose...........................................................................................54
9.4
Safety........................................................................................................................54
9.5
Physical Examinations .........................................................................................54
9.5.1
Vital Signs and Weight and Height Measurements .............................................55
9.5.2
Electrocardiograms ..............................................................................................55
9.5.3
Spirometry............................................................................................................55
9.5.4
Taste-Related Adverse Events .............................................................................55
9.5.5
Clinical Safety Laboratory Assessments..............................................................56
9.5.6
Urine Pregnancy Test – if applicable............................................................56
9.5.6.1
Pharmacokinetics....................................................................................................56
9.6
Blood Collection for Plasma MK-7264 ...............................................................56
9.6.1
Pharmacodynamics.................................................................................................57
9.7
Biomarkers ..............................................................................................................57
9.8
Planned Genetic Analysis Sample Collection......................................................58
9.8.1
Future Biomedical Research Sample Collection ..................................................58
9.9
Visit Requirements..................................................................................................58
9.10
Screening Period ..................................................................................................58
9.10.1
Visit 1............................................................................................................58
9.10.1.1
Visit 2 (Day -2).............................................................................................59
9.10.1.2
Visit 3 (Day -1; Baseline Visit) ....................................................................59
9.10.1.3
Treatment Period (Days 1 through 7) ..................................................................59
9.10.2
Discontinued Participants Continuing to be Monitored in the Study ..................59
9.10.3
Post-study Telephone Follow-Up ........................................................................60
9.10.4
10.
Statistical Analysis Plan ............................................................................................60
Statistical Analysis Plan Summary........................................................................60
10.1
Responsibility for Analyses/In-house Blinding.....................................................62
10.2
 
 
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Hypotheses/Estimation ...........................................................................................63
10.3
Analysis Endpoints..................................................................................................63
10.4
Efficacy Endpoints...............................................................................................63
10.4.1
Safety Endpoints ..................................................................................................63
10.4.2
Pharmacokinetic Endpoints .................................................................................63
10.4.3
Derivations of Efficacy Endpoints.......................................................................64
10.4.4
Analysis Populations...............................................................................................64
10.5
Efficacy Analysis Populations .............................................................................64
10.5.1
Safety Analysis Populations ................................................................................64
10.5.2
Pharmacokinetic Analysis Population .................................................................65
10.5.3
Statistical Methods..................................................................................................65
10.6
Statistical Methods for Efficacy/Immunologic Analyses ....................................65
10.6.1
Statistical Methods for Safety Analyses ..............................................................66
10.6.2
Summaries of Baseline Characteristics, Demographics, and Other 
10.6.3
Analyses...............................................................................................................68
Interim Analyses .....................................................................................................69
10.7
Efficacy Interim Analysis ....................................................................................69
10.7.1
Safety Interim Analyses.......................................................................................71
10.7.2
Multiplicity ..............................................................................................................71
10.8
Sample Size and Power Calculations ....................................................................71
10.9
Subgroup Analyses..................................................................................................72
10.10
Compliance (Medication Adherence)....................................................................72
10.11
Extent of Exposure..................................................................................................72
10.12
11.
References...................................................................................................................73
12.
Appendices..................................................................................................................75
Appendix 1: Study Governance Considerations ..................................................75
12.1
Merck Code of Conduct for Clinical Trials .....................................................................75
Financial Disclosure.........................................................................................................77
Data Protection.................................................................................................................77
Confidentiality of Data ....................................................................................................77
Confidentiality of Participant Records.............................................................................77
Confidentiality of IRB/IEC Information..........................................................................78
 
 
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Committees Structure.......................................................................................................78
Publication Policy ............................................................................................................78
Compliance with Study Registration and Results Posting Requirements .......................79
Compliance with Law, Audit and Debarment .................................................................79
Data Quality Assurance ...................................................................................................80
Source Documents ...........................................................................................................81
Study and Site Closure.....................................................................................................81
Appendix 2: Collection and Management of Specimens for Future 
12.2
Biomedical Research...............................................................................................82
Appendix 3: Contraceptive Guidance and Pregnancy Testing...........................86
12.3
Definitions........................................................................................................................86
Contraception Requirements............................................................................................86
Pregnancy Testing............................................................................................................88
Appendix 4: Adverse Events: Definitions and Procedures for 
12.4
Recording, Evaluating, Follow-up, and Reporting ..............................................89
Definition of AE ..............................................................................................................89
Definition of SAE ............................................................................................................90
Additional Events Reported.............................................................................................91
Recording AE and SAE ...................................................................................................91
Reporting of AE, SAE, and Other Reportable Safety Events to the Sponsor..................94
Appendix 5: Clinical Laboratory Tests.................................................................96
12.5
Appendix 6: Abbreviations and Trademarks.......................................................97
12.6
 
 
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LIST OF TABLES
Table 1
Study Treatments..................................................................................................36
Table 2
Treatment Administration.....................................................................................36
Table 3
Reporting Time Periods and Timeframes for Adverse Events and Other 
Reportable Safety Events......................................................................................51
Table 4
Pharmacokinetic Samples Collection ...................................................................57
Table 5
Pharmacokinetic (Blood) Collection Windows....................................................57
Table 6
Analysis Strategy for Key Efficacy Endpoints.....................................................66
Table 7
Analysis Strategy for Safety Parameters ..............................................................68
Table 10
Scenarios of Total Sample Size............................................................................72
Table 11
Contraceptive Methods.........................................................................................87
Table 12
Protocol-Required Safety Laboratory Assessments .............................................96
 
 
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LIST OF FIGURES
Figure 1
Study Design for Stage 1 (Prior to Efficacy IA)...................................................24
Figure 2
Study Design for Stage 2 (Post-Efficacy IA) with Additional Treatment 
Arm.......................................................................................................................25
 
 
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1. Synopsis
Protocol Title:  
A Phase 2a, Randomized, Placebo-Controlled Clinical Trial to Evaluate the 
Efficacy, Safety and Tolerability of MK-7264 on Acute Cough in Participants with 
Induced Viral Upper Respiratory Tract Infection
Short Title: 
MK-7264 on acute cough in participants with induced viral upper respiratory tract infection 
Objectives/Hypotheses and Endpoints:
In this study, the objectives and endpoints will be evaluated in healthy adult participants 
with induced viral upper respiratory tract infection (URTI) as indicated in the following 
table.  Since this is an exploratory study, hypotheses are not applicable.
Objective/Hypothesis
Endpoint
Primary
Objective: To evaluate the efficacy of 
MK-7264 on cough frequency as 
measured while awake during a 24-hour 
period
Awake cough frequency (coughs per hour) 
on Day 3, as assessed by an objective 
cough-counting device
Secondary

Objective: To evaluate the 
efficacy of MK-7264 on the 
perception of cough severity

Cough Severity visual analog scale 
(VAS) score measured as change from 
baseline on Day 3

Cough Severity Diary (CSD) score 
measured as change from baseline on 
Day 3

Objective: To evaluate the 
efficacy of MK-7264 on cough-
specific quality of life

Leicester Cough Questionnaire-acute 
(LCQ-acute) score measured as change 
from baseline on Day 3

Objective: To evaluate the safety 
and tolerability of MK-7264

Number of participants experiencing 
adverse events (AEs)

Number of participants discontinuing 
study treatment due to AEs
 
 
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Overall Design:
Study Phase
Phase 2a
Clinical Indication
Treatment of acute cough
Population
Healthy adult participants with induced viral URTI
Study Type
Interventional
Type of Design
Parallel study design
Type of Control
Placebo
Study Blinding
Double-blind
Estimated Duration 
of Study
The Sponsor estimates that the study will require 
approximately ~ 45 weeks from the time the first 
participant signs the informed consent until the last 
participant’s last study-related phone call or visit.  
Number of Participants:
Approximately 188 participants will be enrolled.
Treatment Groups and Duration:
Treatment Groups
Stage 1 - Prior to Interim Analysis (efficacy IA):

MK-7264 45 mg twice daily (BID)

Placebo
Stage 2 - Post-efficacy IA:

MK-7264 45 mg BID

MK-7264 15 mg BID*

Placebo
* The MK-7264 15 mg BID treatment group during Stage 2 
is applicable only if a decision is made to add a MK-7264 
lower dose group based on results of the efficacy IA.
Duration of 
Participation
Each participant will participate in the study for 
approximately 50 days from the time the participant signs 
the informed consent form through the final contact.  
After a screening period of up to 28 days, each eligible 
participant will receive assigned treatment for 7 days.  At
the end of the treatment period, each participant will be 
discharged from the clinical research unit and have a 
safety follow-up phone call 14 days after completion or 
discontinuation or withdrawal of the study treatment.
Study governance considerations are outlined in Appendix 1. A list of abbreviations used in 
this document can be found in Appendix 6.
 
 
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2. Schedule of Activities (SoA)
Study Period
Screening
Treatment
Dis-
charge
Telephone
Follow-Up
(14 days 
post last 
dose)
Early 
Discon-
tinuation
Notes
Bas
e-
line
Random
-ization
Visit Number/Title
1
2
3
4
5
6
7
8
9
10
11
Scheduled Day and Window:
Day -28
to 
Day -3
Day 
-2
Day 
-1
Day 
1
Day 
2
Day 
3
Day 
4
Day 
5
Day 
6
Day 
7
Day 
8
Day 
22
(+ 3 days)
Between
Days 1 
and 7
Administrative and General Procedures
Written Informed Consent
X
Informed Consent for Future 
Biomedical Research
X
Participant Identification Card
X
In-Patient Period
X
X
X
X
X
X
X
X
X
Inclusion/Exclusion Criteria
X
X
X
X
Day 1:  Prior to morning dose
Administer Intranasal human 
Rhinovirus Type 16 (HRV-16)
X
Immediately prior to morning 
dose (first dose of study 
treatment)
Demographics
X
Medical History (includes substance 
usage)
X
Substances: drugs, alcohol, 
tobacco, and caffeine
Prior/Concomitant Medication 
Review
X
X
X
X
X
X
X
X
X
X
X
X
X
Treatment Randomization 
X
Treatment (MK-7264/Placebo)
Administration
X
X
X
X
X
X
X
Monitor Compliance with Study 
Treatment 
X
X
X
X
X
X
X
Antibody Titers to HRV-16
X
Ethanol Breath Test
X
X
Performed at site locally
 
 
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Study Period
Screening
Treatment
Dis-
charge
Telephone
Follow-Up
(14 days 
post last 
dose)
Early 
Discon-
tinuation
Notes
Bas
e-
line
Random
-ization
Visit Number/Title
1
2
3
4
5
6
7
8
9
10
11
Scheduled Day and Window:
Day -28
to 
Day -3
Day 
-2
Day 
-1
Day 
1
Day 
2
Day 
3
Day 
4
Day 
5
Day 
6
Day 
7
Day 
8
Day 
22
(+ 3 days)
Between
Days 1 
and 7
Urine Cotinine Test
X
X
Performed at site locally
Urine Drug Screen (UDS)
X
Performed at site locally. 
Additional UDS can be performed
for cause during the study, at the 
investigator’s discretion . 
Nasal Swabs for HRV 16 
polymerase chain reaction (PCR)
X
X
X
After inoculation of HRV-16, 
nasal swabs are collected every 12 
hours for 72 hours (Day 1 to Day
3)
Efficacy Procedures
Attach Cough Monitor
X
Just prior to inoculation with 
HRV-16
Remove Cough Monitor
X
Cough Monitoring
X
X
X
X
X
X
X
Cough monitoring using cough 
monitor device (VitaloJAK™)
begins after first dose of study 
treatment on Day 1 through Day 7
or early discontinuation.
Adenosine Triphosphate (ATP)
Cough Challenge
X
X
X
X
Manual cough monitoring is 
performed during ATP cough 
challenge at designated visits only 
during Stage 1 On Days 1, 4, 
and 7, it is performed 2 hours (±
30 min) post-morning dose.
 
 
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Study Period
Screening
Treatment
Dis-
charge
Telephone
Follow-Up
(14 days 
post last 
dose)
Early 
Discon-
tinuation
Notes
Bas
e-
line
Random
-ization
Visit Number/Title
1
2
3
4
5
6
7
8
9
10
11
Scheduled Day and Window:
Day -28
to 
Day -3
Day 
-2
Day 
-1
Day 
1
Day 
2
Day 
3
Day 
4
Day 
5
Day 
6
Day 
7
Day 
8
Day 
22
(+ 3 days)
Between
Days 1 
and 7
Collect Previous Cough Monitor 
Data
X
X
X
X
X
X
X
X
Collect compact flash (CF) 
memory card from cough monitor 
and insert new CF card and new 
battery pack every ~ 24 hours
Cough Severity Visual Analog Scale 
(VAS)
X
X
X
X
X
X
X
X
Completed in the evening
Cough Severity Diary (CSD)
X
X
X
X
X
X
X
X
Completed in the evening 
Leicester Cough Questionnaire-
Acute (LCQ-acute)
X
X
X
X
X
X
X
X
Completed in the evening
Wisconsin Upper Respiratory 
Syndrome Symptom Survey 
(WURSS-24)
X
X
X
X
X
X
X
X
Completed in the evening
Safety Procedures
Full Physical Examination 
X
X
X
Refer to Section 9.5.1 for details
Height & Weight
X
X
X
X
Day -1, Day 8, and Early 
DiscontinuationVisit: weight only
Vital Signs (heart rate, blood 
pressure, respiratory rate, and 
temperature)
X
X
X
X
X
X
X
X
X
X
X
X
All visits during Treatment 
Period: predose
12-lead Electrocardiogram (ECG)
X
X
X
X
Performed with site equipment 
Spirometry
X
Performed with site equipment 
Hematology
X
X
X
X
Days 1 and 7: premorning dose
Urinalysis
X
X
X
X
Days 1 and 7: premorning dose
 
 
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Study Period
Screening
Treatment
Dis-
charge
Telephone
Follow-Up
(14 days 
post last 
dose)
Early 
Discon-
tinuation
Notes
Bas
e-
line
Random
-ization
Visit Number/Title
1
2
3
4
5
6
7
8
9
10
11
Scheduled Day and Window:
Day -28
to 
Day -3
Day 
-2
Day 
-1
Day 
1
Day 
2
Day 
3
Day 
4
Day 
5
Day 
6
Day 
7
Day 
8
Day 
22
(+ 3 days)
Between
Days 1 
and 7
Chemistry
X
X
X
X
Days 1 and 7: premorning dose
Urine Pregnancy Test (Women of  
Child Bearing Potential [WOCBP]
only)
X
X
X
X
Serum β-Human Chorionic 
Gonadotropin
(β-hCG; WOCBP only)
(this procedure will be performed ONLY if urine pregnancy test is positive)
Adverse Event (AE)/Serious AE 
Review
X
X
X
X
X
X
X
X
X
X
X
X
Taste-related AEs
X
X
X
X
X
X
X
X
X
X
Participants who report taste-
related AEs will have additional 
questioning by the site staff.
Reminder to continue contraceptive 
use (WOCBP only)
X
X
For at least 14 days after last dose 
of study treatment (see Appendix 
3)
Pharmacokinetics/ Biomarkers
Blood for Genetic Analysis 
X
Randomized participants only; 
see Sections 9.8. and 9.9
 
 
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Study Period
Screening
Treatment
Dis-
charge
Telephone
Follow-Up
(14 days 
post last 
dose)
Early 
Discon-
tinuation
Notes
Bas
e-
line
Random
-ization
Visit Number/Title
1
2
3
4
5
6
7
8
9
10
11
Scheduled Day and Window:
Day -28
to 
Day -3
Day 
-2
Day 
-1
Day 
1
Day 
2
Day 
3
Day 
4
Day 
5
Day 
6
Day 
7
Day 
8
Day 
22
(+ 3 days)
Between
Days 1 
and 7
Pharmacokinetic (PK) Blood 
Samples
X
X
X
X
Day 1: premorning dose: and 1, 
2, 4, 8, and 12 hours 
postmorning dose
Day 2: premorning dose
Day 4: premorning dose
Day 7: premorning dose and 1, 2, 
4, 8, and 12 hours postmorning 
dose
See Section 9.6.1 for collection 
windows.
 
 
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3. Introduction
Cough is one of the most common presenting symptoms for patients seeking care from 
primary care specialists, allergists, otolaryngologists, or pulmonologists worldwide. The 
importance of cough as a clinical problem globally has led to multiple societies publishing 
guidelines on the diagnosis and management of cough [Morice, A. H., et al 2004] [Chung, K. 
F., et al 2006] [Morice, A. H., et al 2006] [The committee for The Japanese Respiratory 
Society guidelines 2006] [Kardos, P., et al 2010]. In these clinical guidelines, cough is 
categorized based upon the duration of the cough; within each category (ie, acute, subacute, 
and chronic) are likely diagnostic possibilities [Irwin, R. S., et al 2006]. Acute cough is 
present for less than 3 weeks. Cough that has been present for longer than 3 weeks is 
considered either subacute (3 to 8 weeks) or chronic (>8 weeks).
This protocol will evaluate acute cough. Acute cough is a common condition, most often due 
to an acute viral upper respiratory tract infection (URTI).  Viral URTIs can be diagnosed 
when patients present with an acute respiratory illness with accompanying symptoms and 
signs related to the nasal passages (eg, rhinorrhea, cough, sore throat, sneezing, nasal 
obstruction, and postnasal drip), with or without fever, lacrimation, and irritation of the 
throat. In the absence of any treatment, the prevalence of acute cough due to a URTI ranges 
from 83% within the first 48 hours of the cold to 26% on Day 14 [Curley, F. J., et al 1988].
Cough due to a viral URTI is usually transient and self-limited. If cough is significantly 
bothersome to the patient, symptomatic treatment is appropriate.  Regrettably, there is a 
paucity of over-the-counter (OTC) treatments available that have established efficacy based 
on well-controlled clinical trials. In addition, many of these OTC agents (eg, 
diphenhydramine, dextromethorphan) have undesirable side effects.  Codeine, a prescription 
narcotic, while widely used, has not been shown to be efficacious against acute cough due to 
a URTI in prospective, blinded, controlled trials [Freestone, C. 1997]. Therefore, a 
significant unmet need exists for an agent to demonstrate efficacy and a tolerable side effect 
profile in prospective, randomized, placebo-controlled clinical studies.
Mechanism of Cough
Each cough occurs through the stimulation of a complex reflex arc. Cough is initiated 
following activation of airway sensory nerves in the upper and lower respiratory tract. 
Airway sensory nerves are tailored to detect changes in the physical and chemical 
environment, and, if required, elicit protective reflex events such as cough.  These reflexes 
are normally protective; however, in disease, airway reflexes can become hypersensitized, 
leading to an increase in symptoms and a pathologic cough.
Adenosine triphosphate (ATP) is released by damaged, stressed, and inflamed tissues. P2X3 
and P2X2/3 receptors are ligand-gated ion channels that respond to ATP and are almost 
exclusively localized on C-fiber sensory neurons, which innervate the upper and lower 
airways and are the main nerve fibers responsible for cough. The action of ATP at sensory 
neurons in the periphery and spinal cord contributes to neural excitability and may cause 
hypersensitivity through binding to P2X3-containing receptors and stimulating of C-fiber 
neurons [North, R. A. 2004] [Khakh, B. S. 2006]. Antagonism of P2X3-containing receptors 
is predicted to normalize afferent sensitivity, based on data from P2X3 knock-out mice and 
 
 
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the effects of small interfering ribonucleic acid (siRNA) knock-down and pharmacological 
antagonists [Barclay, J., et al 2002] [Cockayne, D. A., et al 2000] [Souslova, V., et al 2000].
ATP and P2X3-containing receptors have been shown to be involved in airways sensitization 
and their involvement provides a rationale for P2X3 antagonism in the treatment of cough.
The current trial will evaluate MK-7264 in acute cough.
Study Rationale 
3.1
The purpose of this trial is to evaluate the efficacy and safety of MK-7264 on acute cough 
symptoms in healthy participants 18 through 55 years of age who are infected with human 
rhinovirus type 16 (HRV-16).  Evaluation of efficacy will be based on objective cough 
counting and symptoms of viral URTI over 7 days.  Additionally, this trial will perform a 
cough challenge to evaluate the antitussive effect of MK-7264.
Current therapies for acute and subacute cough (ie, narcotic, non-narcotic, and OTC 
medications) have limited or unproven efficacy and an undesirable side effect profile.  This 
trial aims to provide proof of concept for use of MK-7264 in the treatment of acute cough; 
positive results in this trial will support continued study of MK-7264 for the treatment of 
acute cough.
Background
3.2
Refer to the Investigator’s Brochure (IB) for detailed background information on MK-7264
[IB Edition 16 2017].
Pharmaceutical and Therapeutic Background
3.2.1
MK-7264, a P2X3 receptor antagonist, has been evaluated in clinical studies for treatment of 
chronic cough, interstitial cystitis/bladder pain syndrome, osteoarthritis pain, and asthma. 
MK-7264 has also been evaluated in an extensive nonclinical program.
MK-7264 is an oral medication provided as a film-coated tablet.  The MK-7264 tablets 
provided for this trial contain 45 mg of MK-7264.  Based on results of an efficacy interim 
analysis (IA), a lower dose arm (15 mg of MK-7264) may be added to this study.  The 
placebo tablets provided in this trial are indistinguishable from the MK-7264 high- and low-
dose tablets in appearance, respectively.  The placebo tablets contain no MK-7264, but 
contain the same inactive excipients as those included in the active tablets.
Benefit/Risk Assessment
3.3
It cannot be guaranteed that participants in clinical studies will directly benefit from 
treatment during participation, as clinical studies are designed to provide information about 
the safety and effectiveness of an investigational medicine.
MK-7264 has been evaluated in an extensive nonclinical program. To date, there is little 
evidence from nonclinical studies that MK-7264 has any direct cellular or direct target organ 
toxicity.
 
 
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The efficacy and safety of MK-7264 has been evaluated in 8 completed Phase 2 clinical 
studies for cough. In those studies, patients with chronic cough who took MK-7264 showed 
a reduction in awake cough frequency and improvement in patient-reported outcomes
(PROs) [IB Edition 16 2017]. The current study (P013) will be the first study to evaluate 
MK-7264 in participants with acute cough; however, as noted in Section 3, based on the 
involvement of ATP and P2X3-containing receptors in airways sensitization, combined with 
the efficacy observed in the Phase 2 chronic cough studies, it is reasonable to expect that 
MK-7264 will also be effective in reducing acute cough.  Additionally, in the completed and 
ongoing clinical studies (Phase 1 and Phase 2), no major safety concerns have been noted.  
Taste-related adverse experiences (eg, dysgeusia, ageusia, hypogeusia) were the most
frequently reported adverse events (AEs) in the clinical studies, with doses up to 1800 mg
twice daily (BID) for 14 days. Subjects also described oral paresthesias (tingling sensation in 
the mouth and/or throat). In many instances, subjects reported oral paresthesia or 
hypoesthesia concurrent with taste alterations dysgeusia/hypogeusia/ageusia). A rationale for 
taste modification exists with P2X2/3 antagonism because of the putative participation of 
ATP, acting via this receptor, in transducing taste signals from taste buds cells to gustatory 
afferents. Attenuation of taste acuity is considered more of a tolerability concern as opposed 
to a safety concern, and is anticipated to be fully and rapidly reversible after discontinuation 
of the study treatment and amenable to monitoring in clinical studies.
Overall, based on growing clinical evidence supporting efficacy and lack of significant safety 
findings in completed and ongoing nonclinical and clinical studies (see IB for details, 
Section 3.2), the benefit-risk balance of MK-7264 is assessed as positive.
The risks and side effects related to this trial are expected to be manageable.  Because HRV-
16 causes the common cold, participants can expect to have a combination of one or more of 
the following symptoms after inoculation with the virus: runny nose, itchy nose, congested 
nose, sneezing, itchy eyes, headache, low-grade fever, sore throat, and/or cough.  During the 
course of treatment, participants will be medically monitored 24 hours a day at a clinic. 
During the ATP cough challenge, β-agonist will be available if participants experience
bronchoconstriction; if this type of treatment is required, participants will not be exposed to 
further cough challenges on that day, but may participate in the cough challenges on 
subsequent days. Appropriate medical intervention will be provided throughout the trial, as 
needed.
Additional details regarding specific benefits and risks for participants participating in this 
clinical study may be found in the accompanying IB and informed consent documents
(Section 3.2).
 
 
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4. Objectives/Hypotheses and Endpoints
In this study, the objectives and endpoints will be evaluated in healthy adult participants with 
induced viral URTI as indicated in the following table.  Since this is an exploratory study, 
hypotheses are not applicable.
Objective(s)/Hypotheses
Endpoint(s)
Primary
Objective: To evaluate the efficacy of 
MK-7264 on cough frequency as 
measured while awake over a 24-hour 
period
Awake cough frequency (coughs per hour)
on Day 3, as assessed by an objective 
cough-counting device
Secondary

Objective: To evaluate the efficacy of 
MK-7264 on the perception of cough 
severity

Cough Severity VAS score measured as 
change from baseline on Day 3

CSD score measured as change from 
baseline on Day 3

Objective: To evaluate the efficacy of 
MK-7264 on cough-specific quality of 
life

LCQ-acute score measured as change 
from baseline on Day 3

Objective: To evaluate the safety and 
tolerability of MK-7264

Number of participants experiencing 
AEs

Number of participants discontinuing 
study treatment due to AEs
Exploratory

Objective: To evaluate the efficacy of 
MK-7264 on cough frequency as 
measured over a 24-hour period

24-hour cough frequency (coughs per 
hour) on Day 3,  as assessed by an 
objective cough-counting device

Objective: To evaluate the efficacy of 
MK-7264 on cough frequency as 
measured while awake over a 24-hour 
period

Awake cough frequency (coughs per 
hour) on Days 1, 2, 4, 5, 6, and 7, as 
assessed by an objective cough-counting 
device

Objective: To evaluate the impact of 
MK-7264 on quality of life during a 
URTI

Wisconsin Upper Respiratory Symptom 
Survey (WURSS-24) score measured as 
change from baseline on Day 3
 
 
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Objective(s)/Hypotheses
Endpoint(s)

Objective: To evaluate the efficacy of 
MK-7264 on cough reflex sensitivity 
to ATP 

C2 and C5 (ie, concentration of cough 
challenge agent inducing 2 or more 
coughs, and 5 or more coughs, 
respectively) during Stage 1 on Days 1, 
4, and 7

Objective: To assess the plasma 
pharmacokinetics (PK) of MK-7264 

PK parameters (mean maximum 
observed concentration [Cmax], mean 
minimum observed concentration 
[Cmin,], time to reach Cmax [Tmax], and 
area under the concentration time-curve 
[AUC0-] on Days 1, 2, 4, and 7

Objective: To explore the relationship 
between genetic variation and 
response to the treatment(s) 
administered, and mechanisms of 
disease. Variation across the human 
genome may be analyzed for 
association with clinical data collected 
in this trial.

Germline genetic variation
5. Study Design 
Overall Design 
5.1
This is a double-blind, randomized, placebo-controlled, parallel-group trial of MK-7264 for
acute cough in healthy male and female adult participants with induced viral URTI. The total 
trial duration for each participant is approximately 50 days, including a screening period of 
up to 28 days, a 7-day treatment period, 1 day for discharge from the clinic, and a 14-day 
safety follow-up period after the last dose of trial treatment. An efficacy IA is planned for 
the trial after approximately 50 randomized participants complete (or discontinue early from) 
the treatment period (Day 1 to Day 7).  Details of the efficacy IA are described in Section 
10.7.1.
Screening Period
The Screening Period (~ Day -28 to Day -2) should be only as long as it is needed to 
complete all screening activities.
On Day -2, eligible participants will be admitted to the clinic. Participants will remain 
confined to the clinic until completion of the treatment period on Day 7. Between Day -2 
(Visit 2) and Day -1 (Visit 3), participants will be under observation to ensure that they are 
healthy (ie, do not show any signs/symptoms of a community-acquired URTI or any other 
 
 
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type of infection).  During this time, safety labs will be evaluated to ensure lab values do not 
meet criteria for exclusion and are not clinically significant.
Treatment Period
On Day 1 (Visit 4), participants who continue to meet eligibility criteria will be randomized 
according to the Sponsor’s computer-generated allocation schedule via an interactive voice 
response system/integrated web response system (IVRS/IWRS). During Stage 1 of the trial 
(ie, all enrollment prior to the efficacy IA), approximately 50 eligible participants will be 
randomized in a 1:1 ratio to either MK-7264 45 mg BID or placebo.  An efficacy IA will be 
performed when approximately 50 randomized participants in Stage 1 complete (or 
discontinue early from) the Treatment Period (Day 1 to Day 7). Enrollment (ie, screening 
and randomization) will be paused once Stage 1 enrollment is complete, pending the results 
of the efficacy IA. In Stage 2 (ie, all enrollment post- efficacy IA), if a decision is made to 
include a lower dose of MK-7264 based on the efficacy IA results, participants will be 
randomized to MK-7264 45 mg BID, MK-7264 15 mg BID, or placebo in a ratio (1:2:1, 
respectively) that will provide approximately 50 participants per group at the end of the trial.
If the MK-7264 15 mg BID treatment group is not included in Stage 2, depending on the re-
estimated sample size during the efficacy IA as described in Section 10.7.1, a total of 100 to 
188 participants (50 to 94 per treatment group for Stages 1 and 2 combined) will be 
randomized in a 1:1 ratio to either MK-7264 45 mg BID or placebo.
Specific procedures to be performed during the study, as well as their prescribed times and 
associated visit windows, are outlined in the Study SoA - Section 2. Details of each 
procedure are provided in Section 9 – Study Assessments and Procedures.
This trial will use an adaptive design based on pre-specified criteria.  There is one planned 
efficacy IA when approximately 50 randomized participants have completed (or discontinued 
early from) Stage 1 of the trial.
The results of the efficacy IA will be reviewed and the decision regarding trial modifications 
will be made by the standing internal Data Monitoring Committee (siDMC). The following 
actions are possible decisions from the siDMC, based on the results of the efficacy IA:

The trial may be stopped for futility

The sample size may be re-estimated

Continue the trial as planned

A lower dose of MK-7264 (15 mg BID) may be added
Details are described in Section 10.7.1.
Study Diagram
5.1.1
The study design prior to the efficacy IA (Stage 1) is depicted in Figure 1. Based on the 
results of the efficacy IA, in Stage 2 of the trial (post-efficacy IA), a third treatment group 
may be added in which participants would receive a lower dose of MK-7264 (15 mg BID). 
The study design for Stage 2 (post-efficacy IA), if an additional treatment arm is added, is 
presented in Figure 2.
 
 
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Abbreviations: BID = twice daily; IA = interim analysis
Figure 1
Study Design for Stage 1 (Prior to Efficacy IA)
 
 
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Abbreviations: BID = twice daily; IA = interim analysis
Figure 2
Study Design for Stage 2 (Post-Efficacy IA) with Additional Treatment Arm
Number of Participants
5.2
Approximately 100 to 188 participants will be randomized in this study.
Beginning and End of Study Definition
5.3
The overall study begins when the first participant signs the informed consent form (ICF).  
The overall study ends when the last participant completes the last study-related phone-call 
or visit, withdraws from the study or is lost to follow-up (ie, the participant is unable to be 
contacted by the investigator).  
 
 
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Clinical Criteria for Early Study Termination
5.3.1
Early study termination will be the result of the criteria specified below:

Based on the efficacy IA, if the siDMC recommends termination of the trial per the 
stopping rules as stated in the siDMC Charter.
Scientific Rationale for Study Design 
5.4
Rationale for Study Design
5.4.1
Conducting studies that evaluate treatment in participants with naturally occurring URTIs is 
challenging because it is difficult to identify and enroll participants during the early stage of 
the illness.  URTIs are short-lived and self-limited.  In addition, with naturally occurring 
URTIs, it is not possible to know when infection begins or to determine with certainty the 
duration of the illness at the time that the patient presents for enrollment 
[Gwaltney, J. M. Jr., et al 2003].  Due to these limitations, the induced rhinovirus URTI 
model will be used to evaluate MK-7264 in this trial. In this rhinovirus infection model, the 
virus is inoculated into the nose of susceptible volunteers to produce an induced URTI.  
Therefore, the incubation period of the infection and the duration of illness are known.  
Comparisons between naturally occurring infections and induced infections have 
demonstrated that there may be differences in the severity of symptoms or types of 
symptoms, but in general the illnesses associated with the two types of infection were more 
similar than they were different; this may be due to selection bias of the natural cold patients 
[Rao, S. S., et al 1995].  Overall, the induced rhinovirus model is still the preferred model for 
evaluating treatments for the common cold. This model has the advantage of replicating the 
actual pathology of an acute URTI caused by rhinovirus and incorporates knowledge of the 
timing and evolution of the URTI into the study design.
Further, in this protocol, all participants will be required to demonstrate viral shedding within 
72 hours of inoculation of HRV-16 in order to continue in the trial and be included in the 
analyses; thus, this model will provide a controlled environment for evaluation of URTI in 
participants with the same virus and with a similar duration of illness (infection).  It is 
anticipated that approximately 15% to 20% of participants will not demonstrate viral 
shedding within the 72 hour timeframe; these participants will be discontinued from study 
treatment and discharged from the clinic (See Section 9.1.11).
The natural history of URTI, as well as the onset and duration of cough, have not been well 
described.  Data published in 1988 by Curley et al suggests that 80% of patients infected with 
the common cold will develop cough [Curley, F. J., et al 1988]. Consultation with cough 
experts and centers experienced with induced rhinovirus studies suggests that the proportion 
of patients infected with rhinovirus who develop cough is between 60% to 80%.  Data 
published by Gwaltney et al in 2003 suggest that the mean total symptom severity scores for 
participants with experimental rhinovirus colds peak 48 hours after viral inoculation 
[Gwaltney, J. M. Jr., et al 2003]. These symptoms are dramatically reduced by Day 5, and
likely disappear around Day 7.  These findings further support the use of the induced 
infection model (to ensure treatment and evaluation as early as possible in the course of the 
illness) and evaluation of participants over the course of 7 days of treatment.
 
 
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Rationale for Cough Challenge in a Subset of Participants
5.4.2
Inhalation cough challenges allow for quantification of cough and the assessment of 
antitussive effects of specific therapies.  Cough challenges rely on the delivery of tussive 
agents, such as capsaicin, citric acid, or ATP, as aerosols administered from jet or ultrasonic 
nebulizers.
There are 2 main methods used for cough challenges: 
single-dose and dose-response.  
Single-dose inhalation challenges involve the administration of one concentration of the 
tussive agent.  This method has been used for the screening of a large population of 
participants to detect those with reproducible cough.  The second method is the dose-
response cough challenge and involves the inhalation of incremental concentrations of 
tussive agent interspersed with inhalations containing placebo to increase challenge 
blindness. This trial will perform a modified dose-response cough challenge; details will be 
provided in the Procedures Manual.
A large number of tussive agents have been tested in cough challenges, with capsaicin and 
citric acid demonstrating the best reproducibility.  Recent studies have suggested a role for 
ATP-activated P2X3 receptors in the pathophysiology of chronic cough.  In a small trial 
evaluating hypersensitivity to ATP in chronic cough patients, chronic cough patients had 
increased sensitivity to ATP compared with healthy volunteers.  There were no reports of 
bronchospasm in that trial [Fowles, H. E. 2015].
In P013, an ATP cough challenge will be conducted during Stage 1.  All participants in Stage 
1 will undergo the ATP cough challenge during the screening and treatment periods.  It is 
expected that ~ 5 to 10% of participants may not respond to cough challenge during the 
screening period.  ATP has been selected as the tussive agent for the cough challenge based 
on the hypothesis that patients infected with rhinovirus have increased sensitivity to ATP 
cough challenge.  In summary, the ATP cough challenge is included in this trial as it may 
allow a better evaluation of the antitussive effect of MK-7264.
Rationale for Endpoints
5.4.3
Efficacy Endpoints
5.4.3.1
The primary efficacy endpoint is awake coughs per hour (based on 24-hour sound recordings
using an objective cough-counting device) on Day 3 of the treatment period (defined in 
Section 10.4.1).  Cough counting will begin on Day 1 (ie, after randomization, inoculation 
with the rhinovirus, and first dose of study treatment) and continue over the course of 7 days 
of treatment.  Cough count will be measured using a digital recording device (VitaloJAK™ 
cough monitor, Vitalograph, Buckingham, United Kingdom).  Worn similar to a Holter 
monitor with a sensor affixed to the participant’s chest wall with adhesive and a microphone 
attached to the participant’s clothing, the device provides high fidelity recordings and 
facilitates signal processing to accurately identify and quantify cough.  Digital recordings 
will be processed in Vitalograph’s centralized reading center, where recordings are 
condensed using a computer algorithm before human analysts identify and tag individual 
coughs.  The output of this process is a count of coughs for each 24-hour recording period, as 
well as cough counts for portions of the day when the participant is awake and when they are 
asleep.
 
 
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As approximately 83% of participants with a URTI are expected to cough within the first 
48 hours of infection [Curley, F. J., et al 1988], the goal of the trial is to demonstrate that 
MK-7264 is effective in the treatment of acute cough, as evidenced by a decreased frequency 
of awake coughs on Day 3 in participants who are infected with rhinovirus.  In unexplained 
or treatment refractory chronic cough, cough frequency is much higher during the day. This 
pattern is expected to be similar with acute cough, but to assess concretely; P013 will include 
24-hour cough counts as an exploratory endpoint.
An assessment of cough from the participant’s perspective is also important for evaluating 
the response to a given therapy. PROs associated with cough can be measured in terms of 
cough frequency, intensity, and severity; disruptions due to cough; and cough-specific 
quality of life.  The following secondary efficacy endpoints will be measured as change from 
baseline on Day 3 of the treatment period in this trial:

Cough Severity visual analog scale (VAS)

Cough Severity Diary (CSD)

Leicester Cough Questionnaire (LCQ)-acute
The Cough Severity VAS is a single-item questionnaire asking the participant to rate the 
severity of their cough “today” using a 100 mm VAS anchored with “No Cough” at 0 and 
“Extremely Severe Cough” at 100. Similar to the well-established use of VAS in chronic 
pain, the Cough Severity VAS provides a quick and easily interpreted subjective assessment 
to monitor improvement of acute cough during treatment.
The CSD is a 7-item, disease-specific PRO measure with a recall period of “today”. The 
measure evaluates three domains: frequency of cough (3 items), intensity of cough (2 items), 
and disruption due to cough (2 items); each item is rated on an 11-point scale ranging from 0 
to 10, with higher scores indicating greater severity.  A CSD total score and 3 domain scores 
(ie, frequency, intensity, disruption) can be calculated.
The LCQ-acute is a 19-item health-related quality-of-life (HRQoL) questionnaire specific for 
acute cough which contains three domains (ie, physical, psychological, and social), 
calculated as a mean score for each domain ranging from 1 to 7 and total score ranging from 
3 to 21.  Each item on the LCQ-acute assesses symptoms or the impact of symptoms on 
HRQoL in the last 24 hours using a 7-point Likert scale ranging from 1 to 7.  Higher scores 
indicate better HRQoL.
The following exploratory efficacy endpoints will also be measured:
1. 24-hour cough count (based on 24-hour sound recordings) on Day 3
2. Awake cough count on Days 1, 2, 4, 5, 6, 7
3. Wisconsin Upper Respiratory Syndrome Symptom Survey (WURSS-24) as change 
from baseline on Day 3
4. Cough reflex sensitivity (C2 and C5 on Days 1, 4, and 7) measured by standardized 
methodology incorporating an ATP cough challenge (Stage 1 only)
 
 
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The WURSS-24 is a 24-item HRQoL questionnaire specific for acute upper respiratory 
infection, including influenza-like symptoms.  The WURSS-24 assesses symptoms or the 
impact of symptoms on HRQoL ‘over the last 24 hours’ using an 8-point Likert scale ranging 
from 0 to 7.  Higher scores indicate worse HRQoL.
MK-7264 has been shown to reduce cough reflex sensitivity, as measured by ATP cough 
challenges, in healthy participants as well as participants with chronic cough 
[IB Edition 16 2017].  Stage 1 of P013 will evaluate whether similar effects also occur in 
participants with acute cough.
The secondary and exploratory efficacy endpoints will add supportive information to the 
primary efficacy endpoint of awake coughs per hour on Day 3 of treatment.
Safety Endpoints
5.4.3.2
In support of the safety objective to evaluate the safety and tolerability profile of MK-7264, 
the safety and tolerability endpoints will be assessed by clinical evaluation of AEs and 
inspection of other trial parameters including vital signs, physical examination, 
electrocardiogram (ECG), and standard laboratory safety tests at time points specified in the 
SoA (Section 2).  Adverse events are graded and recorded according to Appendix 4.  
Additional safety monitoring may be performed at the discretion of the investigator.
Pharmacokinetic Endpoints
5.4.3.3
The pharmacokinetics (PK) of MK-7264 will be evaluated by measuring mean maximum 
observed concentration [Cmax], mean minimum observed concentration [Cmin,], time to reach 
Cmax [Tmax], and area under the concentration time-curve [AUC0-] on Days 1, 2, 4, and 7 in 
healthy adult participants infected with rhinovirus.  Blood samples will be collected on Days
1, 2, 4, and 7, as outlined in Section 9.6.1. The relationship between MK-7264 plasma 
concentrations and cough frequencies/side effects will be explored.
Planned Exploratory Biomarker Research
5.4.3.4
Planned Genetic Analysis
5.4.3.4.1
Genetic variation may impact a participant’s response to therapy, susceptibility to, and 
severity and progression of disease. Variable response to therapy may be due to genetic 
determinants that impact drug absorption, distribution, metabolism, and excretion; 
mechanism of action of the drug; disease etiology; and/or molecular subtype of the disease 
being treated. Therefore, where local regulations and IRB/IEC allow, a sample will be 
collected for DNA analysis from consenting participants.
DNA samples will be used for research related to the study treatment(s), the disease under 
study and related diseases. They may also be used to develop tests/assays including 
diagnostic tests related to the disease under study, related diseases and study treatment(s). 
Genetic research may consist of the analysis of one or more candidate genes or the analysis 
of genetic markers throughout the genome [or analysis of the entire genome] (as appropriate).
DNA samples will be analyzed for variation across the entire genome. Analyses may be 
conducted if it is hypothesized that this may help further understand the clinical data. 
 
 
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The samples may be analyzed as part of a multi-study assessment of genetic factors involved 
in the response to understand study disease or related conditions.
Future Biomedical Research
5.4.3.5
The Sponsor will conduct Future Biomedical Research on DNA specimens for which consent 
was provided during this clinical study.
Such research is for biomarker testing to address emergent questions not described elsewhere 
in the protocol (as part of the main study) and will only be conducted on specimens from 
appropriately consented participants. 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 
participants receive the correct dose of the correct drug/vaccine at the correct time.  The 
details of this Future Biomedical Research sub-study are presented in Appendix 2  –
Collection and Management of Specimens for Future Biomedical Research.
Rationale for the Use of Placebo
5.4.4
The placebo arm is included in this trial to maintain the study blinding, allowing for an 
unbiased assessment of efficacy and safety.  Additionally, in the event that a lower MK-7264 
dose group is added to the trial in Stage 2 (after the efficacy IA), the placebo arm will help 
ascertain whether the two active doses are equally effective or equally ineffective.  No rescue 
medication will be permitted in the trial.  Participants will be medically monitored during the 
trial and provided appropriate treatment, if warranted.  Participants may discontinue the trial 
at any time if they find the treatment intolerable or for any other reason.
Justification for Dose 
5.5
Rationale for Dose Interval and Study Design
5.5.1
In this trial, MK-7264 45 mg (and potentially MK-7264 15 mg if an additional treatment arm 
is added in Stage 2) will be orally administered in tablet form BID based on the safety and 
PK efficacy results observed to date.  
Based on PK studies conducted to date, MK-7264 is rapidly absorbed with a median Tmax of 
1 to 2 hours and a half-life of approximately 7 to 10 hours, and is consistent with a BID 
dosing schedule.
In the clinical development program, oral doses of MK-7264 up to 1800 mg BID for 14 days 
were evaluated in Phase 1 studies and oral doses of up to 600 mg BID have been evaluated in 
Phase 2 studies.  Overall, MK-7264 has been generally safe and well tolerated.  Across 
studies, taste-related AEs (eg, dysgeusia, ageusia, hypogeusia) and tingling sensation in the 
mouth and/or throat were the most frequently reported events. These AEs have been 
reversible and are amenable to monitoring.
In participants with chronic cough, improved tolerability (relative to higher doses of 
MK-7264) and efficacy have been observed at doses of MK-7264 ≤50 mg BID.  Doses from 
7.5 mg to 200 mg BID were studied in participants with chronic cough (in P010 Cohort 1) 
 
 
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and 50 mg BID was as effective as higher doses; however, doses higher than 50 mg BID 
were associated with less tolerability.
The mechanism of action of MK-7264 and related clinical study results demonstrate that the 
efficacy of MK-7264 in decreasing cough, and the prevalence of the most common AE, 
dysgeusia, are both dose-related.  In order to provide patients and prescribers the flexibility to 
balance efficacy and tolerability based on individual clinical situations, the MK-7264 
development program has targeted two doses (15 mg BID and 45 mg BID) to study.
The 45 mg BID dose has been selected for Stage 1 of this trial to evaluate whether this dose 
will effectively reduce acute cough with a side effect profile that is tolerable to patients. 
During Stage 2 of the trial (after the efficacy IA), a third treatment group with a lower dose 
of MK-7264 (15 mg BID) may be added, based on the results of the IA and PK modeling, 
taking both efficacy and safety/tolerability into consideration.
For additional details on MK-7264, refer to the IB (Section 3.2).
6. Study Population
Healthy male and female participants between the ages of 18 and 55 years (inclusive) will be 
enrolled in this study.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
Inclusion Criteria
6.1
Participants are eligible to be included in the study only if all of the following criteria apply:
Type of Participant and Disease Characteristics
1. In good general health with no clinically relevant abnormalities based on the medical 
history, physical examination, vital sign measurements, clinical laboratory 
evaluations (ie, hematology, clinical chemistry, and urinalysis), and 12-lead ECG.
2. Susceptible to HRV-16, as evidenced by a serum-neutralizing antibody titer of 1:4 or 
less, or the definition used by the individual clinic.
Demographics
3. Between 18 and 55 years of age (inclusive) at the Screening Visit, of either gender, 
and of any race.
4. A female participant is eligible to participate if she is not pregnant (see Appendix 3), 
not breastfeeding, and at least one of the following conditions applies:
a) Not a woman of childbearing potential (WOCBP) as defined in Appendix 3
OR
b) A WOCBP who agrees to follow the contraceptive guidance in Appendix 3
during the treatment period and for at least 14 days after the last dose of study 
treatment.
 
 
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Informed Consent
5. The participant (or legally acceptable representative, if applicable) provides written 
informed consent for the study.  The participant may also provide consent for Future 
Biomedical Research.  However the participant may participate in the study without 
participating in Future Biomedical Research.
Study Procedures
6. Demonstrates an ability to follow study procedures (including use of the digital cough 
recording device [VitaloJAK™] and completing the PROs [Cough Severity VAS, 
CSD, LCQ-acute, and WURSS-24]) to the satisfaction of the investigator/qualified 
designee prior to randomization.
7. Has clinical laboratory tests (complete blood count [CBC], blood chemistries,
including urine pregnancy for female participants of childbearing potential [ie, who
have started menstruating], and urinalysis) conducted during Screening documented 
to be clinically acceptable to the investigator before beginning the Treatment Period. 
A female participant of childbearing potential (ie, who has started menstruating) must 
have a negative urine pregnancy test (or a negative serum pregnancy test, if required) 
at both the Screening Visit and Baseline Visit (Day -1) to be considered eligible for 
the trial.
Exclusion Criteria 
6.2
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1. Donated blood within 56 days or donated plasma within 7 days prior to dosing.
2. Has forced expiratory volume in one second (FEV1) <70% of predicted and/or 
FEV1/forced vital capacity (FVC) ratio <80%.
3. Has a history of significant multiple and/or severe allergies (eg, food, drug, latex 
allergy), or has had an anaphylactic reaction or significant intolerability (ie, systemic 
allergic reaction) to prescription or nonprescription drugs or food.
4. Has recent history of an upper or lower respiratory tract infection or recent significant 
change in pulmonary status within 4 weeks of the Baseline Visit (Day -1).
5. Has estimated glomerular filtration rate (eGFR) <50 mL/min/1.73 m2 (using the 
Chronic Kidney Disease Epidemiology Collaboration (CKD EPI) formula 
[http://mdrd.com/]) at Screening.
6. Has a history of cancer (malignancy).
7. Has any condition possibly affecting drug absorption (eg, gastrectomy, gastroplasty, 
any type of bariatric surgery, or vagotomy).
8. Has screening systolic blood pressure (SBP) >160 mm Hg or a diastolic blood 
pressure >90 mm Hg.
9. Has a body mass index <18 kg/m2 or ≥40 kg/m2.
 
 
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10. Had major surgery or lost 1 unit of blood (approximately 500 mL) within 4 weeks 
prior to Screening.
11. Has history of a cutaneous adverse drug reaction to sulfonamides or signs and 
symptoms suggestive of anaphylaxis to sulfonamides.
12. 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 that 
might expose the participant to risk by participating in the trial or investigational 
product administration or confound the results of the trial, or interfere with the 
participant’s participation for the full duration of the trial, and, in the judgment of the 
investigator or Sponsor, would make the participant inappropriate for entry into this 
trial.
13. Is mentally or legally incapacitated, has significant emotional problems at the time of 
Screening, or is expected to during the conduct of the trial, or has a history of a 
clinically significant psychiatric disorder in the last 5 years. Participants who have 
had situational depression may be enrolled in the trial at the discretion of the 
investigator.
14. A WOCBP who has a positive urine pregnancy test within 72 hours before the first 
dose of study treatment.  If the urine test is positive or cannot be confirmed as 
negative, a serum pregnancy test will be required.
Prior/Concomitant Therapy
15. Has received medications to treat an acute viral URTI within 24 hours of study
enrollment (defined as Day -1) (including dextromethorphan, diphenhydramine, and 
narcotic analgesics).
16. Has received medications within 14 days prior to randomization or needs to continue 
to receive any treatment (prescription or OTC) during the current trial, including 
antacids, high-dose multivitamins, nutritional supplements, and herbal preparations, 
beginning approximately 2 weeks (or 5 half-lives of the prior/concomitant 
medication) prior to administration of the initial dose of study treatment, throughout 
the trial, until the post-treatment visit (Day 8).
Prior/Concurrent Clinical Study Experience
17. Has previously received MK-7264.
18. Has participated in another investigational trial within 4 weeks (or 5 half-lives of the 
investigational product used in the other trial), whichever is greater, prior to the 
screening visit (the window will be derived from the date of the last visit in the 
previous trial) OR plans to take another investigational drug or biologic within 
30 days of study completion of this current trial.
 
 
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Diagnostic Assessments
19. Has significantly abnormal laboratory tests at Screening, including:
a) Alkaline phosphatase, alanine aminotransferase (ALT), aspartate 
aminotransferase (AST), or bilirubin >150% of the upper limit of normal (ULN);
b) Hemoglobin <10 gm/dL, red blood cell (RBC) count < lower limit of normal 
(LLN) range, neutrophil count <LLN, platelet count <100 × 103/mm3
20. Has a clinically significant finding in a 12-lead ECG.
Other Exclusions
21. Current smoker, smoker within 5 years of Screening, or former smoker with a 
smoking history >20 pack-years.
22. Consumes >3 glasses of alcoholic beverages (ie, 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.  Participant that consumes 4 glasses of alcoholic beverages per day 
may be enrolled at the discretion of the investigator.
23. 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.
24. Is a regular user of cannabis or any illicit drugs, or has a history of drug (including 
alcohol) abuse within approximately 3 years of Screening. Participant must have a 
negative urine drug screen prior to randomization.
25. Is or has an immediate family member (eg, spouse, parent/legal guardian, sibling or 
child) who is investigational site or sponsor staff directly involved with this study.
Lifestyle Restrictions
6.3
Meals and Dietary Restrictions
6.3.1
There are no meal or dietary restrictions in this study.
Caffeine Alcohol, and Tobacco Restrictions
6.3.2
Participants will not be allowed to consume alcohol or nicotine-containing products while in 
the clinic unit. The consumption of caffeine or xanthine-containing products (eg, coffee, tea, 
cola drinks, and chocolate) will be limited based on the standard policies of the study clinic 
at which they will remain 24 hours a day from Day -2 to Day 7.
Activity
6.3.3
Participants will be limited in exercise based on the standard policies of the study clinic at 
which they will remain 24 hours a day from Day -2 to Day 7.
On Day 1 to Day 7, participant’s bathing activity will be limited to approximately 15 minutes 
per day as per the study clinic instructions.  Bathing time is restricted in order to ensure that 
as close to 24 hours of recording time is obtained each day.
 
 
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Screen Failures
6.4
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently randomized in the study.  A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure participants to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes demography, 
screen failure details, eligibility criteria, and any adverse events or serious adverse events 
(SAE) meeting reporting requirements as outlined in the eCRF entry guidelines.
Participant Replacement Strategy
6.5
A participant who discontinues study treatment or withdraws from the study will not be 
replaced.
7. Treatments
Study treatment is defined as any investigational treatment(s), marketed product(s), placebo,
or medical device(s) intended to be administered to a study participant according to the study 
protocol.
Clinical supplies [study treatment(s) provided by the Sponsor] will be packaged to support 
enrollment.  Clinical supplies will be affixed with a clinical label in accordance with 
regulatory requirements.
Treatments Administered
7.1
The study treatments to be used in this study are outlined below in Table 1 and administered 
as shown in Table 2.
 
 
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Table 1
Study Treatments
Study Treatment 
Name:
MK-7264
45 mg BID
MK-7264
15 mg BID
Placebo
Dosage 
Formulation:
Tablet
Tablet
Tablet
Unit Dose 
Strength(s):
45 mg
15 mg
Placebo to match 
each of MK-7264 
45 mg and 15 mga
Dosage Level(s):
45 mg BID
15 mg BID
Placebo to match 
MK-7264 45 mg BID 
and 15 mg BIDa
Route of 
Administration:
Oral
Oral
Oral
Sourcing:
Provided centrally 
by the Sponsor 
Provided 
centrally by the 
Sponsor 
Provided centrally by 
the Sponsor 
Abbreviations: BID = twice daily
a  As the images of MK-7264 45 mg and 15 mg are not identical, the placebo to match MK-7264 45 mg is different 
than the placebo to match MK-7264 15 mg.
Table 2
Treatment Administration
Period
Trial 
Day
Double-Blinded 
Study Treatment
Stage 1a
Double-Blinded 
Study Treatmenta
Stage 2b
Treatment Period
1
MK-7264 45 mg BID
or
Placebo
MK-7264 45 mg BID
or
MK-7264 15 mg BIDc
or
Placebo
2
3
4
5
6
7
Abbreviations: BID = twice daily; IA = interim analysis.
a    Stage 1 - Prior to efficacy IA.
b   Stage 2 - Post-efficacy IA.
c   MK-7264 15 mg BID group applicable only if a decision is made to add a lower dose of MK-7264 based on 
results of the efficacy IA.
 
 
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All supplies indicated in Table 1 will be provided per the ‘Sourcing’ row depending upon 
local country operational requirements.  Every attempt should be made to source these 
supplies from a single lot/batch number. The study site is responsible for recording the lot 
number, manufacturer, and expiry date for any locally purchased product (if applicable) as 
per local guidelines unless otherwise instructed by the Sponsor.
Refer to Section 9.1.8 for details regarding administration of the study treatment.
Dose Modification  
7.2
Dose modifications are not allowed in this study.
Method of Treatment Assignment 
7.3
Treatment randomization will occur centrally using an interactive voice response system / 
integrated web response system (IVRS/IWRS).  There are two treatment arms in Stage 1.  
Participants will be assigned randomly in a 1:1 ratio to either MK-7264 45 mg BID or
placebo (approximately 50 total participants, 25 per arm) in Stage 1 (prior to the efficacy IA).  
The randomization schedule will be computer generated using a permuted block algorithm 
and will randomly allocate participants to randomization numbers/allocation numbers on 
Day 1.
In Stage 2 (post-efficacy IA), if a decision is made to include a lower dose of MK-7264
based on the efficacy IA results, there will be 3 treatment arms; participants will be 
randomized in a 1:2:1 ratio to MK-7264 45 mg BID, MK-7264 15 mg BID, or placebo, 
respectively. Otherwise, participants in Stage 2 will be randomized in a 1:1 ratio to either
MK-7264 45 mg BID or placebo.    
Stratification
7.3.1
Treatment allocation/randomization will be stratified according to the following factors:

Gender (Male, Female)

Site
The IVRS/IWRS will stratify participants by gender and at a site level. The study will 
endeavor to enroll a minimum of ~ 40% female participants in each stage.  At the site level, 
the IVRS/IWRS will randomize participants to ensure there is a balance among treatment 
groups.
Blinding 
7.4
A double-blinding technique with in-house blinding will be used.  The MK-7264 doses will 
be packaged identically relative to their matching placebos so that the blind is maintained.  
The participant, the investigator and Sponsor personnel or delegate(s) who are involved in 
the study treatment administration or clinical evaluation of the participants are unaware of 
the group assignments.
See Section 9.1.10 for a description of the method of unblinding a participant during the 
study, should such action be warranted.
 
 
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Preparation/Handling/Storage/Accountability
7.5
Dose Preparation
7.5.1
The rationale for dose interval to be used in this study is provided in Section 5.5.1.  There are 
no specific calculations or evaluations required to be performed in order to administer the 
proper dose to each participant.
Handling, Storage and Accountability
7.5.2
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study treatment received and any discrepancies are reported 
and resolved before use of the study treatment.
Only participants enrolled in the study may receive study treatment and only authorized site 
staff may supply or administer study treatment. All study treatments must be stored in a 
secure, environmentally controlled, and monitored (manual or automated) area in accordance 
with the labeled storage conditions with access limited to the investigator and authorized site 
staff.
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study treatment accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records).
For all study 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.
The study site is responsible for recording the lot number, manufacturer, and expiry date for 
any locally purchased product (if applicable) as per local guidelines unless otherwise 
instructed by the Sponsor.
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 study 
treatments in accordance with the protocol and any applicable laws and regulations.
Treatment Compliance
7.6
Randomized participants will remain in the clinic throughout the Treatment Period until 
Day 7 (or discontinuation). Administration of all study treatments will be witnessed by the 
investigator and/or study staff.
During the Treatment Period in Stage 1, all participants will receive 1 tablet of 
MK-7264 45 mg or placebo BID.
During the Treatment Period in Stage 2 (post-efficacy IA), if there are:

Two treatment arms: all participants will receive 1 tablet of MK-7264 45 mg or 
placebo BID.
 
 
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
Three treatment arms: all participants will receive 1 tablet of MK-7264 45 mg and 
1 tablet of placebo for MK-7264 15 mg OR 1 tablet of MK-7264 15 mg and 1 tablet 
of placebo for MK-7264 45 mg OR 1 tablet of placebo for MK-7264 45 mg and 
1 tablet of placebo for MK-7264 15 mg, BID.
Interruptions from the protocol specified treatment plan for >1 day require consultation 
between the investigator and the Sponsor and written documentation of the collaborative 
decision on participant management.
Concomitant Therapy
7.7
Concomitant medications are not permitted during the trial (see Section 6.2). If there is a 
clinical indication for any medication, discontinuation from study therapy may be required.  
The investigator should discuss any questions regarding this with the Sponsor.  The final 
decision on any supportive therapy or vaccination rests with the investigator and/or the 
participant's primary physician.  However, the decision to continue the participant on study 
treatment requires the mutual agreement of the investigator, the Sponsor and the participant.
Rescue Medications and Supportive Care
7.7.1
No rescue or supportive medications are specified to be used in this study.
Treatment After the End of the Study 
7.8
There is no study-specified treatment following the end of the study.
Clinical Supplies Disclosure
7.9
The emergency unblinding call center will use the treatment/randomization schedule for the 
study to unblind participants and to unmask study treatment identity. In the event that the 
emergency unblinding call center is not available for a given site in this study, the central 
electronic treatment allocation/randomization system (IRT) should be used in order to 
unblind participants and to unmask study treatment identity.  The Sponsor will not provide 
random code/disclosure envelopes or lists with the clinical supplies.
See Section 9.1.10, for a description of the method of unblinding a participant during the 
study, should such action be warranted.
8. Discontinuation/Withdrawal Criteria 
Discontinuation of Study Treatment 
8.1
Discontinuation of study treatment does not represent withdrawal from the study.
As certain data on clinical events beyond study treatment discontinuation may be important 
to the study, they must be collected through the participant’s last scheduled follow-up, even 
if the participant has discontinued study treatment.  Therefore, all participants who 
discontinue study treatment prior to completion of the protocol-specified treatment period 
will still continue to participate in the study as specified in the SoA (Section 2) and 
Section 9.10.3.
 
 
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Participants may discontinue study treatment at any time for any reason or be dropped from 
the study treatment at the discretion of the investigator should any untoward effect occur.  In 
addition, a participant may be discontinued from study treatment by the investigator or the 
Sponsor if study treatment is inappropriate, the study plan is violated, or for administrative 
and/or other safety reasons.  Specific details regarding procedures to be performed at study 
treatment discontinuation are provided in Section 9.1.9.
A participant must be discontinued from study treatment but continue to be monitored in the 
study for any of the following reasons:
○
The participant or participant’s legally acceptable representative requests to discontinue 
study treatment.
o
The participant’s treatment assignment has been unblinded by the investigator, Merck 
Sharp & Dohme. Inc. subsidiary, or through the emergency unblinding call center.
o
The participant interrupts study treatment administration for more than 2 consecutive 
days.
o
The participant has a medical condition (including urolithiasis or reduced eGFR by 30% 
or more from Screening value) or personal circumstance which, in the opinion of the 
investigator and/or Sponsor, places the participant at unnecessary risk from continued 
administration of study treatment.
o
Any drug-related SAE or any SAE which, in the opinion of the investigator and/or 
Sponsor, might affect the ability of the participant to safely continue to receive study
treatment.
o
Chronic failure to comply with the dosing, evaluations, or other requirements of the trial, 
despite documentation at the site of repeated efforts to reinforce compliance.
o
The participant has evidence of a severe hypersensitivity reactions defined as progression 
of a treatment-related rash (eg, erythematous macules and papules), including increasing 
extent on body, rash accompanied by systemic findings (eg, fever, lymphadenopathy) or 
laboratory findings (eg, eosinophilia) or any signs or symptoms suggestive of drug-
induced hypersensitivity syndrome (DIHS), also called drug reaction with eosinophilia 
and systemic symptoms (DRESS), Stevens-Johnson syndrome, or toxic epidermal 
necrolysis.
o
The participant has a confirmed positive serum pregnancy test.
o
The participant has a positive urine drug screen (UDS) at any time during the course of 
the trial. 
o
The participant has no confirmation of HRV-16 infection (based on HRV-16 shedding on 
nasal swab testing) within 72 hours of inoculation and will be discharged from the clinic.
For participants who are discontinued from study treatment but continue to be monitored in 
the study, all visits and procedures, as outlined in the SoA, should be completed.
Discontinuation from study treatment is “permanent.” Once a participant is discontinued, 
he/she shall not be allowed to restart study treatment. 
 
 
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Withdrawal from the Study
8.2
A participant must be withdrawn from the study if the participant or participant’s legally 
acceptable representative withdraws consent from the study.
If a participant withdraws from the study, they will no longer receive study treatment or be 
followed at scheduled protocol visits.
Specific details regarding procedures to be performed at the time of withdrawal from the 
study including the procedures to be performed if the study site is unable to contact the 
participant, as well as specific details regarding withdrawal from Future Biomedical 
Research are outlined in Section 9.1.9. The procedures to be performed if the study site is 
unable to contact the participant are outlined in Section 8.3.
Lost to Follow Up
8.3
If a participant fails to return to the clinic for a required study visit and/or if the site is unable 
to contact the participant, the following procedures are to be performed:
●
The site must attempt to contact the participant and reschedule the missed visit.  If the 
participant is contacted, the participant should be counseled on the importance of 
maintaining the protocol-specified visit schedule.
●
The investigator or designee must make every effort to regain contact with the 
participant at each missed visit (eg, phone calls and/or a certified letter to the 
participant’s last known mailing address or locally equivalent methods). These 
contact attempts should be documented in the participant’s medical record.
●
Note:  A participant is not considered lost to follow-up until the last scheduled visit 
for the individual participant.  The missing data for the participant will be managed 
via the pre-specified statistical data handling and analysis guidelines.
9. Study Assessments and Procedures
●
Study procedures and their timing are summarized in the SoA. 
●
Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.
●
The Investigator is responsible for assuring that procedures are conducted by 
appropriately qualified or trained staff.  Delegation of study site personnel 
responsibilities will be documented in the Investigator Trial File Binder (or 
equivalent).
●
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log 
to record details of all participants screened and to confirm eligibility or record 
reasons for screening failure, as applicable. 
 
 
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●
Additional evaluations/testing may be deemed necessary by the investigator and or 
the Sponsor for reasons related to participant safety. In some cases, such 
evaluation/testing may be potentially sensitive in nature (eg, HIV, Hepatitis C, etc.), 
and thus local regulations may require that additional informed consent be obtained 
from the participant.  In these cases, such evaluations/testing will be performed in 
accordance with those regulations.
The maximum amount of blood collected from each participant over the duration of the 
study, including any extra assessments that may be required, will not exceed approximately 
85 mL.
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with 
the samples.
Administrative and General Procedures
9.1
Informed Consent
9.1.1
The investigator or qualified designee must obtain documented consent from each potential 
participant or each participant’s legally acceptable representative prior to participating in a 
clinical study or Future Biomedical Research. If there are changes to the participant’s status 
during the study (eg, health or age of majority requirements), the investigator or qualified 
designee must ensure the appropriate consent is in place. 
General Informed Consent
9.1.1.1
Consent must be documented by the participant’s dated signature or by the participant’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 participant before 
participation in the study.
The initial ICF, any subsequent revised written ICF and any written information provided to 
the participant must receive the IRB/IEC’s approval/favorable opinion in advance of use.  
The participant or his/her legally acceptable representative should be informed in a timely 
manner if new information becomes available that may be relevant to the participant’s 
willingness to continue participation in the study.  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 participant’s dated signature or by the participant’s legally 
acceptable representative’s dated signature.
Specifics about a study and the study population will be added to the consent form template 
at the protocol level.  
The informed consent will adhere to IRB/IEC requirements, applicable laws and regulations 
and Sponsor requirements.
 
 
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Consent and Collection of Specimens for Future Biomedical Research
9.1.1.2
The investigator or qualified designee will explain the Future Biomedical Research consent 
to the participant, answer all of his/her questions, and obtain written informed consent before 
performing any procedure related to the Future Biomedical Research sub-study.  A copy of 
the informed consent will be given to the participant.
Inclusion/Exclusion Criteria
9.1.2
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee 
at the Screening Visit and on Days -2, -1, and 1 to ensure that the participant qualifies for the 
study. Inclusion and exclusion criteria for this study are defined in Sections 6.1 and 6.2, 
respectively.
Participant Identification Card
9.1.3
All participants will be given a Participant Identification Card identifying them as 
participants in a research study. The card will contain study site contact information 
(including direct telephone numbers) to be utilized in the event of an emergency. The 
investigator or qualified designee will provide the participant with a Participant Identification 
Card immediately after the participant provides written informed consent. At the time of 
treatment allocation/randomization, site personnel will add the treatment/randomization 
number to the Participant Identification Card.
The participant identification card also contains contact information for the emergency 
unblinding call center so that a health care provider can obtain information about study 
treatment in emergency situations where the investigator is not available.
Medical History
9.1.4
A medical history will be obtained by the investigator or qualified designee. It will include a 
history of medical conditions within 30 days prior to the Screening Visit.
Prior and Concomitant Medications Review
9.1.5
Prior Medications
9.1.5.1
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the participant 
within 30 days (or longer if appropriate) prior to the Screening Visit (See Section 6.2).
Concomitant Medications
9.1.5.2
The investigator or qualified designee will record medication, if any, taken by the participant 
during the study.
Assignment of Screening Number
9.1.6
All consented participants will be given a unique screening number that will be used to 
identify the participant for all procedures that occur prior to randomization.  Each participant 
 
 
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will be assigned only one screening number.  Screening numbers must not be re-used for 
different participants.
Any participant 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 9.10.1.  
Assignment of Treatment/Randomization Number
9.1.7
All eligible participants will be randomly allocated and will receive a 
treatment/randomization number.  The treatment/randomization number identifies the 
participant for all procedures occurring after treatment allocation/randomization.  Once a 
treatment/randomization number is assigned to a participant, it can never be re-assigned to 
another participant.
A single participant cannot be assigned more than 1 treatment/randomization number.
Treatment Administration
9.1.8
Throughout the treatment period, administration of study treatment (all doses) will be 
witnessed by the investigator and/or study staff.
Study treatment will begin in the morning (before 11 am approximately) on the day of 
treatment randomization (Day 1).  After randomization, the study participant will first have 
the VitaloJAK™attached.  The participant will then be inoculated with HRV-16 and then 
administered the first dose of study treatment.  The VitaloJAK will then be immediately 
turned “on” after the first dose is administered.  As dosing is BID, the next dose of study 
treatment on Day 1 should be taken orally in the evening, approximately 12 hours after the 
morning dose. Subsequent dosing through Day 7 will be performed in the same manner.
In Stage 1, all participants will be administered 1 tablet of study treatment BID (total daily 
dose: 2 tablets).
In Stage 2, if there are 2 treatment arms, all participants will be administered 1 tablet BID
(total daily dose: 2 tablets).  If there are 3 treatment arms (in order to maintain the blinding 
of the 2 different MK-7264 dose images), all participants will be administered 2 tablets of 
study treatment BID (totally daily dose: 4 tablets).
For more details about treatment compliance, see Section 7.6.
Timing of Dose Administration
9.1.8.1
Study treatments will be administered orally, BID (in the morning and in the evening), 
approximately 12 hours apart for 7 days and at approximately the same times each day.
Discontinuation and Withdrawal
9.1.9
Participants who discontinue study treatment prior to completion of the treatment period
should be encouraged to continue to be followed for all remaining study visits.
 
 
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When a participant withdraws from participation in the study, all applicable activities 
scheduled for the Early Discontinuation visit as described in the SoA (Section 2) should be 
performed (at the time of withdrawal).  Any adverse events which are present at the time of 
withdrawal should be followed in accordance with the safety requirements outlined in 
Section 9.3.
Withdrawal From Future Biomedical Research
9.1.9.1
Participants may withdraw their consent for Future Biomedical Research.  Participants may 
withdraw consent at any time by contacting the principal investigator for the main study.  If 
medical records for the main study are still available, the investigator will contact the 
Sponsor using the designated mailbox (clinical.specimen.management@merck.com).  
Subsequently, the participant'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 participant 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 
study data and results.  No new analyses would be generated after the request is received.
In the event that the medical records for the main study are no longer available (eg, if the 
investigator is no longer required by regulatory authorities to retain the main study records) 
or the specimens have been completely anonymized, there will no longer be a link between 
the participant’s personal information and their specimens.  In this situation, the request for 
specimen withdrawal cannot be processed.
Participant Blinding/Unblinding
9.1.10
Participants whose treatment assignment has been unblinded by the investigator/delegate 
and/or non-study treating physician must be discontinued from study treatment, but should 
continue to be monitored in the study.
Additionally, the investigator must go into the IRT system and perform the unblind in the 
IRT system to update drug disposition.  In the event that the emergency unblinding call 
center is not available for a given site in this study, the IRT system should be used for 
emergency unblinding in the event that this is required for participant safety.
Study treatment identification information is to be unmasked ONLY if necessary for the 
welfare of the participant.  Every effort should be made not to unblind the participant unless 
necessary. 
In the event that unblinding has occurred, the circumstances around the unblinding (eg, date, 
reason and person performing the unblinding) must be documented promptly, and the 
Sponsor Clinical Director notified as soon as possible. Only the principal investigator or 
delegate and the respective participant’s code should be unblinded. Other study site 
personnel and Sponsor personnel directly associated with the conduct of the study should not 
be unblinded.
 
 
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Domiciling
9.1.11
On Day -2 of the screening period, eligible participants will be admitted to the study clinic 
and remain confined to the clinic until completion of the treatment period on Day 7 
(Section 5.1).
Note: Participants who fail screening between Day -2 and Day 1 (prior to randomization) 
will be discharged from the clinic and excluded from the trial.
Participants who lack confirmation of HRV-16 shedding by nasal swab testing within 72 
hours of inoculation will be notified (once results are available), discontinued from study 
treatment, have discontinuation procedures performed (as specified in the SoA [Section 2]), 
and be discharged from the clinic; a safety follow-up telephone call will be performed 14
days after the last dose of study treatment.
Calibration of Critical Equipment
9.1.12
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 study that provides 
important information about inclusion/exclusion criteria and/or safety or efficacy parameters 
shall be suitably calibrated and maintained to ensure that the data obtained is reliable and/or 
reproducible.  Documentation of equipment calibration must be retained as source 
documentation at the study site.
Critical Equipment for this study includes:

VitaloJAK™cough monitor (study sourced): Calibration by the site is not necessary
(See VitaloJAK™Site Manual)

Spirometer (site equipment): The spirometer should be calibrated according to 
American Thoracic Society/European Respiratory Society (ATS/ERS) guidelines. 
Calibration checks should be performed (ie, with a 3-liter syringe) at a minimum of 
each day that a trial participant performs a spirometry assessment. The calibration 
check records should be printed and kept in a reviewable log. It is preferred that the 
calibration syringe used to check calibration of the spirometer also be subjected to a 
validated calibration according to the manufacturer’s specifications.

ECG machine (site equipment): Calibration should be performed according to the 
manufacturer’s specifications.

Equipment for Cough Challenge (locally sourced): Calibration should be performed
according to the manufacturer’s specifications.

Equipment for HRV-16 administration (locally sourced): Calibration should be 
performed according to the manufacturer’s specifications as necessary.
 
 
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Other Study Procedures
9.1.13
Antibody Titers to Human Rhinovirus Type 16
9.1.13.1
Sample collection, storage, and shipment instructions to quantify antibody titers for HRV-16 
at the Screening Visit are provided in the Central Laboratory Manual.
Ethanol Breath Test
9.1.13.2
The ethanol breath test, commonly known as alcohol breath test, will be performed at the 
site, as specified in the SoA (Section 2), to determine the level of ethanol in the blood. 
Alcohol in the mouth gives a rapid peak in ethanol concentration on the evidential test.
Urine Cotinine Test
9.1.13.3
Urine cotinine testing will be performed, as specified in the SoA (Section 2), to determine
use of tobacco products by biochemical measurement of cotinine (nicotine metabolite) in a 
urine specimen.  
Nasal Swabs for Human Rhinovirus Polymerase Chain Reaction
9.1.13.4
During the treatment period, experienced site staff will collect nasopharyngeal swabs from 
each participant every 12 hours for the 72-hour period immediately following inoculation 
with HRV-16, as specified in the SoA (Section 2). Instructions for collection, storage, and 
handling/shipment of nasal swab specimen and testing for HRV-16 by polymerase chain 
reaction (PCR) are provided in the Central Laboratory Manual.
Efficacy Assessments 
9.2
Compliance with the efficacy and safety assessments (along with study treatment use) is 
essential, and any non-compliance noted by the investigator or designee should result in 
consultation with the participant on corrective measures needed to ensure compliance.
Cough Monitoring – VitaloJAK™Recording Device
9.2.1
The assessment of awake coughs per hour (based on 24-hour sound recordings) will be 
evaluated using the VitaloJAK™ cough monitor, a 510k approved (Premarket Notification 
per the United States Food, Drug and Cosmetic Act) that has been implemented successfully 
in clinical studies of potential cough therapies, including two Phase 2 studies of MK-7264.
The VitaloJAK™ cough monitor recording device uses two input channels. The first channel 
records sounds from the lungs and trachea through a chest contact sensor, which is attached 
to the skin at the top of the sternum with adhesive. The second channel captures ambient 
sounds through a lapel air microphone. Sounds are stored on a high-capacity compact flash 
(CF) II card. The device will be carried in a cloth belt bag worn around the participant’s 
waist, and it will record all sounds the participant makes during cough monitoring.
When the digital recording arrives at the central reading center, a human analyst uses 
standardized criteria to identify transitions between awake and asleep states. To reduce 
review time, the 24-hour recordings are processed through a computerized algorithm that 
 
 
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removes periods of silence and a high proportion of non-cough sounds. A cough analyst then 
evaluates the abbreviated recording by listening to both audio channels and inspecting the 
visual wave form of potential cough sounds. The analyst tags the explosive portion of each 
cough using the Vitalograph Web Portal for analysis and annotation of sound recordings. 
Cough counts are then tallied automatically from the annotated audio file.
During the Treatment Period, the cough monitor will be attached to all randomized 
participants and set up prior to first dose of study treatment (see Section 9.10.2 and the 
VitaloJAK™Site Manual for further details). The monitor will be set to begin recording
immediately after the first morning dose. The device will be worn 24 hours a day for the 7-
day treatment period with approximately 15 minutes/day ”off-time” permitted for showering.
Participants will continue to wear the cough monitor during the cough challenge procedures 
on Days 1, 4, and 7, as the cough counting data from the cough monitor will be used to 
support the primary analysis.
Intranasal Administration of Rhinovirus
9.2.2
All randomized participants will be administered HRV-16 intranasally on Day 1.  A detailed 
description of the preparation and administration of HRV-16 is provided in the Procedures
Manual.
If there is no confirmation of viral infection within 72 hours post-inoculation with HRV-16
by PCR assay, the participant will be discontinued from treatment.
The trial site will be responsible for recording the lot number, manufacturer, and expiry date 
of applicable supplies related to HRV-16 administration.
Note: Participants will receive the first dose of study treatment immediately after 
administration of HRV-16. There is no requirement for participants to display symptoms of 
infection prior to administration of first dose of trial treatment.
ATP Cough Challenge (Stage 1 Only)
9.2.3
Cough reflex sensitivity is measured by standard clinical methodology incorporating ATP 
cough challenge in accordance with the Procedures Manual. The ATP cough challenge will 
be administered ONLY during Stage 1 of the trial.
The standard endpoints measured in cough challenge testing are reflex sensitivity to ATP 
measured by C2 and C5 (ie, concentration of cough challenge agent [ATP] inducing at least 
2 or 5 coughs, respectively) during Stage 1 on Days -1, 1, 4, and 7.
The number of coughs during the ATP cough challenge will be assessed manually by site 
staff during all ATP cough challenges.
Participants will continue to wear the cough monitor during the cough challenge procedures 
on Days 1, 3, and 7, as the cough counting data from the cough monitor will be used to 
support the primary analysis. All analyses related to the ATP cough challenge will be 
performed using manual cough counting data, including the exploratory analysis related to 
cough reflex sensitivity.
 
 
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The challenge should be discontinued for the day if a participant experiences severe side
effects or coughs excessively and makes a clear request to stop taking the challenge test (see 
Procedures Manual).
β-agonist should be available for participants who experience bronchoconstriction; other 
appropriate medical interventions should be provided as necessary. Those who need to 
discontinue the cough challenge may still participate in the cough challenges on subsequent 
days.
Patient-reported Outcomes
9.2.4
At Baseline (Day -1), each participant will be properly trained and instructed on the 
completion of all PRO assessments/questionnaires: CSD, Cough Severity VAS, LCQ-acute, 
and WURSS-24.  These assessments/questionnaires should be provided to the participant and 
conducted in the same order each day at approximately the same time in the evening, as 
specified in the SoA (Section 2.0). Data must be reviewed by the investigator or designee
each time a participant completes an assessment/questionnaire. Overall completeness and 
accuracy of all recorded entries should be reviewed. Deficiencies should be immediately 
discussed with the participant to improve the quality of future assessment/ questionnaire 
entries. The investigator and qualified designee should ensure that any relevant comments 
that refer to possible AEs are discussed or clarified with the participant, and any AEs are 
collected in the AE electronic case report form (eCRF).
Cough Severity Diary
9.2.4.1
Participants are instructed to record their cough frequency, intensity, and associated 
disruptions using the 7-item CSD. Participants will rate each item using an 11-point scale 
ranging from 0 to 10, with higher scores indicating greater severity of cough.
Cough Severity Visual Analog Scale
9.2.4.2
Participants are instructed to rate the severity of their cough “today” using a 100 mm VAS 
single-item questionnaire with the response ranging from 0 (“no cough”) to 100 (“extremely
severe cough”).
Leicester Cough Questionnaire-Acute
9.2.4.3
Participants are instructed to complete the 19-item LCQ-acute to assess the impact of their 
cough severity in the last 24 hours on physical, social, and psychological functioning, using a 
7-point Likert scale ranging from 1 to 7; higher scores indicate better HRQoL.
Wisconsin Upper Respiratory Symptom Survey-24
9.2.4.4
Participants are instructed to complete the WURSS-24 questionnaire, an illness-specific 
quality of life instrument designed to assess the negative impact of acute URTI, using an 8-
point Likert scale ranging from 0 to 7; higher scores indicate worse HRQoL. Influenza-like 
illness symptoms of headache, body aches, and fever are included on the WURSS-24.
 
 
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Adverse Events (AE), Serious Adverse Events (SAE) and Other Reportable Safety 
9.3
Events 
The definitions of an adverse event (AE) or serious adverse event (SAE), as well as the 
method of recording, evaluating, and assessing causality of AE and SAE and the procedures 
for completing and transmitting AE, SAE and other reportable safety event reports can be 
found in Appendix 4.
AE, SAEs, and other reportable safety events will be reported by the participant (or, when 
appropriate, by a caregiver, surrogate, or the participant's legally authorized representative). 
The investigator, who is a qualified physician, and any designees are responsible for 
detecting, assessing, documenting, and reporting events that meet the definition of an AE or 
SAE as well as other reportable safety events. Investigators remain responsible for following 
up AE, SAEs and other reportable safety events for outcome according to Section 9.3.3.
Adverse events will not be collected for participants during the pre-screening period (for 
determination of archival tissue status) as long as that participant has not undergone any 
protocol-specified procedure or intervention.  If the participant requires a blood draw, fresh 
tumor biopsy etc., the participant is first required to provide consent to the main study and 
AEs will be captured according to guidelines for standard AE reporting.
Time Period and Frequency for Collecting AE, SAE and Other Reportable 
9.3.1
Safety Event Information 
All AEs, SAEs and other reportable safety events that occur after the consent form is signed 
but before treatment allocation/randomization must be reported by the investigator if the 
participant is receiving placebo run-in or other run-in treatment, if the event causes the 
participant to be excluded from the study, or is the result of a protocol-specified intervention, 
including but not limited to washout or discontinuation of usual therapy, diet, or a procedure. 
From the time of treatment allocation/randomization through 14 days following cessation of 
treatment, all AEs, SAEs and other reportable safety events must be reported by the 
investigator. 
Additionally, any SAE brought to the attention of an investigator at any time outside of the 
time period specified in the previous paragraph must be reported immediately to the Sponsor 
if the event is considered to be drug-related.
Investigators are not obligated to actively seek AE or SAE or other reportable safety events 
in former study participants. However, if the investigator learns of any SAE, including a 
death, at any time after a participant has been discharged from the study, and he/she 
considers the event to be reasonably related to the study treatment or study participation, the 
investigator must promptly notify the sponsor.
All initial and follow-up AEs, SAEs and other reportable safety events will be recorded and 
reported to the sponsor or designee within the timeframes as indicated in Table 3.
 
 
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Table 3
Reporting Time Periods and Timeframes for Adverse Events and Other 
Reportable Safety Events
Type of Event
Reporting Time 
Period:
Consent to 
Randomization/ 
Allocation
Reporting Time 
Period:
Randomization/ 
Allocation 
through 
Protocol-
Specified 
Follow-up 
Period
Reporting Time 
Period:
After the Protocol 
Specified Follow-up 
Period
Timeframe 
to Report 
Event and 
Follow-up 
Information 
to 
SPONSOR:
Non-Serious 
Adverse Event 
(NSAE)
Report if:
- due to protocol-
specified 
intervention
- causes 
exclusion
- participant is 
receiving placebo 
run-in or other 
run-in treatment
Report all
Not required
Per data 
entry 
guidelines
Serious Adverse 
Event (SAE)
Report if:
- due to protocol-
specified 
intervention
- causes 
exclusion
- participant is 
receiving placebo 
run-in or other 
run-in treatment
Report all
Report if:
- drug/vaccine related.
(Follow ongoing to 
outcome)
Within 24 
hours of 
learning of 
event
Pregnancy/Lactation 
Exposure
Report if:
- due to 
intervention
- causes 
exclusion
Report all
Previously reported –
Follow to 
completion/termination; 
report outcome
Within 24 
hours of 
learning of 
event
Event of Clinical 
Interest (require 
regulatory 
reporting)
Report if:
- due to 
intervention
- causes 
exclusion
Report
- Potential drug-
induced liver 
injury (DILI)
- Require 
regulatory 
reporting
Not required
Within 24 
hours of 
learning of 
event
Event of Clinical 
Interest (Do not 
require regulatory 
reporting)
Report if:
- due to 
intervention
- causes 
exclusion
Report
- non-DILI ECIs
and those not 
requiring 
regulatory 
reporting
Not required
Within 5 
calendar 
days of 
learning of 
event
 
 
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Type of Event
Reporting Time 
Period:
Consent to 
Randomization/ 
Allocation
Reporting Time 
Period:
Randomization/ 
Allocation 
through 
Protocol-
Specified 
Follow-up 
Period
Reporting Time 
Period:
After the Protocol 
Specified Follow-up 
Period
Timeframe 
to Report 
Event and 
Follow-up 
Information 
to 
SPONSOR:
Cancer
Report if:
- due to 
intervention
- causes 
exclusion
Report all
Not required
Within 5 
calendar 
days of 
learning of 
event
Overdose
Report if:
- receiving 
placebo run-in or 
other run-in 
medication 
Report all
Not required
Within 5 
calendar 
days of 
learning of 
event
Method of Detecting AE, SAE and Other Reportable Safety Events
9.3.2
Care will be taken not to introduce bias when detecting AE and/or SAE and other reportable 
safety events. Open-ended and non-leading verbal questioning of the participant is the 
preferred method to inquire about AE occurrence.
Follow-up of AE, SAE and Other Reportable Safety Event Information 
9.3.3
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All AE, SAE and other reportable safety events 
including pregnancy and exposure during breastfeeding, ECI, Cancer and Overdose will be 
followed until resolution, stabilization, until the event is otherwise explained, or the 
participant is lost to follow-up (as defined in Section 8.3). In addition, the investigator will 
make every attempt to follow all non-serious AEs that occur in randomized participants for 
outcome.  Further information on follow-up procedures is given in Appendix 4.
Regulatory Reporting Requirements for SAE
9.3.4
●
Prompt notification (within 24 hours) by the investigator to the sponsor of SAE is 
essential so that legal obligations and ethical responsibilities towards the safety of 
participants and the safety of a study treatment under clinical investigation are met. 
●
The sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study treatment under clinical 
investigation. All Adverse Events will be reported to regulatory authorities, IRB/IECs 
and investigators in accordance with all applicable global laws and regulations, ie, per 
ICH Topic E6 (R1) Guidelines for Good Clinical Practice.
 
 
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●
Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSAR) according to local regulatory requirements and sponsor policy and 
forwarded to investigators as necessary.
●
An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAE) from the sponsor will file 
it along with the Investigator’s Brochure and will notify the IRB/IEC, if appropriate 
according to local requirements.
Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as AEs 
9.3.5
or SAEs
There are no disease-related events and/or disease-related outcomes not qualifying as AEs or 
SAEs.
Pregnancy and Exposure During Breastfeeding
9.3.6
Although pregnancy and infant exposure during breastfeeding are not considered adverse 
events, any pregnancy or infant exposure during breastfeeding in a participant (spontaneously 
reported to the investigator or their designee) that occurs during the study are reportable to 
the Sponsor.
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.
Events of Clinical Interest (ECI)
9.3.7
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI) and must be reported to the Sponsor.
Events of clinical interest for this study include: 
1. an elevated AST or ALT lab value that is greater than or equal to 3X the upper limit 
of normal and an elevated total bilirubin lab value that is greater than or equal to 2X the 
upper limit of normal and, at the same time, an alkaline phosphatase lab value that is less 
than 2X the upper limit of normal, as determined by way of protocol-specified laboratory 
testing or unscheduled laboratory testing.*
*Note:  These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may require 
an additional evaluation for an underlying etiology. The study site guidance for 
assessment and follow up of these criteria can be found in the Investigator Trial File 
Binder (or equivalent).
 
 
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Treatment of Overdose
9.4
In this study, an overdose is any dose >1 tablet BID in Stage 1 and Stage 2 (if only 
2 treatment arms are included).  If a 3rd treatment arm is added in Stage 2 based on the results 
of the efficacy IA, an overdose will be defined as >2 tablets BID (Section 7.1).
No specific information is available on the treatment of overdose. Oral doses of up to 
1800 mg BID for 14 days were explored in earlier clinical studies without any untoward 
clinical effects [IB Edition 16 2017]. Overdoses should be treated according to the 
participant’s clinical signs and symptoms.
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the Sponsor Clinical Director based on the clinical evaluation of the 
participant.
Safety 
9.5
Details regarding specific safety procedures/assessments to be performed in this study are 
provided below.
Planned time points for all safety assessments are provided in the SoA.
Physical Examinations
9.5.1
All participants will undergo a full physical examination (except for rectal and genital 
examination) at the visits specified in the SoA (Section 2).
The full examination will be conducted as per institutional standard on the following body 
systems: general appearance, head (ie, oral inspection, ears, eyes, nose, and throat), 
respiratory (ie, auscultation/stethoscope examination of the lungs), heart (ie, 
auscultation/stethoscope examination of the heart), abdomen, musculoskeletal, neurological, 
lymph nodes, and skin. Participants with evidence of current, clinically significant, 
intercurrent illness (eg, significant cold or flu) may be rescheduled for rescreening upon 
resolution of their illness (See Section 9.10.1.1).
Based on investigator judgment, questioning regarding symptoms may be sufficient for the 
following body systems: abdomen, urogenital, musculoskeletal, and neurological. If deemed 
necessary by the investigator, a physical examination of these body systems will be 
performed.
Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
A physical exam (full or limited) may be performed at any clinic visit that does not already 
include a physical exam or at any unscheduled visit if deemed necessary by the investigator 
due to signs/symptoms.
Clinically significant changes from baseline will be recorded as AEs.  Baseline for physical 
examination is defined as the examination performed during the Screening Visit.
 
 
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Vital Signs and Weight and Height Measurements
9.5.2
Vital signs (including oral body temperature (centigrade), blood pressure (mm Hg), pulse rate 
(beats per minute), and respiratory rate (breaths per minute)), height (cm), and weight (kg)
will be assessed at the visits specified in the SoA (Section 2).  All vital signs will be 
measured after each participant has been sitting/resting for at least 5 minutes. Blood pressure 
measurements should be performed on the same arm, preferably by the same person. At the 
Screening Visit, vital signs will be measured just before the spirometry measurement.  
Any clinically significant abnormalities in vital signs noted after the Screening Visit will be 
recorded as AEs in the AE eCRF.
Electrocardiograms
9.5.3
A single 12-lead ECG will be obtained as outlined in the SoA (Section 2) using local 
standard procedures. Clinically significant abnormal findings should be recorded in the AE 
eCRF.
Spirometry
9.5.4
A spirometry assessment will be performed at the Screening Visit using a local calibrated 
spirometer.
Spirometry should be performed in accordance with guidelines established by ATS/ERS 
(Available from: http://www.thoracic.org/statements). For safety reasons, spirometry should 
be performed with the participant sitting, using a chair with arms and without wheels; 
however, if necessary to undertake the testing with the participant standing or in another 
position, this should be noted on the spirometry report.
Taste-Related Adverse Events
9.5.5
The tolerance to taste-related AEs will be evaluated during the study if a taste-related AE(s) 
is reported.  At the time the taste-related AE is reported and every day until the AE is 
reported as resolved, the site staff will obtain information on the timing, duration, intensity, 
etc., of the taste-related AE.
The information will be entered into the appropriate eCRFs based on the eCRF entry 
guidelines, which will be provided to the sites by the Sponsor.
 
 
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Clinical Safety Laboratory Assessments
9.5.6
Refer to Appendix 5 for the list of clinical laboratory tests to be performed and to the SoA for 
the timing and frequency. 
●
The investigator must review the laboratory report, document this review, and record 
any clinically relevant changes occurring during the study in the AE section of the 
CRF. The laboratory reports must be filed with the source documents. Clinically 
significant abnormal laboratory findings are those which are not associated with the 
underlying disease, unless judged by the investigator to be more severe than expected 
for the participant's condition.
●
All protocol-required laboratory assessments, as defined in Appendix 5, must be 
conducted in accordance with the Central Laboratory Manual and the SoA
(Section 2).
●
If laboratory values from non-protocol specified laboratory assessments performed at 
the institution’s local laboratory require a change in study participant management or 
are considered clinically significant by the investigator (eg, SAE or AE or dose 
modification), then the results must be recorded in the appropriate CRF (eg, SLAB).
●
For any laboratory tests with values considered clinically significantly abnormal 
during participation in the study or within 14 days after the last dose of study 
treatment, every attempt should be made to perform repeat assessments until the 
values return to normal or baseline or if a new baseline is established as determined 
by the investigator. 
Urine Pregnancy Test – if applicable
9.5.6.1
Urine pregnancy test will be performed at the site on female participants of childbearing 
potential as specified in the SoA (Section 2). A positive urine pregnancy test should be 
followed up with a serum pregnancy test performed by the central laboratory. Collection, 
storage, and shipment of serum for pregnancy testing should be performed as described in the 
Central Laboratory Manual.
Pharmacokinetics
9.6
The decision as to which plasma samples collected will be assayed for evaluation of PK will 
be collaboratively determined by the Department of Quantitative Pharmacology and 
Pharmacometrics (QP2) for assay in an exploratory manner for metabolites and/or additional 
PK markers.
Blood Collection for Plasma MK-7264
9.6.1
PK samples will be collected at the time points specified in Table 4 and in the SoA 
(Section 2). Blood collection, storage, and shipment instructions for plasma samples are
provided in the Central Laboratory Manual.
 
 
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Table 4
Pharmacokinetic Samples Collection
Period
Trial Day
PK 
Sample
Time of Collection of PK Sample
Treatment 
Period 
(Stages 1 and 2)
1
X
Predose,
1, 2, 4, 8, and 12 hours 
postmorning dose
2
X
Premorning dose
3
NA
4
X
Premorning dose
5
NA
6
NA
7
X
Premorning dose, 1, 2, 4, 8, and 12 hours 
postmorning dose
Abbreviations: NA = not applicable; PK = pharmacokinetic
A variance in procedure collection times as specified in Table 5 will be permitted.
Table 5
Pharmacokinetic (Blood) Collection Windows
PK Collection Time
PK Collection Window
Pre-dose
Within 15 minutes before dose
1 hr post-dose
± 5 minutes
2 hrs post-dose
± 10 minutes
4 hrs post-dose
± 10 minutes
8 hrs post-dose
± 15 minutes
12 hrs post-dose
± 15 minutes
Abbreviations: PK = pharmacokinetic
Pharmacodynamics
9.7
Pharmacodynamic parameters will not be evaluated in this study.
Biomarkers
9.8
Collection of samples for other biomarker research is also part of this study. The following 
samples for biomarker research are required and will be collected from all participants in this 
study as specified in the SoA (Section 2):

Blood for genetic analysis
 
 
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Planned Genetic Analysis Sample Collection
9.8.1
The Planned Genetic Analysis sample should be drawn 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 
participant signs the Future Biomedical Research consent. If the planned genetic analysis is 
not approved, but Future Biomedical Research is approved and consent is given, this sample 
will be collected for the purpose of Future Biomedical Research.
Sample collection, storage and shipment instructions for Planned Genetic Analysis samples 
will be provided in the Central Laboratory Manual.
Future Biomedical Research Sample Collection 
9.9
If the participant signs the Future Biomedical Research consent, the following specimens will 
be obtained as part of Future Biomedical Research:

DNA for future research
Visit Requirements
9.10
Visit requirements are outlined in Section 2 – Schedule of Activities (SoA).  Specific 
procedure-related details are provided above in Section 9 – Study Assessments and 
Procedures.
All study procedures will be performed as specified in the SoA (Section 2).
The PROs (CSD, Cough Severity VAS, LCQ-acute, and WURSS-24) should be performed in 
the same order each evening, as listed in the SoA (Section 2.0).
Additional details of certain procedures at specific visits are described in this section.
Screening Period
9.10.1
Visit 1
9.10.1.1
During the Screening Period, between Days -28 to -3, potential participants will be evaluated 
to determine their eligibility as described in Sections 6.1 and 6.2. Screening procedures may 
be repeated after consultation with the Sponsor.
Participants may be rescreened once within 30 days of not meeting entry criteria during the 
screening period. Rescreening should include all screening procedures listed in the SoA
(Section 2), including consent review. A consultation or Sponsor Consultation Form is not 
required for rescreening a participant.  Note: Participants who were previously randomized 
and discontinued due to lack of viral shedding within 72 hours of inoculation (or 
discontinued for any other reason) may not be rescreened for this trial.
 
 
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Visit 2 (Day -2)
9.10.1.2
Eligible participants will be admitted to the clinic on Day -2 and will remain confined to the 
clinic until completion of the treatment period on Day 7 and discharged on Day 8 (or until 
discontinuation).
Visit 3 (Day -1; Baseline Visit)
9.10.1.3
Study clinic staff will instruct participants on how to properly complete study-related 
questionnaires (ie, Cough Severity VAS, CSD, LCQ-acute, and WURSS-24) and evaluate 
participant’s capability to understand and complete the questionnaires for the duration of the 
trial.  Note: Study clinic staff must never implement any updates on behalf of the participant
or provide any interpretation of the questions.
On Day -1 of Stage 1, the ATP cough challenge will be administered to participants as 
described in Section 9.2.3. The number of coughs will be monitored manually at this visit.  
Details of the cough challenge procedures are provided in the Procedures Manual.
Note: ATP cough challenge is NOT performed during Stage 2 of the trial.
Treatment Period (Days 1 through 7)
9.10.2
Beginning at the randomization visit (Day 1), the cough monitor will be attached to the 
participant as described in Section 9.2.1.  On Days 1 through 7, the CF card and battery pack 
must be removed from the cough monitor and replaced with a new CF card and new battery 
pack every 24 hours.  Each CF card will then be sent for analysis, as described in the 
VitaloJAK™Manual.
Note: The cough monitor can be removed for approximately 15 minutes each day, prior to 
taking a shower, with the assistance of site staff.
During Stage 1 of the trial, ATP cough challenge will be performed on all randomized 
participants 2 hours (± 30 minutes) postmorning dose as per the SoA (Section 2). The ATP 
cough challenge will NOT be performed during Stage 2 of the trial.
At the Discharge Visit (Day 8), a limited physical exam may be performed instead of a full 
physical exam, based on investigator judgment.  Women of child bearing potential should be 
reminded to continue use of appropriate contraception (see Appendix 3) for at least 14 days 
after the last dose of study treatment.
Discontinued Participants Continuing to be Monitored in the Study
9.10.3
If a participant is discontinued from the study treatment, discontinuation procedures should 
be performed as specified in the SoA (Section 2).  The participant will then be discharged 
from the study clinic and will be informed that they will receive a post-study telephone 
follow-up approximately 14 days (+ 3 days) after the last dose of study treatment.  
Details about discontinuation of participants who do not show confirmation of HRV-16
shedding by nasal swab testing within 72 hours of inoculation are described in 
Section 9.1.11.
 
 
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Post-study Telephone Follow-Up
9.10.4
Participants will be contacted for a safety follow-up phone call approximately 14 days 
(+ 3 days) after the last dose of study treatment.  If the post-study telephone contact visit 
occurs less than 14 days after the last dose of study treatment, a subsequent follow-up phone 
call should be made at 14 days after the last dose of study treatment to determine if any AEs
have occurred since the post-study telephone contact visit.
No other safety or efficacy assessments are required after discharge from the clinic; however, 
additional safety follow up may be performed, at the discretion of the investigator.
WOCBP potential must continue to use an acceptable birth control (defined in Appendix 3) 
for at least 14 days after the last dose of study treatment.
10. Statistical Analysis Plan 
This section outlines the statistical analysis strategy and procedures for the study. Changes 
to analyses made after the protocol has been finalized, but prior to unblinding, will be 
documented in a supplemental Statistical Analysis Plan (sSAP) and referenced in the Clinical 
Study Report (CSR) for the study.  Post hoc exploratory analyses will be clearly identified in 
the CSR.
Statistical Analysis Plan Summary
10.1
Key elements of the Statistical Analysis Plan (SAP) are summarized below. The 
comprehensive plan is provided in Sections 10.2 to 10.12.
Study Design Overview
A Phase 2a, double-blind, randomized, placebo-
controlled, parallel-group trial to study efficacy, safety, 
and tolerability in male and female healthy participants 
with induced viral URTI.
Treatment Assignment
In Stage 1 (prior to the IA), participants will be 
randomized in a 1:1 randomization ratio to MK-7264 
45 mg BID or placebo.
In Stage 2 (post-IA), if a decision is made to include a 
lower dose of MK-7264 based on the IA results, 
participants will be randomized to MK-7264 45 mg 
BID, MK-7264 15 mg BID, or placebo in a 1:2:1 ratio, 
respectively. Otherwise, the 1:1 randomization ratio to 
MK-7264 45 mg BID or placebo will be used in 
Stage 2.
Randomization will be stratified by gender and site.
 
 
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Analysis Populations
Efficacy: The modified Full Analysis Set (mFAS) 
population, which consists of all randomized 
participants who receive at least one dose of study 
treatment and have confirmation of viral shedding 
within 72 hours of administration of HRV-16; and Per 
Protocol (PP) Population, which excludes participants 
due to major deviations from the protocol from the 
mFAS population.
Safety: All Participants as Treated (APaT) population,
which consists of all randomized participants who 
received at least one dose of study treatment.
PK: Population that includes all participants with at 
least one measurable PK sample.
Primary Endpoint
Awake coughs per hour on Day 3 of treatment.
Key Secondary Endpoints

Cough Severity VAS score measured as change from 
baseline on Day 3

CSD score measured as change from baseline on 
Day 3

LCQ-acute score measured as change from baseline 
on Day 3
Statistical Methods for 
Key Efficacy Analyses
The primary efficacy endpoint will be analyzed using a 
longitudinal data analysis model (LDA). In this model, 
the response vector consists of daily awake coughs per 
hour at each postbaseline visit. Covariates will include 
treatment, visit, the interaction of treatment by visit, 
gender, and site. The unstructured approach will be 
used to model the covariance of the repeated cough 
measurements over time within participants. 
Additional covariance structures, such as Toeplitz
covariance, may be considered if convergence issues 
are encountered with the analysis model.
Statistical Methods for 
Key Safety Analyses
The analysis of safety endpoints will follow a tiered 
approach. The tiers differ with respect to the analyses 
that will be performed. Tier 1 safety endpoints will be 
subject to inferential testing for statistical significance 
with p-values and 95% confidence intervals (CIs)
provided for between-group comparisons.  Tier 2 safety 
endpoints will be evaluated via point estimates and 
95% CIs for between-group comparisons. Tier 3 safety 
endpoints will be evaluated via point estimates only. 
 
 
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Interim Analyses
One planned efficacy IA will be performed in this 
study. Results will be reviewed by an internal data 
monitoring committee (ie, siDMC). This IA is
summarized below.

Timing: To be performed when approximately 
50 participants have completed (or discontinued 
early from) Stage 1 of the trial

Purposes:
o
Conduct a futility analysis
o
Re-estimate sample size
o
Potentially add a lower dose (15 mg BID) of 
MK-7264 if a certain magnitude of efficacy of 
MK-7264 45 mg BID is detected compared 
with placebo
o
Evaluate safety and tolerability of MK-7264
Details are described in Section 10.7.1.
Multiplicity
No multiplicity adjustment is planned as there are no 
hypotheses for this study.
Sample Size and Power 
The planned sample size is 100 participants, up to a 
maximum of 188 participants.
 
 
Responsibility for Analyses/In-house Blinding
10.2
The statistical analysis of the data obtained from this study will be the responsibility of the 
designee of the Sponsor.
The study will be conducted as a double-blind study under in-house blinding procedures.
The official, final database will not be unblinded until medical/scientific review has been 
performed, protocol violators have been identified, and data have been declared final and 
complete.
Treatment assignment will be implemented by the external vendor of the study IVRS 
according to the adaptive allocation scheme provided in Section 7.3.
Unblinding for Efficacy and Safety Interim Analyses
Treatment-level results and/or participant-level data of the IA will be provided by an internal
unblinded statistician to the siDMC.
The interim efficacy and safety analyses will be conducted by the unblinded statistician; the 
results will be reviewed and decision made by a siDMC that consists of Sponsor personnel. 
Limited additional Sponsor personnel may be unblinded to the treatment-level results of the 
IA, if required, in order to act on the recommendations of the siDMC. The details of the 
 
 
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siDMC monitoring guidelines, scope of work, the schedule of the interim safety monitoring, 
and stopping rules will be described in the Protocol-specific siDMC Charter. The extent to 
which individuals are unblinded with respect to results of IAs will be documented by the 
unblinded statistician. These individuals will not be involved in the day-to-day operations of 
the study.
The processes by which recommendations and decisions are reached and communicated are 
documented in the siDMC charter for the Sponsor.  The protocol-specific siDMC charter will 
be referenced in the CSR.  Prior to final study unblinding, individuals who have been 
unblinded at any level will not be involved in any discussions regarding modifications to the 
protocol, statistical methods, identification of protocol deviations, or data validation efforts 
after the interim analyses.
Hypotheses/Estimation
10.3
There are no hypotheses for this study.
Analysis Endpoints
10.4
Efficacy and safety endpoints that will be evaluated for within- and between-treatment 
differences are listed below, followed by the descriptions of the derivations of selected 
endpoints.
Efficacy Endpoints
10.4.1
Primary Efficacy Endpoint
Awake cough frequency (coughs per hour) on Day 3, as assessed by an objective cough-
counting device
Secondary Efficacy Endpoints

Cough Severity VAS score measured as change from baseline on Day 3

CSD score measured as change from baseline on Day 3

LCQ-acute score measured as change from baseline on Day 3
Exploratory Efficacy Endpoints
Exploratory efficacy endpoints are stated in Section 4.
Safety Endpoints
10.4.2
Safety endpoints are stated in Section 4.
Pharmacokinetic Endpoints
10.4.3
PK endpoints are stated in Section 4.
 
 
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Derivations of Efficacy Endpoints
10.4.4
The primary efficacy endpoint of this study is the awake coughs per hour on Day 3 of the 
treatment period. It is calculated as:
Awake coughs per hour = Total number of cough events during the monitoring period (24-
hour interval) the participant is awake / Total duration (in hours) for the monitoring period 
the participant is awake
Awake is time between waking up and sleep during the 24-hour monitoring period. 
Analysis Populations
10.5
Efficacy Analysis Populations
10.5.1
The modified Full Analysis Set (mFAS) population will serve as the primary population for 
the analysis of efficacy data in this study. The mFAS population consists of all randomized 
participants who receive at least one dose of study treatment and have confirmation of viral 
shedding within 72 hours of administration of HRV-16.
The Per Protocol (PP) population excludes participants due to major deviations from the 
protocol that may substantially affect the results of the primary efficacy endpoint. Potential 
deviations that may result in the exclusion of a participant from the PP population will be 
specified in the sSAP. The final determination on major protocol deviations, and thereby the 
composition of the PP population, will be made prior to the final unblinding of the database 
and will be documented in a separate memo. A supportive analysis using the PP population 
may be performed for the primary efficacy endpoint if the proportion of the participants with 
major protocol deviations is >10%.
Participants will be included in the treatment group to which they are randomized for the 
analysis of efficacy data using both the mFAS and PP populations.  Details on the approach 
to handling missing data are provided in Section 10.6.
Safety Analysis Populations
10.5.2
The All Participants as Treated (APaT) population will be used for the analysis of safety data 
in this study.  The APaT population consists of all randomized participants who received at 
least one dose of study treatment. Participants will be included in the treatment group 
corresponding to the study treatment they actually received for the analysis of safety data 
using the APaT population.
At least one laboratory or vital sign measurement obtained subsequent to at least one dose of 
study treatment is required for inclusion in the analysis of each specific parameter.  To assess 
change from baseline, a baseline measurement is also required.
Details on the approach to handling missing data for safety analyses are provided in 
Section 10.6.
 
 
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Pharmacokinetic Analysis Population
10.5.3
The evaluable PK population for PK data analysis is defined as all participants with at least 
one measurable PK sample.
Statistical Methods
10.6
Statistical testing and inference for efficacy and safety analyses are described in 
Section 10.6.1 and Section 10.6.2, respectively.
Statistical Methods for Efficacy/Immunologic Analyses
10.6.1
Primary Efficacy Analysis
The primary analysis will be conducted on the mFAS population.
The primary efficacy endpoint for the study is the awake coughs per hour on Day 3 of 
treatment. It will be analyzed using a longitudinal data analysis (LDA) model. In this 
model, the response vector consists of daily awake coughs per hour at each post-baseline 
visit; and covariates will include treatment, visit, the interaction of treatment by visit, gender, 
and site. The unstructured approach will be used to model the covariance of the repeated 
cough measurements over time within participants. Additional covariance structures, such as 
Toeplitz covariance, may be considered if convergence issues are encountered with the 
analysis model.
Point estimates and two-sided 95% confidence interval (CI) of the treatment difference in 
adjusted means will be presented.
Secondary Efficacy Analysis
The secondary efficacy endpoints will be analyzed based on the mFAS population using a 
longitudinal analysis of covariance (ANCOVA) model. In this model, the response vector 
consists of the change from baseline value at each post-baseline visit. The model will adjust 
for treatment, visit, the interaction of treatment by visit, gender, site, and baseline value as a 
covariate. Further details of the model specification, assumptions, and SAS implementation 
codes will be provided in the sSAP.  Table 6 summarizes the key analyses.
 
 
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Table 6
Analysis Strategy for Key Efficacy Endpoints
Endpoint
Statistical 
Method
Missing Data Approach
Primary Efficacy Endpoint
Awake coughs per hour on Day 3
LDA
Model-based
Secondary Efficacy Endpoints
Change from Baseline in daily 
Cough Severity VAS on Day 3
Longitudinal 
ANCOVA
Model-based
Change from Baseline in daily CSD 
on Day 3
Longitudinal 
ANCOVA
Change from Baseline in daily
LCQ-acute total score on Day 3
Longitudinal 
ANCOVA
Abbreviations:  LDA = longitudinal data analysis; ANCOVA = analysis of covariance; VAS = Visual 
Analogue Scale; CSD = Cough Severity Diary; LCQ = Leicester Cough Questionnaire; mFAS = modified 
Full Analysis Set 
Note: Efficacy analysis will be based on the mFAS.
Exploratory Efficacy Analysis
Details of the exploratory efficacy analysis methods will be provided in the sSAP.
Handling of Missing Data
No missing data will be imputed. All analyses will be conducted based on the observed data 
only.
Statistical Methods for Safety Analyses
10.6.2
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
AEs, laboratory tests, vital signs, and ECG measurements.
The analysis of safety results will follow a tiered approach (Table 7).  The tiers differ with 
respect to the analyses that will be performed. Tier 1 safety endpoints will be subject to 
inferential testing for statistical significance with p-values and 95% CIs provided for 
between-group comparisons.  Tier 2 safety endpoints will be evaluated via point estimates 
and 95% CIs for between-group comparisons. Tier 3 safety endpoints will be evaluated via 
point estimates only.
Adverse experiences (specific terms as well as system organ class terms) and predefined 
limits of change in laboratory, vital sign, and ECG parameters will be classified as belonging 
to "Tier 2" or "Tier 3", based on the number of events observed.  Membership in Tier 2 
requires that at least 4 participants in any treatment group exhibit the event; all other AEs and 
predefined limits of change will belong to Tier 3.
 
 
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The threshold of at least 4 events was chosen because the 95% CI for the between-group 
difference in percent incidence will always include zero when treatment groups of equal size 
each have less than 4 events and thus, would add little to the interpretation of potentially 
meaningful differences.  Because many 95% CIs may be provided without adjustment for 
multiplicity, the CIs should be regarded as a helpful descriptive measure to be used in 
review, not a formal method for assessing the statistical significance of the between-group 
differences in AEs and predefined limits of change.
Continuous measures such as changes from baseline in laboratory, vital sign, and ECG 
parameters will be considered Tier 3 safety parameters.  Summary statistics for Baseline, 
on-treatment, and change from Baseline values will be provided by treatment group in table 
format.
For this protocol, a composite endpoint of taste-related AEs (including dysgeusia, ageusia, 
and hypogeusia, as well as other related terms) is considered a Tier 1 event. In addition, the 
broad clinical and laboratory AE categories consisting of the percentage of participants with 
any AE, a drug-related AE, an SAE, an AE which is both drug-related and serious, any oral 
paresthesia AE, any oral hypoesthesia AE, and discontinuations due to an AE will be 
considered Tier 2 endpoints.  P-values (Tier 1 only) and 95% confidence intervals (Tier 1 and 
Tier 2) will be provided for between-treatment differences in the percentage of participants 
with events; these analyses will be performed using the Miettinen and Nurminen method 
(1985), an unconditional, asymptotic method [Miettinen, O. and Nurminen, M. 1985].
 
 
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Table 7
Analysis Strategy for Safety Parameters
Safety 
Tier
Safety Endpoint†
p-Value
95% CI for 
Treatment 
Comparison
Descriptive 
Statistics
Tier 1
Any taste-related AE
X
X
X
Tier 2
Any oral paresthesia AE
X
X
Any oral hypoesthesia AE
X
X
Any AE
X
X
Any SAE
X
X
Any drug-related AE
X
X
Any serious and drug-related AE
X
X
Discontinuation due to AE
X
X
Specific AEs, SOCs, or PDLCs‡ (incidence 
≥4 participants in one of the treatment 
groups)
X
X
X
X
Tier 3
Specific AEs, SOCs or PDLCs‡ (incidence 
<4 participants in all of the treatment 
groups)
X
Change from Baseline Results (Labs, 
ECGs, Vital Signs)
X
Abbreviations: AE = adverse event; CI = confidence interval; ECG = electrocardiogram; PDLC = pre-defined limit 
of change; SAE = serious adverse event; SOC = system organ class; X  = results will be provided
†
Adverse Experience references refer to both Clinical and Laboratory AEs.
‡
Includes only those endpoints not pre-specified as Tier 1 or not already pre-specified as Tier-2 endpoints.
Summaries of Baseline Characteristics, Demographics, and Other Analyses
10.6.3
Demographic and Baseline Characteristics
The number and percentage of participants screened, randomized, the primary reasons for 
screening failure, and the primary reason for discontinuation will be displayed.
Demographic variables (including age, gender, race, weight, height, and body mass index
(BMI), baseline characteristics, primary and secondary diagnoses, and prior and concomitant 
therapies will be summarized by treatment either by descriptive statistics or categorical 
tables. The comparability of the treatment groups for each relevant characteristic will be 
assessed by the summary tables. No statistical hypothesis tests will be performed on these 
characteristics.
 
 
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Interim Analyses
10.7
Efficacy Interim Analysis
10.7.1
One planned efficacy IA will be conducted once approximately 50 participants have 
completed (or discontinued early from) Stage 1 of the trial, and, although this trial is strictly 
exploratory/for estimation, the decision criteria will be based on the observed effect of the 
45 mg BID dose group to help guide future studies. The efficacy IA is intended to: 

Conduct a futility analysis

Re-estimate sample size

Potentially add a lower dose (15 mg BID) of MK-7264 if a certain magnitude of 
efficacy of MK-7264 45 mg BID is detected compared with placebo
The criteria adopted for the IA decision rule will be based on the posterior probability and 
clinical relevance on the primary endpoint of awake coughs per hour on Day 3. 
 
 
 
 
 
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The efficacy IA will be conducted by an internal unblinded statistician and programmer; the 
results will be reviewed and the decision will be made by siDMC. The details of the siDMC 
monitoring guidelines, scope of work, schedule of the interim safety monitoring, and 
decision rules will be described in the Protocol-specific siDMC Charter.
 
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Safety Interim Analyses
10.7.2
Safety interim analyses will be performed periodically (ie, determined either by calendar date 
or enrollment milestones, to be specified separately in the siDMC charter).  For these IAs, a 
general review of safety results will be performed based on review of AEs, laboratory safety 
parameters, and other safety endpoints.
Multiplicity
10.8
There are no hypotheses for this study. For Tier 1 safety endpoints, 95% CIs for between-
group differences will be provided with nominal p-values as a descriptive measure without 
adjustment for multiplicity. There will be no formal method for assessing statistical 
significance.
Sample Size and Power Calculations
10.9
The final sample size of the trial depends on the outcome of the efficacy IA described in 
Section 10.7.1.  If the trial design is unchanged based on the results of the efficacy IA, a total 
of 100 participants (50 per treatment group) will be randomized in a 1:1 ratio to either 
MK-7264 or placebo. Assuming a 20% attrition rate (including treatment discontinuation due 
to lack of viral shedding), this gives approximately 40 evaluable participants per treatment 
group.
An IA will be conducted once approximately 50 participants (25 per arm) have completed (or 
discontinued early from) Stage 1 of the trial. Depending on the decision from the IA, the 
total sample size of the trial will be up to a maximum of 188. Table 10 describes various 
scenarios of the sample sizes for the trial.  The details of the IA decision rules will be 
described in the Protocol-specific siDMC Charter.
 
 
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Table 10
Scenarios of Total Sample Size
Decision from the IA
Treatment Groups
Included in Final Trial 
Design
Sample Size per 
Treatment Group
Total 
Sample Size
The trial will stop for futility
MK-7264 45 mg BID
Placebo
25
50
Sample size will be increased
MK-7264 45 mg BID
Placebo
>50 to 94
>100 to 188
Continue the trial as planned
MK-7264 45 mg BID
Placebo
50
100
A lower dose of MK-7264 
will be added
MK-7264 45 mg BID
MK-7264 15 mg BID
Placebo
50
150
Abbreviations:  BID = twice daily; IA = interim analysis
Subgroup Analyses
10.10
Analysis for the primary efficacy endpoint will be provided for the following subgroups of 
baseline factors:

Gender (Male, Female)

Site

Age group (18 to 36 years, 37 to 55 years)
The same LDA model as the primary efficacy endpoint will be performed.
For each subgroup, summary statistics including mean, SD, and 95% CI will be provided for 
each treatment group.
Compliance (Medication Adherence)
10.11
Total number of doses and total number of days on study treatment will be summarized by 
treatment group. Compliance will also be summarized. Since the participants are inpatient 
participants, the compliance will only measure the compliance up to the end of study 
participation. That is, the compliance rate will not be impacted by premature discontinuation 
from the study. 
Summary statistics will be provided on percent compliance for the APaT population.
Extent of Exposure
10.12
The duration of treatment for each participant will be evaluated by calculating the number of 
days on therapy.  Exposure to study treatment will be summarized using descriptive statistics 
(ie, mean, SD, median, minimum, and maximum) for the APaT population.
 
 
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11. References
[Barclay, J., et al 
2002]
Barclay J, Patel S, Dorn G, Wotherspoon G, Moffatt S, 
Eunson L, et al. Functional downregulation of P2X3 
receptor subunit in rat sensory neurons reveals a significant 
role in chronic neuropathic and inflammatory pain. J 
Neurosci. 2002 Sep 15;22(18):8139-47.
04JQYJ
[Chung, K. F., et 
al 2006]
Chung KF, McGarvey L, Widdicombe J. American 
College of Chest Physicians' cough guidelines. Lancet. 
2006 Mar 25;367(9515):981-2.
04KQMY
[Cockayne, D. A., 
et al 2000]
Cockayne DA, Hamilton SG, Zhu QM, Dunn PM, Zhong 
Y, Novakovic S, et al. Urinary bladder hyporeflexia and 
reduced pain-related behaviour in P2X3-deficient mice. 
Nature. 2000 Oct 26;407(6807):1011-5.
04K6LW
[Curley, F. J., et 
al 1988]
Curley FJ, Irwin RS, Pratter MR, Stivers DH, Doern GV, 
Vernaglia PA, et al. Cough and the common cold. Am Rev 
Respir Dis. 1988 Aug;138(2):305-11.
04KQNY
[Fowles, H. E. 
2015]
Fowles HE, Morice AH. Hypersensitivity to adenosine 
triphosphate in chronic cough patients [abstract]. Thorax. 
2015;70(3 Suppl):A51. Abstract no. S89.
04PPWK
[Freestone, C. 
1997]
Freestone C, Eccles R. Assessment of the antitussive 
efficacy of codeine in cough associated with common cold. 
J Pharm Pharmacol. 1997 Oct;49(10):1045-9.
04KQN7
[Gwaltney, J. M. 
Jr., et al 2003]
Gwaltney JM Jr, Hendley JO, Patrie JT. Symptom severity 
patterns in experimental common colds and their 
usefulness in timing onset of illness in natural colds. Clin 
Infect Dis. 2003 Mar 15;36(6):714-23.
04KRJQ
[IB Edition 16 
2017]
MK-7264, Investigator's Brochure, Edition Number 16, 25-
Sep-2017
04MBXT
[Irwin, R. S., et al 
2006]
Irwin RS, Baumann MH, Bolser DC, Boulet LP, Braman 
SS, Brightling CE, et al. Diagnosis and management of 
cough executive summary: ACCP evidence-based clinical 
practice guidelines. Chest. 2006 Jan;129(1 Suppl):1S-23S.
04KW7B
[Kardos, P., et al 
2010]
Kardos P, Berck H, Fuchs KH, Gillissen A, Klimek L, 
Morr H, et al. Guidelines of the German Respiratory 
Society for diagnosis and treatment of adults suffering 
from acute or chronic cough. Pneumologie. 2010 
Nov;64(11):701-11.
04KQP6
[Khakh, B. S. 
2006]
Khakh BS, North RA. P2X receptors as cell-surface ATP 
sensors in health and disease. Nature. 2006 Aug 
3;442(7102):527-32.
04JRKF
 
 
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[Miettinen, O. and 
Nurminen, M. 
1985]
Miettinen O, Nurminen M. Comparative analysis of two 
rates. Stat Med 1985;4:213-26.
03R2SH
[Morice, A. H., et 
al 2004]
Morice AH, Fontana GA, Sovijarvi AR, Pistolesi M, 
Chung KF, Widdicombe J, et al. The diagnosis and 
management of chronic cough. Eur Respir J. 2004 
Sep;24(3):481-92.
04KQPD
[Morice, A. H., et 
al 2006]
Morice AH, McGarvey L, Pavord I, on behalf of the 
British Thoracic Society Cough Guideline Group. 
Recommendations for the management of cough in adults. 
Thorax 2006;61(Suppl 1):i1-i24.
03QMXM
[North, R. A. 
2004]
North RA. P2X3 receptors and peripheral pain 
mechanisms. J Physiol. 2004 Jan 15;554(Pt 2):301-8.
04JRR8
[Rao, S. S., et al 
1995]
Rao SS, Hendley JO, Hayden FG, Gwaltney JM. Symptom 
Expression in Natural and Experimental Rhinovirus Colds. 
American Journal of Rhinology. 1995 Jan-Feb; 9(1):49-52.
04RCZJ
[Souslova, V., et 
al 2000]
Souslova V, Cesare P, Ding Y, Akopian AN, Stanfa L, 
Suzuki R, et al. Warm-coding deficits and aberrant 
inflammatory pain in mice lacking P2X3 receptors. Nature. 
2000 Oct 26;407(6807):1015-7.
04K76C
[The committee 
for The Japanese 
Respiratory 
Society guidelines 
2006]
The committee for The Japanese Respiratory Society 
guidelines for management of cough. Concept and use of 
guidelines. Respirology. 2006:11(Suppl 4);S135-S136
04KW9M
 
 
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12. Appendices
Appendix 1: Study Governance Considerations
12.1
Merck Code of Conduct for Clinical Trials
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 participant 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 (eg, 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 
participant preferences, etc.  
The design (ie, participant population, duration, statistical power) must be adequate to address the specific purpose 
of the trial.  Research participants 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 participants, 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. Participant Protection
A. IRB/IEC review
All clinical trials will be reviewed and approved by an independent IRB/IEC before being initiated at each site.  
Significant changes or revisions to the protocol will be approved by the IRB/IEC prior to implementation, except that 
changes required urgently to protect participant safety and well-being may be enacted in anticipation of IRB/IEC 
approval. For each site, the IRB/IEC and Merck will approve the participant informed consent form. 
B. Safety
The guiding principle in decision-making in clinical trials is that participant welfare is of primary importance.  
Potential participants 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. Participants are never denied access to 
appropriate medical care based on participation in a Merck clinical trial. 
All participation in Merck clinical trials is voluntary.  Participants are enrolled only after providing informed consent 
for participation.  Participants 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 participant 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 participant 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 participants 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 participant referrals.  However, Merck may compensate referring physicians for time spent 
on chart review to identify potentially eligible participants.
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/IEC 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 (eg, 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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Financial Disclosure
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.
Data Protection
Participants will be assigned a unique identifier by the sponsor. Any participant records or 
datasets that are transferred to the sponsor will contain the identifier only; participant names 
or any information which would make the participant identifiable will not be transferred. 
The participant must be informed that his/her personal study-related data will be used by the 
sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant. 
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities.
Confidentiality of Data
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/IEC) or similar 
or expert committee; affiliated institution and employees, only under an appropriate 
understanding of confidentiality with such board or committee, affiliated institution and 
employees.  Data generated by this study will be considered confidential by the investigator, 
except to the extent that it is included in a publication as provided in the Publications section 
of this protocol.
Confidentiality of Participant Records
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/IEC, or regulatory authority representatives may consult and/or copy study documents in 
order to verify worksheet/case report form data.  By signing the consent form, the participant 
agrees to this process.  If study documents will be photocopied during the process of 
 
 
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verifying worksheet/case report form information, the participant 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 participant data used and 
disclosed in connection with this study in accordance with all applicable privacy laws, rules 
and regulations.
Confidentiality of IRB/IEC Information
The Sponsor is required to record the name and address of each IRB/IEC that reviews and 
approves this study.  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.
Committees Structure
To supplement the routine monitoring outlined in this protocol, a separate Standing Internal 
Data Monitoring Committee (siDMC) will monitor the interim data from this study. The 
siDMC comprises members of Sponsor Senior Management, none of whom are directly 
associated with the conduct of this study. The siDMC will monitor the study at an 
appropriate frequency (see Section 10.7 - Interim Analyses) for evidence of adverse effects 
of MK-7264; for re-estimation of the treatment effect and variability of the primary endpoint 
to ensure the study is sufficiently powered; and for investigating the possibility of adding a 
lower dose (15 mg BID) of MK-7264 if a certain magnitude of efficacy of MK-7264 45 mg 
BID is detected compared with placebo as described in the siDMC Charter]. The siDMC will 
determine whether the study should continue (or other modifications, pre-specified or 
otherwise, should be made) according to the protocol, considering the overall risk and benefit 
to study participants. The siDMC will also make recommendations to the Sponsor protocol 
team regarding steps to ensure both participant safety and the continued ethical integrity of 
the study.
Specific details regarding responsibilities of the siDMC will be described in a separate 
charter that is reviewed and approved by the siDMC.
All personnel involved in the adjudication process will remain blinded to study treatment 
allocation throughout the study.
Publication Policy
The results of this study may be published or presented at scientific meetings. The sponsor 
will comply with the requirements for publication of study results. In accordance with 
standard editorial and ethical practice, the sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data. In this case, a 
coordinating investigator will be designated by mutual agreement.
If publication activity is not directed by the sponsor, the investigator agrees to submit all 
manuscripts or abstracts to the sponsor before submission.  This allows the sponsor to protect 
proprietary information and to provide comments.  
 
 
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Authorship will be determined by mutual agreement and in line with International Committee 
of Medical Journal Editors authorship requirements.
Compliance with Study Registration and Results Posting Requirements
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 study is solely responsible for determining whether the study and its results are 
participant to the requirements for submission to http://www.clinicaltrials.gov, 
www.clinicaltrialsregister.eu or other local registries.  MSD, as Sponsor of this study, will 
review this protocol and submit the information necessary to fulfill these requirements. MSD
entries are not limited to FDAAA or the EMA clinical trial directive mandated trials.  
Information posted will allow participants to identify potentially appropriate studies for their 
disease conditions and pursue participation by calling a central contact number for further 
information on appropriate study locations and site contact information.  
By signing this protocol, the investigator acknowledges that the statutory 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 study or its results to those 
registries.
Compliance with Law, Audit and Debarment
By signing this protocol, the investigator agrees to conduct the study in an efficient and 
diligent manner and in conformance with this protocol; generally accepted standards of Good 
Clinical Practice (eg, International Conference on Harmonization of Technical Requirements 
for Registration of Pharmaceuticals for Human Use Good Clinical Practice: Consolidated 
Guideline and other generally accepted standards of good clinical practice); and all 
applicable federal, state and local laws, rules and regulations relating to the conduct of the 
clinical study.
The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by MSD, is provided in this appendix 
under the Merck Code of Conduct for Clinical Trials.
The investigator agrees not to seek reimbursement from participants, their insurance 
providers or from government programs for procedures included as part of the study
reimbursed to the investigator by the Sponsor.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this study.
The Investigator agrees to provide the Sponsor with relevant information from inspection 
observations/findings to allow the Sponsor to assist in responding to any citations resulting 
from regulatory authority inspection, and will provide the Sponsor with a copy of the 
proposed response for consultation before submission to the regulatory authority. 
Persons debarred from conducting or working on clinical studies by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s studies. The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
 
 
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conducting the study is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the sponsor or designee electronically (eg, laboratory data). The investigator or 
qualified designee is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF. 
Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
Study documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the study 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 or regulatory authority as a result of an audit or inspection to cure 
deficiencies in the study documentation and worksheets/case report forms.
The sponsor or designee is responsible for the data management of this study including 
quality checking of the data. 
Study monitors will perform ongoing source data review and verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that the 
study is being conducted in accordance with the currently approved protocol and any other 
study agreements, ICH GCP, and all applicable regulatory requirements. 
Records and documents, including signed ICF, pertaining to the conduct of this study must 
be retained by the investigator for 15 years after study completion unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during 
the retention period without the written approval of the sponsor. No records may be 
transferred to another location or party without written notification to the sponsor. 
 
 
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Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site.
Data reported on the CRF or entered in the eCRF that are transcribed from source documents 
must be consistent with the source documents or the discrepancies must be explained. The 
investigator may need to request previous medical records or transfer records, depending on 
the study. Also, current medical records must be available.
Study and Site Closure
The sponsor or its designee may stop the study or study site participation in the study for 
medical, safety, regulatory, administrative, or other reasons consistent with applicable laws, 
regulations, and GCP. 
In the event the Sponsor prematurely terminates a particular study site, the Sponsor will 
promptly notify that study site’s IRB/IEC.
 
 
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Appendix 2: Collection and Management of Specimens for Future Biomedical 
12.2
Research
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 study as outlined in Section 9.9 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.
Participants for Enrollment
All participants enrolled in the clinical study will be considered for enrollment in the 
Future Biomedical Research sub-study.
b. Informed Consent
Informed consent for specimens (ie, DNA, RNA, protein, etc.) will be obtained 
during screening for protocol enrollment from all participants or legal guardians, at a 
study visit by the investigator or his or her designate.  Informed consent for Future 
Biomedical Research should be presented to the participants on the visit designated in 
the SoA.  If delayed, present consent at next possible Participant Visit.  Consent 
 
 
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forms signed by the participant will be kept at the clinical study site under secure 
storage for regulatory reasons.  
A template of each study 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 participant 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 SoA. In general, if additional blood specimens are being collected for 
Future Biomedical Research, these will usually be obtained at a time when the 
participant is having blood drawn for other study purposes.
4. Confidential Participant 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 participant' clinical information with future test results. In 
fact little or no research can be conducted without connecting the clinical study data to 
the specimen. The clinical data allow specific analyses to be conducted. Knowing 
participant 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 study 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 participant 
identifiers and this unique code will be held at the study 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 (eg, 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-study. Future 
Biomedical Research specimens remaining with the third party after specific analysis is 
performed will be reported to the Sponsor.
6. Withdrawal From Future Biomedical Research 
Participants may withdraw their consent for Future Biomedical Research and ask that 
their biospecimens not be used for Future Biomedical Research.  Participants may 
 
 
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withdraw consent at any time by contacting the principal investigator for the main study. 
If medical records for the main study are still available, the investigator will contact the 
Sponsor using the designated mailbox (clinical.specimen.management@merck.com). 
Subsequently, the participant'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 participant 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 study data and results. No new analyses would be generated 
after the request is received.
In the event that the medical records for the main study are no longer available (eg, if the 
investigator is no longer required by regulatory authorities to retain the main study
records) or the specimens have been completely anonymized, there will no longer be a 
link between the participant’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 study 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 
study, the study 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 study 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.
9. Reporting of Future Biomedical Research Data to Participants
No information obtained from exploratory laboratory studies will be reported to the 
participant, family, or physicians. Principle reasons not to inform or return results to the 
participant include: Lack of relevance to participant health, limitations of predictive 
capability, and concerns regarding misinterpretation.
 
 
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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 participants.  Participants 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 participants diagnosed and treated on Sponsor 
clinical studies for Future Biomedical Research.
11. Risks Versus Benefits of Future Biomedical Research 
For future biomedical research, risks to the participant have been minimized and are 
described in the Future Biomedical Research informed consent.
The Sponsor has developed strict security, policies and procedures to address participant 
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: https://www.cancer.gov/publications/dictionaries/cancer-
terms?cdrid=45618
2. International Conference on Harmonization: DEFINITIONS FOR GENOMIC 
BIOMARKERS, PHARMACOGENOMICS, PHARMACOGENETICS, GENOMIC 
DATA AND SAMPLE CODING CATEGORIES - E15; Available from: 
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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Appendix 3: Contraceptive Guidance and Pregnancy Testing
12.3
Definitions 
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile (see below) 
Women in the following categories are not considered WOCBP:
●
Premenarchal
●
Premenopausal female with 1 of the following:
○
Documented hysterectomy
○
Documented bilateral salpingectomy
○
Documented bilateral oophorectomy
Note:  Documentation can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview.
●
Postmenopausal female
○
Postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. 
▪
A high follicle stimulating hormone (FSH) level in the postmenopausal range may 
be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormonal replacement therapy (HRT). However, in the absence 
of 12 months of amenorrhea, confirmation with two FSH measurements in the 
postmenopausal range is required.
○
Females on HRT and whose menopausal status is in doubt will be required to use one 
of the non-hormonal highly effective contraception methods if they wish to continue 
their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment.
Contraception Requirements
Female Participants
Female participants of childbearing potential are eligible to participate if they agree to use 
one of the contraception methods described in consistently and correctly during the protocol-
defined timeframe in Section 6.1 and Section 9.10.4.
 
 
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Table 11
Contraceptive Methods
Acceptable Contraceptive Methods
Highly Effective Contraceptive Methods That Are User Dependenta 
Failure rate of <1% per year when used consistently and correctly.
●
Combined (estrogen- and progestogen-containing) hormonal contraceptionb
○
Oral 
○
Intravaginal 
○
Transdermal 
○
Injectable
●
Progestogen-only hormonal contraceptionb
○
Oral 
○
Injectable 
Highly Effective Methods That Have Low User Dependency 
Failure rate of <1% per year when used consistently and correctly.
●
Progestogen-only contraceptive implantb, c 
●
Intrauterine hormone-releasing systemb
●
Intrauterine device
●
Bilateral tubal occlusion
●
Vasectomized partner 
A vasectomized partner is a highly effective contraception method provided that the partner 
is the sole male sexual partner of the WOCBP and the absence of sperm has been 
confirmed. If not, an additional highly effective method of contraception should be used. 
●
Sexual abstinence 
Sexual abstinence is considered a highly effective method only if defined as refraining 
from heterosexual intercourse during the entire period of risk associated with the study 
treatment. The reliability of sexual abstinence needs to be evaluated in relation to the 
duration of the study and the preferred and usual lifestyle of the participant.) 
Notes: 
Use should be consistent with local regulations regarding the use of contraceptive methods for 
participants of clinical studies.
a  Typical use failure rates are higher than perfect-use failure rates (ie, when used consistently 
and correctly). 
b If hormonal contraception efficacy is potentially decreased due to interaction with study 
treatment, condoms must be used in addition to the hormonal contraception during the 
treatment period and for at least 14 days after the last dose of study treatment.
c If locally required, in accordance with Clinical Trial Facilitation Group guidelines, acceptable 
hormonal contraceptives are limited to those which inhibit ovulation. 
 
 
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Pregnancy Testing
WOCBP should only be included after a negative highly sensitive urine test. If the urine 
pregnancy test is positive, a serum pregnancy test should be performed and if the test result is 
negative, the participant may be enrolled in the trial.
Pregnancy testing will be performed as specified in the SoA (Section 2) and whenever an 
expected menstrual cycle is missed or when pregnancy is otherwise suspected.
 
 
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Appendix 4: Adverse Events: Definitions and Procedures for Recording, 
12.4
Evaluating, Follow-up, and Reporting
Definition of AE
AE Definition
●
An AE is any untoward medical occurrence in a patient or clinical study participant, 
temporally associated with the use of study treatment, whether or not considered 
related to the study treatment.
●
NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study treatment.
●
NOTE: for purposes of AE definition, study treatment (also referred to as Sponsor’s 
product) includes any pharmaceutical product, biological product, vaccine, device, 
diagnostic agent or protocol specified procedure whether investigational (including 
placebo or active comparator product) or marketed, manufactured by, licensed by, 
provided by or distributed by the sponsor for human use in this study.
Events Meeting the AE Definition 
●
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, or are considered clinically significant in 
the medical and scientific judgment of the investigator.
●
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.
●
New conditions detected or diagnosed after study treatment administration even 
though it may have been present before the start of the study.
●
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.
●
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication. 
●
For all reports of overdose (whether accidental or intentional) with an associated 
adverse event, the AE term should reflect the clinical symptoms or abnormal test 
result.  An overdose of study treatment without any associated clinical symptoms or 
abnormal laboratory results is reported using the terminology “accidental or 
intentional overdose without adverse effect.”
●
Any new cancer or progression of existing cancer.
 
 
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Events NOT Meeting the AE Definition 
●
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that 
leads to the procedure is the AE.
●
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).
●
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen.
●
Surgery planned prior to informed consent to treat a pre-existing condition that has 
not worsened.
●
Refer to Section 9.3.5 for protocol specific exceptions
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met 
A SAE is defined as any untoward medical occurrence that, at any dose:
a.
Results in death
b. Is life-threatening
●
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, 
which hypothetically might have caused death, if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing 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 an MSD product and is documented in the patient’s
medical history.
d. Results in persistent or significant disability/incapacity
●
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.
●
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and 
accidental trauma (eg, sprained ankle) which may interfere with or prevent everyday life 
functions but do not constitute a substantial disruption.
 
 
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e.
Is a congenital anomaly/birth defect
●
in offspring of participant taking the product regardless of time to diagnosis
f.
Other important medical events:
●
Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may not 
be immediately life-threatening or result in death or hospitalization but may jeopardize 
the participant or may require medical or surgical intervention to prevent one of the other 
outcomes listed in the above definition. These events should usually be considered 
serious.
Examples of such events include invasive or malignant cancers, intensive treatment 
in an emergency room or at home for allergic bronchospasm, blood dyscrasias or
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.
Additional Events Reported
Additional Events which require reporting 
●
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.
●
Is a cancer;
●
Is associated with an overdose.
Recording AE and SAE
AE and SAE Recording
●
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) 
related to the event.
●
The investigator will record all relevant AE/SAE information on the Adverse Event 
case report forms/worksheets at each examination.
●
It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to the Sponsor in lieu of completion of the AE CRF page.
●
There may be instances when copies of medical records for certain cases are 
requested by the Sponsor. In this case, all participant identifiers, with the exception of 
the participant number, will be blinded on the copies of the medical records before 
submission to the Sponsor.
●
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.
 
 
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Assessment of Intensity
●
An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes as
described in the definition of an SAE, NOT when it is rated as severe.
●
The investigator will make an assessment of intensity for each AE and SAE (and 
other reportable safety event) reported during the study and assign it to 1 of the 
following categories: 
●
Mild: An event that is easily tolerated by the participant, causing minimal 
discomfort and not interfering with everyday activities (for pediatric studies, 
awareness of symptoms, but easily tolerated).
●
Moderate: An event that causes sufficiently discomfort and interferes with normal 
everyday activities (for pediatric studies, definitely acting like something is 
wrong).
●
Severe: An event that prevents normal everyday activities. An AE that is assessed 
as severe should not be confused with an SAE. Severe is a category utilized for 
rating the intensity of an event; and both AE and SAE can be assessed as severe 
(for pediatric studies, extremely distressed or unable to do usual activities).
Assessment of Causality
●
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 product 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 participant 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 studies with investigational 
medicinal product)?
 
 
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●
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 study is a single-dose drug study); or (4) 
Sponsor's product(s) is/are only used one time).
●
Rechallenge:  Was the participant re-exposed to the Sponsor's product in this 
study?
●
If yes, did the AE recur or worsen?
●
If yes, this is a positive rechallenge. 
●
If no, this is a negative rechallenge.
(Note:  This criterion is not applicable if:  (1) the initial AE resulted in death 
or permanent disability, or (2) the study is a single-dose drug study); 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 PARTICIPANT THEN 
THE RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE SPONSOR 
CLINICAL DIRECTOR, AND IF REQUIRED, THE INSTITUTIONAL REVIEW 
BOARD/INDEPENDENT ETHICS COMMITTEE.
●
Consistency with Study 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.
●
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 
 
 
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another cause. 
●
No, there is not a reasonable possibility of Sponsor's product relationship:
Participant 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 participant with overdose without an associated AE.)
●
For each AE/SAE, the investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality.
●
There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to the Sponsor. However, it is very 
important that the investigator always make an assessment of causality for every event 
before the initial transmission of the SAE data to the Sponsor.
●
The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality assessment.
●
The causality assessment is one of the criteria used when determining regulatory 
reporting requirements
Follow-up of AE and SAE
●
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Sponsor 
to elucidate the nature and/or causality of the AE or SAE as fully as possible. This 
may include additional laboratory tests or investigations, histopathological 
examinations, or consultation with other health care professionals.
●
New or updated information will be recorded in the CRF.
●
The investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information.
Reporting of AE, SAE, and Other Reportable Safety Events to the Sponsor 
AE, SAE, and Other Reportable Safety Event Reporting to Sponsor via Electronic 
Data Collection Tool
●
The primary mechanism for reporting to the Sponsor will be the electronic data 
collection (EDC) tool.  
●
Electronic reporting procedures can be found in the EDC data entry guidelines (or 
equivalent).
●
If the electronic system is unavailable for more than 24 hours, then the site will 
use the paper AE Reporting form.  
●
Reference section 9.3.1 – Time Period and Frequency for Collecting AE and 
SAE and Other Reportable Safety Event Information for reporting time 
requirements 
 
 
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●
The site will enter the SAE data into the electronic system as soon as it becomes 
available.
●
After the study is completed at a given site, the electronic data collection tool will be 
taken off-line to prevent the entry of new data or changes to existing data.
●
If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken off-line, then the site can report this information on a paper SAE form or by 
telephone (see next section).
●
Contacts for SAE reporting can be found in the Investigator Trial File Binder (or 
equivalent).
SAE Reporting to the Sponsor via Paper CRF
●
If the electronic data collection tool is not operational, facsimile transmission or 
secure e-mail of the SAE paper CRF is the preferred method to transmit this 
information to the Sponsor.
●
In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service.
●
Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.
●
Contacts and instructions for SAE reporting and paper reporting procedures can be 
found in the Investigator Trial File Binder (or equivalent).
 
 
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Appendix 5: Clinical Laboratory Tests 
12.5

The tests detailed in Table 12 will be performed by the central laboratory.

Local laboratory results are only required in the event that the central laboratory 
results are not available in time for either study treatment administration and/or 
response evaluation. If a local sample is required, it is important that the sample for 
central analysis is obtained at the same time. Additionally, if the local laboratory 
results are used to make either a study treatment decision or response evaluation, the 
results must be entered into the eCRF.

Protocol-specific requirements for inclusion or exclusion of participants are detailed 
in Section 6 of the protocol.

Additional tests may be performed at any time during the study as determined 
necessary by the investigator or required by local regulations.
Table 12
Protocol-Required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet count 
White blood cell (WBC) count with 
differential:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
Red blood cell (RBC) count
Hemoglobin
Hematocrit
Chemistry
Albumin
estimated glomerular filtration rate 
(eGFR) calculation
Alkaline phosphatase
Glucose (nonfasting)
Alanine aminotransferase (ALT) 
Phosphorous
Aspartate aminotransferase (AST)
Potassium
Bicarbonate
Sodium
Blood urea nitrogen (BUN)
Total protein
Calcium
Total bilirubin (and direct bilirubin, if 
total bilirubin is elevated above the upper 
limit of normal)
Chloride
Creatinine
Routine 
Urinalysis
Specific gravity, pH, glucose, protein, and blood; microscopic examination will 
be performed if abnormal results are observed
Other 
Screening 
Tests
Follicle-stimulating hormone and estradiol (as needed in women of non-
childbearing potential only)
Serum β-human chorionic gonadotropin (β-hCG) pregnancy test (as needed for 
women of childbearing potential) if urine pregnancy test is positive. Refer to SoA 
(Section 2)
Notes: eGFR will be calculated with serum creatinine measurement (using the Chronic Kidney Disease Epidemiology 
Collaboration formula [http://mdrd.com/])
Investigators must document their review of each laboratory safety report.
 
 
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Appendix 6: Abbreviations and Trademarks
12.6
Abbreviation
Term
β-hCG
β-human chorionic gonadotropin
AE
adverse event
ALT
alanine aminotransferase
AMA
American Medical Association
ANCOVA
analysis of covariance
APaT
all participants as treated
AST
aspartate aminotransferase
ATP
adenosine triphosphate
ATS
American Thoracic Society
AUC
area under the concentration time-curve
BID
twice daily
BMI
body mass index
Bpm
beats per minute
BUN
blood urea nitrogen
C2
concentration of cough challenge agent [ATP] inducing at least 2 coughs
C5
concentration of cough challenge agent [ATP] inducing at least 5 coughs
CBC
complete blood count
CF
compact flash
CFR
Code of Federal Regulations
CI
confidence interval
CKD EPI
Chronic Kidney Disease Epidemiology Collaboration
Cmax
mean maximum observed concentration
Cmin
mean minimum observed concentration
CONSORT
Consolidated Standards of Reporting Trials
CRF
case report form
CSD
Cough Severity Diary
CSR
clinical study report
CTFG
Clinical Trial Facility Group
DBP
diastolic blood pressure
DIHS
drug-induced hypersensitivity syndrome 
 
 
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Abbreviation
Term
DILI
drug-induced liver injury
DNA
deoxyribonucleic acid
DRESS
drug reaction with eosinophilia and systemic symptoms
ECG
electrocardiogram
ECI
event of clinical interest
EDC
electronic data collection
ERS
European Respiratory Society
eCRF
electronic case report form
eGFR
estimated glomerular filtration rate
EMA
European Medicines Agency
FDA
United States Food and Drug Administration
FDAAA
Food and Drug Administration Amendments Act
FSH
follicle stimulating hormone
GERD
gastroesophageal reflux disease
GCP
Good Clinical Practice(s)
HIV
human immunodeficiency virus
HRQoL
health-related quality-of-life
HRT
hormonal replacement therapy
HRV-16
human rhinovirus type 16
IA
interim analysis
IB
Investigator’s brochure
ICF
informed consent form
ICH
International Conference on Harmonisation
IEC
independent ethics committee
IRB
institutional review board
IRT
interactive response technology
IUD
intrauterine device
IUS
intrauterine hormone-releasing system
IVRS
interactive voice response system
IWRS
interactive web response system
LCQ-acute
Leicester Cough Questionnaire-acute
LDA
longitudinal data analysis
 
 
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Abbreviation
Term
LLN
lower limit of normal
mFAS
modified full analysis set
NA
not applicable
NSAE
non-serious adverse event
OTC
over-the-counter
PCR
polymerase chain reaction
PDLC
Pre-defined Limit of Change
PK
pharmacokinetic
PP
per protocol
PROs
patient-reported outcomes
QP2
Quantitative Pharmacology and Pharmacometrics
QTc
corrected QT
RBC
red blood cell (count)
RR
relative reduction
SAE
serious adverse event
SAP
statistical analysis plan
SBP
systolic blood pressure
SD
standard deviation
siDMC
Standing Internal Data Monitoring Committee
siRNA
small interfering ribonucleic acid
SLAB
supplemental laboratory tests
SoA
schedule of activities
SOC
System Organ Class
sSAP
supplemental statistical analysis plan
SUSAR
suspected unexpected serious adverse reactions
Tmax
time to reach Cmax
ULN
upper limit of normal
URTI
upper respiratory tract infection
US
United States
VAS
visual analog scale
WBC
white blood cell (count)
WOCBP
women of childbearing potential
 
 
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Abbreviation
Term
WURSS-24
Wisconsin Upper Respiratory Syndrome Symptom Survey
 
 
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