Clinical trial NCT03482713
Conditions: Chronic Cough
Sponsor: Merck Sharp & Dohme LLC
Start date: 2018-03-16; Completion date: 2018-06-07
Enrollment: 23 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This estimation study (no hypotheses) will evaluate the safety, tolerability, and efficacy of gefapixant (MK-7264) in Japanese adult participants with unexplained or refractory chronic cough.

Detailed description:

Arms: arm 1: Participants will receive a gefapixant 45 mg film-coated tablet BID for 28 days. arm 2: Participants will receive a film-coated placebo tablet matching gefapixant BID for 28 days.
Interventions: intervention 1: Gefapixant 45 mg intervention 2: Placebo
Intervention descriptions: intervention 1: Gefapixant 45 mg (film-coated tablet) to be administered orally BID intervention 2: Placebo (film-coated tablet) matching gefapixant to be administered orally BID

Protocol documents:
Prot_SAP_000.pdf: 
Official Protocol Title: 
NCT number: 
NCT03482713 
Document Date: 
21-Dec-2017
Phase II study, Randomized, Double-Blind, Placebo-Controlled 4-
Week Clinical Study, to Evaluate the Efficacy and Safety of 
MK-7264 in Adult Japanese Participants with Unexplained or 
Refractory Chronic Cough


Product:  MK-7264
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Title Page
THIS PROTOCOL AMENDMENT AND ALL OF THE INFORMATION RELATING 
TO IT ARE CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK 
SHARP & DOHME CORP., A SUBSIDIARY OF MERCK & CO., INC., 
WHITEHOUSE STATION, NJ, U.S.A.
Protocol Title: Phase II study, Randomized, Double-Blind, Placebo-Controlled 4-Week 
Clinical Study, to Evaluate the Efficacy and Safety of MK-7264 in Adult Japanese 
Participants with Unexplained or Refractory Chronic Cough
Protocol Number: 033-01
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):
  
EudraCT NUMBER:
Approval Date:  21-Dec-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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PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment 01
Overall Rationale for the Amendment:
Correction to the schedule of assessment in terms of CSD and Pharmacokinetics sample. Other clarifications required throughout,
including the treatment compliance and study procedures.
Summary of Changes Table:
Section # and 
Name
Description of Change
Brief Rationale
2 – Schedule of
Assessments
9.2.2.2 – Cough 
Severity Diary
Added that CSD should be 
completed daily from Visit 1
CSD should be completed daily from Visit 1 in order to collect baseline data 
(mean weekly total score prior to first dose). 
2 – Schedule of
Assessments
Removed “d” from 
Pharmacokinetic Sample 
(blood) at Disc visit
Cough monitor will not be attached at Disc visit.
7.6 – Treatment
Compliance
Added additional details
regarding how compliance with 
blinded study treatment will be 
assessed and what steps are to 
be taken when there are 
compliance concerns.
To better clarify how compliance with blinded study treatment will be
assessed and how concerns with compliance will be addressed.
9.5.5 - Spirometry
Added that spirometry is not
required if done within 1 year 
of Screening, and during a 
clinically stable period.
To better clarify the requirements for spirometry assessment during
Screening.
 
 
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Section # and 
Name
Description of Change
Brief Rationale
9.5.7 – Renal and
Urological Safety
Procedures
Clarified procedure for
evaluation of crystals and 
removed figure.
Based on the evaluation of crystals, decision on continued participation will 
be made on case-by-case basis.
Throughout
Minor editorial and document
formatting revisions.
Minor, therefore have not been summarized.
 
 
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Table of Contents
PROTOCOL AMENDMENT SUMMARY OF CHANGES ...............................................3
1.
Synopsis.......................................................................................................................13
2.
Schedule of Activities (SoA) ......................................................................................15
3.
Introduction................................................................................................................18
Study Rationale .......................................................................................................19
3.1
Background..............................................................................................................19
3.2
Pharmaceutical and Therapeutic Background .....................................................19
3.2.1
Clinical Studies in Japan......................................................................................20
3.2.2
Benefit/Risk Assessment.........................................................................................20
3.3
4.
Objectives/Hypotheses and Endpoints.....................................................................21
5.
Study Design...............................................................................................................22
Overall Design .........................................................................................................22
5.1
Study Diagram .....................................................................................................22
5.1.1
Number of Participants ..........................................................................................23
5.2
Beginning and End of Study Definition ................................................................23
5.3
Clinical Criteria for Early Study Termination .....................................................23
5.3.1
Scientific Rationale for Study Design....................................................................23
5.4
Rationale for Endpoints .......................................................................................23
5.4.1
Safety Endpoints ...........................................................................................23
5.4.1.1
Efficacy Endpoints........................................................................................23
5.4.1.2
Pharmacokinetic Endpoints ..........................................................................25
5.4.1.3
Pharmacodynamic Endpoints........................................................................25
5.4.1.4
Planned Exploratory Biomarker Research....................................................25
5.4.1.5
Planned Genetic Analysis ......................................................................25
5.4.1.5.1
Future Biomedical Research.........................................................................26
5.4.1.6
Rationale for the Use of Placebo .........................................................................26
5.4.2
Justification for Dose ..............................................................................................26
5.5
Starting Dose for This Study................................................................................26
5.5.1
 
 
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Maximum Dose/Exposure for This Study ...........................................................27
5.5.2
Rationale for Dose Interval and Study Design.....................................................27
5.5.3
6.
Study Population........................................................................................................27
Inclusion Criteria ....................................................................................................28
6.1
Exclusion Criteria ...................................................................................................29
6.2
Lifestyle Restrictions...............................................................................................30
6.3
Meals and Dietary Restrictions............................................................................30
6.3.1
Caffeine Alcohol, and Tobacco Restrictions .......................................................30
6.3.2
Activity ................................................................................................................31
6.3.3
Screen Failures ........................................................................................................31
6.4
Participant Replacement Strategy.........................................................................31
6.5
7.
Treatments..................................................................................................................31
Treatments Administered.......................................................................................32
7.1
Dose Modification ...................................................................................................32
7.2
Method of Treatment Assignment.........................................................................32
7.3
Stratification.........................................................................................................32
7.3.1
Blinding....................................................................................................................32
7.4
Preparation/Handling/Storage/Accountability ....................................................33
7.5
Dose Preparation..................................................................................................33
7.5.1
Handling, Storage and Accountability.................................................................33
7.5.2
Treatment Compliance...........................................................................................33
7.6
Concomitant Therapy.............................................................................................34
7.7
Rescue Medications and Supportive Care ...........................................................35
7.7.1
Treatment After the End of the Study ..................................................................35
7.8
Clinical Supplies Disclosure ...................................................................................35
7.9
8.
Discontinuation/Withdrawal Criteria......................................................................35
Discontinuation of Study Treatment .....................................................................35
8.1
Withdrawal from the Study ...................................................................................36
8.2
Lost to Follow Up ....................................................................................................37
8.3
9.
Study Assessments and Procedures..........................................................................37
Administrative and General Procedures ..............................................................38
9.1
 
 
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Informed Consent.................................................................................................38
9.1.1
General Informed Consent............................................................................38
9.1.1.1
Consent and Collection of Specimens for Future Biomedical 
9.1.1.2
Research........................................................................................................38
Inclusion/Exclusion Criteria ................................................................................38
9.1.2
Participant Identification Card.............................................................................39
9.1.3
Medical History ...................................................................................................39
9.1.4
Prior and Concomitant Medications Review .......................................................39
9.1.5
Prior Medications..........................................................................................39
9.1.5.1
Concomitant Medications .............................................................................39
9.1.5.2
Assignment of Screening Number .......................................................................39
9.1.6
Assignment of Treatment/Randomization Number .............................................39
9.1.7
Treatment Administration....................................................................................40
9.1.8
Timing of Dose Administration....................................................................40
9.1.8.1
Discontinuation and Withdrawal .........................................................................40
9.1.9
Withdrawal From Future Biomedical Research ...........................................40
9.1.9.1
Participant Blinding/Unblinding..........................................................................41
9.1.10
Calibration of Equipment.....................................................................................41
9.1.11
Efficacy Assessments...............................................................................................42
9.2
24-Hour Coughs Per Hour ...................................................................................42
9.2.1
Patient-reported Outcomes...................................................................................43
9.2.2
Leicester Cough Questionnaire.....................................................................43
9.2.2.1
Cough Severity Diary ...................................................................................43
9.2.2.2
Cough Severity Visual Analog Scale............................................................43
9.2.2.3
Adverse Events (AE), Serious Adverse Events (SAE) and Other 
9.3
Reportable Safety Events .......................................................................................44
Time Period and Frequency for Collecting AE, SAE and Other 
9.3.1
Reportable Safety Event Information ..................................................................44
Method of Detecting AE, SAE and Other Reportable Safety Events ..................46
9.3.2
Follow-up of AE, SAE and Other Reportable Safety Event Information............46
9.3.3
Regulatory Reporting Requirements for SAE .....................................................46
9.3.4
Disease-Related Events and/or Disease-Related Outcomes Not 
9.3.5
Qualifying as AEs or SAEs..................................................................................47
 
 
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Pregnancy and Exposure During Breastfeeding ..................................................47
9.3.6
Events of Clinical Interest (ECI)..........................................................................47
9.3.7
Treatment of Overdose...........................................................................................48
9.4
Safety........................................................................................................................48
9.5
Chest Radiography/Computed Tomography Thorax Scan ..................................48
9.5.1
Physical Examinations .........................................................................................48
9.5.2
Vital Signs and Weight and Height Measurements .............................................49
9.5.3
Electrocardiograms ..............................................................................................49
9.5.4
Spirometry............................................................................................................49
9.5.5
Clinical Safety Laboratory Assessments..............................................................49
9.5.6
Renal and Urological Safety Procedures .............................................................50
9.5.7
Pharmacokinetics....................................................................................................50
9.6
Blood Collection for Plasma MK-7264 ...............................................................50
9.6.1
Pharmacodynamics.................................................................................................50
9.7
Biomarkers ..............................................................................................................50
9.8
Planned Genetic Analysis Sample Collection......................................................51
9.8.1
Future Biomedical Research Sample Collection ..................................................51
9.9
Visit Requirements..................................................................................................51
9.10
Screening..............................................................................................................51
9.10.1
Baseline................................................................................................................51
9.10.2
Treatment Period..................................................................................................51
9.10.3
Discontinued Participants Continuing to be Monitored in the Study ..................52
9.10.4
Post-Study............................................................................................................52
9.10.5
10.
Statistical Analysis Plan ............................................................................................52
Statistical Analysis Plan Summary........................................................................53
10.1
Responsibility for Analyses/In-House Blinding....................................................54
10.2
Hypotheses/Estimation ...........................................................................................54
10.3
Analysis Endpoints..................................................................................................54
10.4
Efficacy Endpoints...............................................................................................54
10.4.1
Safety Endpoints ..................................................................................................55
10.4.2
Derivations of Efficacy Endpoints.......................................................................55
10.4.3
Analysis Populations...............................................................................................56
10.5
 
 
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Efficacy Analysis Population...............................................................................56
10.5.1
Safety Analysis Population ..................................................................................56
10.5.2
Pharmacokinetic Analysis Population .................................................................57
10.5.3
Statistical Methods..................................................................................................57
10.6
Statistical Methods for Efficacy Analyses ...........................................................57
10.6.1
Statistical Methods for Safety Analyses ..............................................................58
10.6.2
Summaries of Baseline Characteristics, Demographics, and Other 
10.6.3
Analyses...............................................................................................................59
Interim Analyses .....................................................................................................59
10.7
Multiplicity ..............................................................................................................59
10.8
Sample Size and Power Calculations ....................................................................59
10.9
Subgroup Analyses..................................................................................................60
10.10
Compliance (Medication Adherence)....................................................................60
10.11
Extent of Exposure..................................................................................................61
10.12
11.
References...................................................................................................................61
12.
Appendices..................................................................................................................63
Appendix 1: Study Governance Considerations ..................................................63
12.1
Merck Code of Conduct for Clinical Trials .....................................................................63
Financial Disclosure.........................................................................................................65
Data Protection.................................................................................................................65
Confidentiality of Data ....................................................................................................65
Confidentiality of Participant Records.............................................................................66
Confidentiality of IRB/IEC Information..........................................................................66
Publication Policy ............................................................................................................66
Compliance with Study Registration and Results Posting Requirements .......................66
Compliance with Law, Audit and Debarment .................................................................67
Data Quality Assurance ...................................................................................................67
Source Documents ...........................................................................................................68
Study and Site Closure.....................................................................................................68
Appendix 2: Collection and Management of Specimens for Future 
12.2
Biomedical Research...............................................................................................69
Appendix 3: Contraceptive Guidance and Pregnancy Testing...........................73
12.3
 
 
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Definitions........................................................................................................................73
Contraception Requirements............................................................................................73
Pregnancy Testing............................................................................................................74
Appendix 4: Adverse Events: Definitions and Procedures for 
12.4
Recording, Evaluating, Follow-up, and Reporting..............................................75
Definition of AE ..............................................................................................................75
Definition of SAE ............................................................................................................76
Additional Events Reported.............................................................................................77
Recording AE and SAE ...................................................................................................77
Reporting of AE, SAE, and Other Reportable Safety Events to the Sponsor ..................80
Appendix 5: Clinical Laboratory Tests.................................................................82
12.5
Appendix 6: Abbreviations and Trademarks.......................................................84
12.6
 
 
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LIST OF TABLES
    
Table 1
Study Treatment(s) ...............................................................................................32
Table 2
Example of Concomitant Treatments Permitted in the Study ..............................35
Table 3
Reporting Time Periods and Timeframes for Adverse Events and Other 
Reportable Safety Events......................................................................................45
Table 4
Analysis Strategy for Secondary Efficacy Endpoints...........................................58
Table 5
Analysis Strategy for Safety Parameters ..............................................................59
Table 6
Half-width of the 95% CI for Different Common Standard Deviations 
(SDs).....................................................................................................................60
Table 7
Contraceptive Methods.........................................................................................74
Table 8
Protocol-Required Safety Laboratory Assessments .............................................82
 
 
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LIST OF FIGURES
          
Figure 1
Study Design.........................................................................................................22
 
 
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1. Synopsis
Protocol Title:  
Phase II study, Randomized, Double-Blind, Placebo-Controlled 4-Week Clinical 
Study, to Evaluate the Efficacy and Safety of MK-7264 in Adult Japanese 
Participants with Unexplained or Refractory Chronic Cough
Short Title: 
MK-7264 Phase II in Japanese adult participants with unexplained or refractory chronic 
cough
Objectives/Hypotheses and Endpoints:
This is an estimation study and there are no hypotheses in this study. In this study, the 
objectives and endpoints below will be evaluated in adult participants with unexplained 
or treatment refractory chronic cough as follows:
Objective
Endpoint
Primary

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
Secondary

To estimate the efficacy of MK-
7264 in reducing cough frequency 
as measured over a 24-hour period

24-hour coughs per hour at Week 4

To estimate the efficacy of MK-
7264 in reducing cough frequency
while awake during a 24-hour 
period

Awake coughs per hour at Week 4
 
 
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Overall Design:
Study Phase
Phase II
Clinical Indication
Treatment of unexplained or refractory chronic cough
Population
Japanese adult participants at least 20 years of age with 
unexplained or refractory chronic cough
Study Type
Interventional
Type of Design
Parallel
Type of Control
Placebo
Study Blinding
Double-blind
Estimated Duration 
of Study
The Sponsor estimates that the study will require 
approximately 5 months 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 20 participants will be enrolled.
Treatment Groups and Duration:
Treatment Groups
Participants will be randomized in a 1:1 ratio to either 
oral MK-7264 45 mg BID or placebo.
Duration of 
Participation
Each participant will participate in the study for 
approximately up to 8 weeks from the time the 
participant signs the Informed Consent Form (ICF) 
through the final contact.  After a screening phase of up 
to approximately 2 weeks each participant will be 
receiving assigned treatment for approximately 4 weeks.  
After the end of treatment each participant will be 
followed for 2 weeks.
Study governance considerations are outlined in Appendix 1. A list of abbreviations used in 
this document can be found in Appendix 7.
 
 
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2. Schedule of Activities (SoA)
Study Period
Screening
Baseline
Treatment
Follow-up
Disc
Notes
Visit Number
Visit 1
Visit 2
Visit 3
TC
Visit 4
Visit 5
Visit 6
Scheduled Day
Day -14 to 
Day -7
Day 0
Day 1
Day 14
Day 28
Day 29
Day 42
Scheduling Window
NA
NA
NA
±3 dys
±3 dys
The next 
day of V4
14 dys after last 
dose
+3 dys
Scheduled Week
Wk -2 to 
Wk -1
Wk 0
Wk 1
Wk 2
Wk 4
Wk 4
Wk 6
Administrative Procedures
Informed Consent
X
Informed Consent for Future 
Biomedical Research
X
Participant Identification Card
X
Inclusion/Exclusion Criteria
X
X
Prior/Concomitant Medication Review
X
X
X
X
X
X
X
X
Demographics and Medical History
X
X
Treatment Randomizationa
X
MK-7264/Placebo Distribution 
X
MK-7264/Placebo Accountability
X
X
X
X
At TC (Day 14), general 
treatment compliance will be 
checked 
Efficacy Procedures
Attach Cough Monitor
X
X
Cough monitor should be 
attached before 11 am and worn 
for 24 hours during each 
assessment
Collect Cough Monitor
X
X
 
 
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Study Period
Screening
Baseline
Treatment
Follow-up
Disc
Notes
Visit Number
Visit 1
Visit 2
Visit 3
TC
Visit 4
Visit 5
Visit 6
Scheduled Day
Day -14 to 
Day -7
Day 0
Day 1
Day 14
Day 28
Day 29
Day 42
Scheduling Window
NA
NA
NA
±3 dys
±3 dys
The next 
day of V4
14 dys after last 
dose
+3 dys
Scheduled Week
Wk -2 to 
Wk -1
Wk 0
Wk 1
Wk 2
Wk 4
Wk 4
Wk 6
LCQ
X
X
Cough Severity VAS
X
X
X
CSD
Daily
Safety Procedures
Chest Radiograph or CT Thorax
X
Not required if done in past 
5 years
Physical examination
X
X
X
Height
X
Weight
X
X
X
Vital Signs 
X
X
X
X
X
X
12-lead ECG
X
X
X
Spirometry
X
Spirometry performed within 
the past year is acceptable (see 
Section 6.2)
Urine Pregnancy Test (WCBP only)
X
Pregnancy testing (after V1) 
will be performed whenever an 
expected menstrual cycle is 
missed or when pregnancy is 
otherwise suspected (see 
Appendix 3).
Serum Pregnancy Test (WCBP only)
X
Only if urine test is positive.
Hematology and Chemistry
X
X
X
 
 
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Study Period
Screening
Baseline
Treatment
Follow-up
Disc
Notes
Visit Number
Visit 1
Visit 2
Visit 3
TC
Visit 4
Visit 5
Visit 6
Scheduled Day
Day -14 to 
Day -7
Day 0
Day 1
Day 14
Day 28
Day 29
Day 42
Scheduling Window
NA
NA
NA
±3 dys
±3 dys
The next 
day of V4
14 dys after last 
dose
+3 dys
Scheduled Week
Wk -2 to 
Wk -1
Wk 0
Wk 1
Wk 2
Wk 4
Wk 4
Wk 6
Urinalysis (w/Microscopy)
X
X
X
Dipstick to be performed at the 
study site.
AE/SAE review
X
X
X
X
X
X
X
X
Pharmacokinetics/ Biomarkers
Blood for Genetic Analysis
X
Collected from randomized 
participants only; See Section 
9.8. and 9.9
Pharmacokinetic Sample (blood)
Xb
Xc
Xd
X
Abbreviations: AE = adverse event; CSD = cough severity diary; CT = computed tomography; Disc = discontinuation; dys = days; ECG = electrocardiogram; LCQ = Leicester 
Cough Questionnaire; NA = not applicable; TC=telephone contact; V = visit; VAS = visual analogue scale; WK = week
a
Treatment randomization (prescription) can be done at V2 only if a participant has been confirmed to meet the all entry criteria and the study site has schedule conflict to 
randomize (prescribe) at V3.
b
Sample should be drawn prior to dosing and after removing cough monitor.(V3, Day 1) 
c
Sample should be drawn prior to dosing and before attaching cough monitor.(V4, Day 28)
d
Sample should be drawn after removing cough monitor.(V5, Day 29)
 
 
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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] [Irwin, R. 
S., 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, including Japan, 
cough is categorized based upon the duration of the cough; within each category (acute, sub-
acute, and chronic) are likely diagnostic possibilities [Irwin, R. S., et al 2006]  Acute cough 
is present for less than 3 weeks and most often due to acute viral upper respiratory tract 
infection (URTI).  A cough that has been present longer than 3 weeks is either sub-acute (3 to 
8 weeks) or chronic (> 8 weeks).
It is reported in Japan that the prevalence of the chronic cough is approximately 2% of the 
population and the most common underlying condition is asthma/cough-variant asthma 
followed by sinobronchial syndrome, atopic cough, gastroesophageal reflux disease (GERD) 
and postinfections. Most of the patients with cough could be effectively managed by 
optimizing therapy for the underlying condition. However, a minority of patients with a
potential underlying co-morbid condition cannot be effectively managed by optimizing 
therapy for the condition and are considered to have refractory chronic cough. Also, the 
cause of chronic cough remains unexplained in ~10% of patients seeking medical attention 
specific to their cough [Gibson, P., et al 2016]. This protocol aims to study participants with 
either refractory chronic cough or unexplained chronic cough.
Professional guidelines describe systematic approaches to the evaluation and management of 
chronic cough. These guidelines are based largely on consensus opinion and observational 
data from the medical literature. There are currently no treatments approved by the United 
States Food and Drug Administration, European Medicines Agency or Japan Ministry of 
Health, Labour and Welfare for the treatment of chronic cough. Given the prolonged nature,
significant morbidity , and the lack of effective treatment, unexplained or refractory chronic 
cough is a major unmet medical need.
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 hyper-sensitized, 
leading to an increase in symptoms and a pathologic cough.  
P2X3 receptors are ligand-gated ion channels that respond to adenosine triphosphate (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. ATP is released by 
damaged, stressed, and inflamed tissues. 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 
 
 
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normalize afferent sensitivity, based on data from P2X3 knock-out mice and the effects of 
small interfering ribonucleic acid (RNA) 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.
Cough Hypersensitivity Syndrome
Recently, the term cough hypersensitivity syndrome has been proposed to describe a group of 
patients with chronic cough and similar clinical characteristics [Chung, K. F. 2014]. These 
similar clinical characteristics include irritation in the throat or upper chest, cough triggered 
by non-tussive stimuli, increased cough sensitivity to inhaled stimuli, and cough paroxysms. 
A potential biologic explanation for cough hypersensitivity syndrome suggests an underlying 
sensory neuropathy characterized by afferent nerve hyper-sensitization. Sensory afferent 
nerves are susceptible to sensitization by neuroactive mediators and altered expression of ion 
channels which regulate afferent nerve excitability to many chemical stimuli. As described 
above, the action of ATP at sensory neurons may cause hypersensitivity through binding to 
P2X3-containing receptors and contribute to the pathophysiology of patients with chronic 
cough. As described elsewhere in the protocol, the data from Protocol 012 support the role of 
P2X3 inhibition in the treatment of patients with treatment refractory or unexplained chronic 
cough.
Study Rationale 
3.1
The purpose of this study is to evaluate the efficacy and safety of MK-7264, an orally 
available P2X3 antagonist, in adult Japanese participants, at least 20 years of age, who have 
either unexplained or refractory chronic cough.
Current therapies for cough (narcotic, non-narcotic, and over-the-counter medications) have 
limited efficacy and an undesirable side effect profile. There are no therapies which were 
proven their efficacy for chronic cough.
Previous studies have demonstrated dose-related efficacy and acceptable safety and 
tolerability for MK-7264 in adult non-Japanese participants who have chronic cough (refer to 
the Investigator’s Brochure Edition 16, 2017). This study will evaluate the safety and 
efficacy of MK-7264 in adult Japanese participants with unexplained or refractory chronic 
cough.
Background
3.2
Refer to the Investigator’s Brochure (IB) for detailed nonclinical and clinical background 
information on MK-7264.
Pharmaceutical and Therapeutic Background
3.2.1
MK-7264, a P2X3 receptor antagonist, has been evaluated in clinical studies for the 
treatment of chronic cough, interstitial cystitis/bladder pain syndrome, osteoarthritis pain, 
and asthma. MK-7264 has also been evaluated in an extensive nonclinical program.
 
 
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MK-7264 is an oral treatment provided as a film coated tablet. The MK-7264 tablets 
provided for this study contain MK-7264 45 mg. The placebo tablets provided in this study 
are indistinguishable from the MK-7264 tablet in appearance. The placebo tablets contain no 
MK-7264, but contain the same inactive excipients as those included in the active tablets.
Clinical Studies in Japan
3.2.2
In single and multiple dose study in Japanese healthy subjects (Protocol 024), the safety, 
tolerability and PK of MK-7264 was evaluated following MK-7264 (15, 30, 50 and 100 mg/ 
N=8 [MK-7264: 6, PBO: 2]) as a single dose under fasting conditions in Part 1 and following 
repeated MK-7264 (15, 30 and 50 mg/ N=8 [MK-7264: 6, PBO: 2] in each dose) BID dosing 
for 15 days (morning dose only at Day 15) administration under fed conditions in Part 2.  The 
results suggest that there is no specific safety concern in Japanese and no major difference in 
PK profile between Japanese and non-Japanese.
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
In the completed and ongoing clinical studies, no major safety concerns have been noted. 
Across studies, taste-related adverse events (AEs) were the most frequent reported AEs. The 
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. The taste-related AEs are considered mechanism based non-
serious adverse drug reactions expected for MK-7264. To date, they have been fully and 
rapidly reversible after discontinuation of the drug.
Overall, based on growing clinical evidence supporting the efficacy of MK-7264 in 
participants with refractory or unexplained chronic cough described in Investigator’s 
Brochure (IB) and the lack of significant safety findings in completed and ongoing 
nonclinical and clinical studies, the benefit risk balance of MK-7264 is assessed as positive.
Additional details regarding specific benefits and risks for participants participating in this 
clinical study may be found in the accompanying Investigators Brochure (IB) and Informed 
Consent documents.
 
 
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4. Objectives/Hypotheses and Endpoints
This is an estimation study and there are no hypotheses in this study. In this study, the 
objectives and endpoints below will be evaluated in Japanese adult participants with 
unexplained or treatment refractory chronic cough as follows:
Objective
Endpoint
Primary

To evaluate the safety and tolerability of 
MK-7264 

Number of participants experiencing an
adverse event (AE)

Number of participants discontinuing study 
treatment due to AE
Secondary

To estimate  the efficacy of MK-7264 in 
reducing cough frequency as measured 
over a 24-hour period

24-hour coughs per hour at Week 4

To estimate the efficacy of MK-7264 in 
reducing cough frequency while awake 
during 24-hour period

Awake coughs per hour at Week 4
Exploratory

To estimate the efficacy of MK-7264 in 
cough specific quality of life

LCQ total score at Week 4

To estimate the efficacy of MK-7264 in 
improving self-rated cough severity

Mean weekly CSD total score at Week 4

Cough Severity VAS score at Week 4

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 study.

Germline genetic variation

To explore the relationship between MK-
7264 plasma concentrations and safety and 
efficacy data

Plasma concentrations of MK-7264
 
 
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5. Study Design 
Overall Design 
5.1
This is a randomized, placebo-controlled, parallel group, multi-site, double-blind, study of 
MK-7264 in adult Japanese participants with unexplained or refractory chronic cough. 
Approximately 20 participants who meet entry criteria will enter the study. The duration of 
study period for each participant is as follows:
•
Screening Period: a minimum of 7 days and up to 14 days
•
Baseline: 1 day (including 24 hours of objective measurement of cough)
•
Treatment Period: 28 days
•
Follow-Up Period: 14 days
Individual participation is expected to be approximately up to 8 weeks from Screening 
through the Follow-up period.
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.
Study Diagram
5.1.1
The study design is depicted in Figure 1.
Figure 1
Study Design
There will be one randomization for the entire study. Participants will be randomized in a 1:1 
ratio to MK-7264 45 mg BID or placebo.
 
 
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A safety follow-up visit will be conducted 14 days (+ 3 days) after Visit 4 or after last dose 
of study treatment (for participants who discontinue from treatment and continue in the 
study). Please refer to details in Section 9.10.5.
Number of Participants
5.2
Approximately 20 participants will be randomized in this study as described in section 10.9.
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).  
Clinical Criteria for Early Study Termination
5.3.1
There are no pre-specified criteria for terminating the study early.
Scientific Rationale for Study Design 
5.4
Rationale for Endpoints
5.4.1
Safety Endpoints
5.4.1.1
The safety data for MK-7264 to date has been described in detail in the IB 
In support of the safety objective to evaluate the safety and tolerability profile of MK-7264 in 
Japanese adults, the safety and tolerability endpoints will be assessed by clinical evaluation 
of adverse events and inspection of other study parameters including vital signs, physical 
examination, and standard laboratory safety tests at time points specified in the SoA.
Adverse events are graded and recorded according to Section 9.3 and Appendix 4.
Efficacy Endpoints
5.4.1.2
The first secondary endpoint of this study is the 24-hour coughs per hour (i.e., average hourly 
cough frequency based on 24-hour sound recordings) at Week 4. Cough counts will be 
measured using a digital recording device (VitaloJAK™, Vitalograph, Buckingham, United 
Kingdom). Worn similar to a Holter monitor, with microphones affixed to the participant’s 
chest wall and 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 asleep.
 
 
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The preliminary efficacy of MK-7264 in the treatment of unexplained or refractory chronic 
cough in Japanese adults will be estimated, as evidenced by a change (reduction) from 
baseline at Week 4 in 24-hour coughs per hour in MK-7264 relative to placebo. Utilizing 24-
hour coughs per hour as the efficacy endpoint is further supported with successful data from 
MK-7264 Protocol 012. Results from MK-7264 Protocol 012 demonstrated statistically 
significant reduction, in change from baseline in 24-hour coughs per hour, with 50 mg MK-
7264 BID compared to placebo at Week 12. This reduction was observed from Week 4 
though Week 8 and Week 12 with statistically significant difference in all time points. 
The awake coughs per hour at Week 4 is included as second secondary endpoint. As 
described above, the 24 hour period can be divided into periods of awake and asleep. In 
Protocol 012, awake baseline cough rates were numerically higher than 24 hour baseline 
cough rates and higher than sleep cough rates. Based on these data, awake time may be a 
meaningful time period for refractory and unexplained chronic cough participants. Therefore 
awake coughs per hour will be evaluated as a secondary endpoint in this study
An assessment of cough from the participant’s perspective is also important for evaluating 
the response to therapy. Patient-reported outcomes (PRO) associated with cough can be 
measured in terms of cough-specific quality of life, cough frequency, intensity, disruption 
due to cough and cough severity. To supplement information obtained from cough counting, 
the following measures will be included:
1. Leicester Cough Questionnaire (LCQ).
2. Cough Severity Diary (CSD);
3. Cough Severity Visual Analog Scale (VAS);
As validated PRO measures of cough-specific health-related quality of life and cough 
severity, data obtained from the LCQ, CSD, and Cough Severity VAS, will provide 
important information relevant to the efficacy of MK-7264 in participants with unexplained 
or refractory chronic cough. 
In regards to Japanese translated version, LCQ has been validated for the use in Japanese chronic 
cough patients [Kanemitsu, Y., et al 2016]. On the other hand, there is no experience of using 
Japanese translated version of CSD and Cough Severity VAS. Both PROs will be linguistically 
validated. 
The impact of chronic cough on health-related quality of life (HRQoL) as assessed by the 
LCQ is included as the exploratory endpoint.
The LCQ is a 19-item cough-specific health-related quality of life (HRQoL) questionnaire 
which contains three domains (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 assesses symptoms or the impact of symptoms on HRQoL over the past two 
weeks using a 7-point Likert scale ranging from 1 to 7.  Higher scores indicate better 
HRQoL.  Data obtained from the LCQ will provide information on the impact of chronic 
cough on patients’ daily lives, beyond objective cough counts and severity, which is valuable 
information for assessing the full benefit of effective cough control.
 
 
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The CSD is a 7-item, disease-specific PRO measure completed daily in the evening, with a 
recall period of “today”. The measure evaluates frequency of cough (3 items), intensity of 
cough (2 items) and disruption (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 
(frequency, intensity, disruption) can be calculated.
As part of the psychometric assessment of the CSD in Protocol 012, distribution- and 
anchor-based analyses were conducted to determine a clinically meaningful change in the 
mean weekly CSD total score between baseline and Week 4. Results of the distribution-based 
analyses combined with the anchor-based analyses indicate that a reduction of 1.3 points 
and 2.7 (on the 0 to 10-point scale) are appropriate to define clinically meaningful 
improvements in the CSD total score. 
The Cough Severity VAS is a single-item question asking the participant to rate the severity 
of their cough over the past 24 hours 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 scales in 
chronic pain, the Cough Severity VAS measure provides a quick, valid and easily-interpreted 
subjective assessment useful for clinicians to monitor improvement of their chronic cough 
patients following treatment. 
Based on the results from MK-7264 Protocol 012, analyses to define a clinically meaningful 
reduction in cough severity indicated that a reduction of 30 mm was found to be predictive 
of patient-reported improvement in cough as rated on the Patient Global Impression of 
Change (PGIC) questionnaire. This cut-point is also consistent with the provisional 
benchmarks outlined by the Initiative on Methods, Measurement, and Pain Assessment in 
Clinical Trials which recommends that an improvement of approximately 30% on a 0 to 10 
numeric rating scale can be considered clinically meaningful [Dworkin, R. H., et al 2009].
Pharmacokinetic Endpoints
5.4.1.3
Plasma samples for pharmacokinetic analyses will be drawn and concentrations of MK-7264 
will be summarized. Exploratory population pharmacokinetic (PK) analyses may be 
conducted to understand the exposure-response relationships between MK-7264 and efficacy 
and safety data.
Pharmacodynamic Endpoints
5.4.1.4
No PD biomarkers that will require modeling are planned for this study.
Planned Exploratory Biomarker Research
5.4.1.5
Planned Genetic Analysis
5.4.1.5.1
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.
 
 
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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 drug(s). Genetic 
research may consist of the analysis of one or more candidate genes, the analysis of genetic 
markers throughout the genome, or analysis of the entire genome.
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. 
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
5.4.1.6
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
5.4.2
A placebo is included in this study to maintain the study blinding, allowing for an unbiased 
assessment of efficacy and safety. Participants may discontinue the study treatment at any 
time. Given that there is no approved treatment for chronic cough, use of a placebo is 
justified.
Justification for Dose 
5.5
Starting Dose for This Study
5.5.1
The dose for this study will be either MK-7264 45 mg BID or placebo as determined by the 
individual allocation per the assigned treatment group (see Section 7).
 
 
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The known mechanism of action of MK-7264 and related clinical study results support that 
the efficacy of MK-7264 in decreasing cough, and the prevalence of the most common AE, 
dysgeusia, are both dose related. The exposure -response model was developed from the 
previously conducted studies and simulations were performed to characterize the dose-
response profile. 45 mg BID was selected to achieve a high benefit/risk ratio; likely to 
maximize the cough frequency reduction in conjunction with acceptable tolerability.
Considering that the PK profiles of Japanese and non-Japanese were expected to be similar 
and there has been no report suggesting an ethnic difference in P2X3 receptor expression, it 
would be difficult to conclude that the exposure - response relationship would differ between 
Japanese and non-Japanese. Therefore, a 45 mg BID is selected to evaluate preliminary 
efficacy and safety of MK-7264 in Japanese participants with unexplained or refractory 
chronic cough.
Maximum Dose/Exposure for This Study
5.5.2
The maximum dose/exposure for this study will be at 45 mg BID. Participants will be 
exposed to MK-7264 for approximately 28 days (see Section 7).
Rationale for Dose Interval and Study Design
5.5.3
In this study, MK-7264 will be orally administered as MK-7264 45 mg BID based on the 
safety and pharmacokinetic efficacy results observed to date.
Based on pharmacokinetic studies, MK-7264 is rapidly absorbed with a median time to reach 
maximum plasma concentration (Tmax) of 1.0 to 2.0 hours. In addition, the a half-life of MK-
7264 is approximately 7 to 10 hours and consistent with a BID dosing schedule.
In protocol 012, evidence of a reduction in the 24-hour Cough Frequency at the 50 mg dose 
was also observed at Week 4, which was sustained through Week 12.
For this study, 4 weeks duration of treatment was selected to evaluate efficacy, safety and 
tolerability of MK-7264 in the treatment of refractory or unexplained chronic cough.
6. Study Population
This study will enroll male and female participants with chronic cough ≥ 1 year and a 
diagnosis of unexplained or refractory chronic cough according to the American College of 
Chest Physician (ACCP) guidelines. For the purposes of this study, refractory chronic cough 
is defined as participants who have had a clinical evaluation that suggested a comorbid 
condition that may be related to cough (eg, gastroesophageal reflux disease [GERD], asthma,
or upper airway cough syndrome), the participant has received appropriate diagnostic work-
up and therapy according to ACCP guidelines, and the participant continues to cough. Also 
for the purposes of this study, unexplained chronic cough is defined as participants who have 
had a clinical evaluation of their cough per ACCP guidelines and this evaluation has not 
suggested a comorbid condition that may be related to cough. Participants with refractory 
chronic cough or unexplained chronic cough and who are at least 20 years of age 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.
 
 
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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. Chest radiograph or computed tomography scan of the thorax (within 5 years of 
Screening/Visit 1 and after the onset of chronic cough) not demonstrating any 
abnormality considered to be significantly contributing to the chronic cough or any 
other clinically significant lung disease in the opinion of the principal investigator or 
the sub-investigator.
2. Have chronic cough for ≥ 1 year and a diagnosis of refractory chronic cough or 
unexplained chronic cough.
3. Have a score of ≥ 40 mm on the Cough Severity VAS at both the Screening and 
Baseline visits.
Demographics
4. Japanese women and men at least 20 years of age at the time of informed consent.
Female participants:
5. 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 
thestudy period and for at least 14 days after the last dose of study treatment.
Informed Consent
6. The participant is able to provide written informed consent for the study on their own 
behalf.  The participant may also provide consent for Future Biomedical Research.  
However the participant may participate in the main study without participating in 
Future Biomedical Research.
Study Participation
7. The participant is willing and able to comply with all aspects of the protocol
including demonstrating an ability to follow study procedures (including use of the 
digital cough recording device) [VitaloJAK™], and completion of the Cough Severity 
VAS, CSD, and LCQ) to the satisfaction of the investigator/qualified designee prior 
to randomization.
 
 
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Exclusion Criteria 
6.2
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions 
1. Current smoker.
2. Individuals who have given up smoking within 12 months of Screening/Visit 1.
3. Former smokers with a pack-year history greater than 20 pack-years.
4. Forced expiratory volume in 1 second (FEV1)/ forced vital capacity (FVC) ratio
<60% (spirometry performed within the past year is acceptable if the investigator 
confirms that spirometry was done during a period where the participant was 
clinically stable (eg, not during an upper respiratory infection).
5. History of upper or lower respiratory tract infection or recent clinically significant 
change in pulmonary status within 4 weeks of Screening/Visit 1.
6. History of chronic bronchitis, defined as a cough that produces a clinically significant 
amount of sputum (greater than approximately 1 tablespoon of phlegm) that occurs 
every day for at least 3 months in a row, with those periods occurring at least 2 years 
in a row.
7. Individuals who are currently taking an angiotensin converting enzyme inhibitor or 
have taken an angiotensin converting enzyme inhibitor within 3 months of 
Screening/Visit 1.
8. Estimated glomerular filtration rate (eGFR) <50 mL/min/1.73 m2 (using the Japanese 
Equation for Estimating GFR [Japanese Society of Nephrology]) at Screening/Visit 1.
9. Has a history of malignancy ≤ 5 years prior to signing informed consent except for 
adequately treated basal cell or squamous cell skin cancer or in situ cervical cancer.
10. Is, at the time of signing informed consent, a user of recreational or illicit drugs or has 
had a recent history (within the last year) of drug or alcohol abuse or dependence in 
the opinion of the principal investigator or the sub-investigator.
11. Screening systolic blood pressure >160 mm Hg or a diastolic blood pressure >90 mm 
Hg.
12. History of cutaneous adverse drug reaction to sulfonamides with or without systemic 
symptoms or history of anaphylaxis to sulfonamides.
13. Has a known allergy/sensitivity or contraindication to MK-7264 or its excipients.
(note: refer to the IB for details regarding excipients for MK-7264)
14. Has donated or lost ≥1 unit of blood (approximately 300 mL) within 8 weeks prior to 
the first dose of MK-7264.
15. A WOCBP who has a positive urine and serum pregnancy test at Visit 1.  If the urine 
test is positive or cannot be confirmed as negative, a serum pregnancy test is required. 
 
 
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Prior/Concomitant Therapy
16. Requiring treatment with a therapy that does not adhere to the guidance parameters 
specified in Section 7.7.
Prior/Concurrent Clinical Study Experience
17. Has previously received MK-7264.
18. Is currently participating in or has participated in an interventional clinical study with 
an investigational compound or device within 30 days of participating in this current 
study.
Diagnostic Assessments
19. Significantly abnormal laboratory tests at Screening (see Sections 9.5.6 and 9.5.7), 
including:
a.
alkaline phosphatase (AP), alanine aminotransferase (ALT, SGPT), aspartate 
aminotransferase (AST, SGOT)>200% of the upper limit of normal, or 
bilirubin >150% of the upper limit of normal.
b. hemoglobin <10 gm/dL, white blood cell count (WBC) <2500 mm3, 
neutrophil count <1500 mm3, platelet count <100 × 103/mm3.
20. Has history or current evidence of any condition, therapy, laboratory abnormality or 
other circumstance that may increase the risk associated with study participation or 
investigational product administration or may interfere with the interpretation of 
study results and, in the judgment of the Investigator or Sponsor, would make the 
participant inappropriate for entry into this study.
21. 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
No restrictions are required.
Caffeine Alcohol, and Tobacco Restrictions
6.3.2
Participants who currently smoke, who have given up smoking within the past 12 months, as 
well as participants who are former smokers with a pack/year history greater than 20 pack-
years will not be permitted in the study. Smoking is also not permitted during the course of 
the trial (from Screening/Visit 1 though completion of Treatment period/Visit 5).
Based on known metabolism of MK-7264, there are no effect of alcohol and caffeine 
associated with the study treatment and therefore no related restrictions.However, 
participants will refrain from consumption of alcohol 24 hours prior to and after the all study
visits(including the PK sampling visits).  
 
 
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On intermediate days, and at all other times, alcohol consumption is limited to no more than 
approximately 3 alcoholic beverages or equivalent (1 glass is approximately equivalent to: 
beer [354 mL/12 ounces], wine [118 mL/4 ounces], or distilled spirits [29.5 mL/1 ounce]) per 
day.
Activity
6.3.3
Participants should abstain from strenuous exercise and avoid noisy environments (eg, hair 
dryer, lawn equipment, open windows while driving, cinemas, listening to music, etc.) while 
the VitaloJAK™ monitor is attached over a 24 hour period. However, participants may 
participate in light recreational activities (eg, watching television at a low volume, reading). 
Participants will also avoid getting the VitaloJAK™ device, microphone, or chest sensor wet. 
Thus, they must avoid bathing or showering for the duration of the 24 hour recording.
The chest sensor will be applied to the participant’s chest with an adhesive (sticky pad). If 
the participant has a known allergic sensitivity/reaction to adhesives, and in the opinion of
the investigator the sensitivity/reaction is severe enough to impact the ability of the 
participant to complete the study, the participant should not be enrolled in this study.
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.  Participants identified as screen failures can 
be rescreened once (within 45 days of original Screening Visit) for possible participation, and 
only with Sponsor consultation. Any participant who is re-screened will retain the original 
screening number assigned at the initial screening visit. If the Cough Severity VAS inclusion 
criterion is not met at screening at Visit 1, the participant will not be allowed to be 
rescreened. If the Cough Severity VAS criterion is not met at Visit 2 (Baseline), the 
participant may be re-screened only with Sponsor consultation.  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 data entry guidelines.
Participant Replacement Strategy
6.5
A participant who discontinues from 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 as required.  Clinical supplies will be affixed with a clinical label in accordance 
with regulatory requirements.
 
 
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Treatments Administered
7.1
The study treatment(s) to be used in this study are outlined below in Table 1.
Table 1
Study Treatment(s)
Study Treatment Name:
MK-7264
Placebo
Dosage Formulation:
Film coated tablet
Film coated tablet
Unit Dose Strength(s):
45 mg
0 mg
Dosage Level(s):
1 tablet BID
1 tablet BID
Route of Administration:
Oral
Oral
Sourcing:
Provided centrally by the 
Sponsor
Provided centrally by the 
Sponsor
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 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
No dose modification is allowed in this study.
Method of Treatment Assignment 
7.3
Treatment allocation/randomization will occur centrally using an interactive response
technology (IRT) system. There are 2 study treatment arms. Participants will be assigned
randomly in a 1:1 ratio to MK-7264 45mg BID and placebo, respectively.
Stratification
7.3.1
Treatment allocation/randomization will be stratified according to the following factor:
1. Gender (Male; Female)
Blinding 
7.4
A double-blinding technique with in-house blinding will be used.  MK-7264 and placebo will 
be packaged identically so that 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 selection of doses to be used in this study is provided in Section 5.5 –
Background.  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 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
Records of treatment compliance for each participant will be kept during the study. The 
clinical research associates (CRAs) will review treatment compliance during investigational 
site visits and at the completion of the study. Compliance should be based on participant 
reporting and confirmed by tablet count where possible. Issues with compliance should be 
discussed with the participant and addressed as deemed appropriate by the investigator.
Interruptions from the protocol specified treatment plan of <80% compliance between visits, 
based on the review with the participant require consultation between the investigator and the 
Sponsor and written documentation of the collaborative decision on participant management.
 
 
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Concomitant Therapy
7.7
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing study unless as stated otherwise in this section.  If there is a clinical 
indication for any medication or vaccination specifically prohibited, discontinuation from 
study therapy or vaccination may be required.  The investigator should discuss any questions 
regarding this with the Sponsor Clinical Director.  The final decision on any supportive 
therapy or vaccination rests with the 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.
For participants who receive study treatment, any medication (including over-the-counter 
medications) or therapy administered to the participant during the course of the study will be 
recorded on the Prior and Concomitant Therapy case report form (CRF). Treatments for 
chronic cough received by the participant within 1 year prior to Screening will also be 
recorded. The Investigator(s) will record any AE on the AEs CRF for which a concomitant 
therapy was administered.
Listed below are specific restrictions for prior/concomitant therapy during the course of the 
study:
1. Opioids (including codeine) for the treatment of cough are not allowed from 1 week 
prior to Screening/Visit 1 through Randomization/Visit 3. Participants should not 
initiate therapy with opioids (including codeine) for the treatment of cough from 
Randomization/Visit 3 through completion of Treatment period/Visit 5. 
Opioids (including codeine) for indications other than chronic cough are permitted 
provided the participant is receiving a stable dose for at least 1 week prior to 
Screening/Visit 1 and in the opinion of the investigator, is likely to remain on the 
stable dose through completion of Treatment period/Visit 5..
2. Pregabalin, gabapentin, or amitriptyline for the treatment of cough is not allowed 
from 2 weeks prior to Screening/Visit 1 through Randomization/Visit 3. Participants 
should not initiate therapy with pregabalin, gabapentin, or amitriptyline for the 
treatment of cough from Randomization/Visit 3 through completion of Treatment 
period/Visit 5.  
Pregabalin, gabapentin, or amitriptyline for indications other than chronic cough are 
permitted provided the participant is receiving a stable dose for at least 2 weeks prior 
to Screening/Visit 1 and in the opinion of the investigator, is likely to remain on the 
stable dose through completion of s Treatment period/Visit 5. 
3. Dextromethorphan, guaifenesin, benzonatate and any other over the counter or 
prescription for the treatment of cough are not allowed from 2 weeks prior to 
Screening/Visit 1 through Randomization/Visit 3. Participants should not initiate 
therapy with any over the counter or prescription treatments for cough from 
Randomization/Visit 3 through completion of Treatment period/Visit 5.
 
 
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4. Treatments for conditions such as GERD, asthma, sinobronchial syndrome (SBS), or 
atopic cough, associated with chronic cough are permitted provided that participants 
are receiving a stable dose for at least 2 weeks prior to Screening/Visit 1and in the 
opinion of the investigator, are likely to remain on the stable dose through completion 
of Treatment period/Visit 5.  Possible treatments are provided in Table 2. Note, this 
list is not meant to be comprehensive. Sponsor to be consulted for further 
information.
Table 2
Example of Concomitant Treatments Permitted in the Study
Condition
Treatment
GERD
Anti-reflux therapy (proton pump or H2 blockers), and/or
pro-kinetic agents
Asthma
Bronchodilators, inhaled corticosteroids, and/or other 
anti-inflammatory agents
SBS
14-membered ring macrolides (e.g. erythromycin)
Atopic cough
Antihistamine
5. Non-pharmacologic treatments (eg, physiotherapy, speech and language therapy) for 
cough are not allowed from 3 months prior to Screening/Visit 1 through completion 
of Treatment period/Visit 5.
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 allocation/randomization
schedule for the study 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 - Participant Blinding/Unblinding, 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 Section 2 - Schedule of Activities 
and Section 9.10.4– Discontinued Participants Continuing to be Monitored in the Study.
 
 
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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 9.10.4 – Discontinued Participants 
Continuing to be Monitored in the Study..
A participant must be discontinued from study treatment but continue to be monitored in the 
study for any of the following reasons:
○
The participant 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 has a medical condition or personal circumstance which, in the opinion of 
the investigator and/or Sponsor, placed the participant at unnecessary risk from continued 
administration of study treatment (including recommendation to discontinue participant 
from study treatment as part of monitoring for crystalluria/urolithiasis, see Section 9.5.7–
Renal and Urological Safety Procedures)..
o
The participant has a confirmed positive serum pregnancy test.
o
In case of clinically significant and potentially drug related rash or signs and/or 
symptoms consistent with anaphylaxis to study treatment.
o
Chronic failure to comply with the dosing, evaluations, or other requirements of the 
study, despite documentation at the site of repeated efforts to reinforce compliance.
For participants who are discontinued from study treatment but continue to be monitored in 
the study, see Section 2 – Schedule of Activities (SoA), and Section 9.10.4– Discontinued 
Participants Continuing to be Monitored in the Study for those procedures to be completed at 
each specified visit.
Discontinuation from study treatment is “permanent.” Once a participant is discontinued, 
he/she shall not be allowed to restart study treatment.
Withdrawal from the Study
8.2
A participant must be withdrawn from the study if the participant 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, as well as specific details regarding withdrawal from Future Biomedical Research are 
outlined in Section 9.1.9 – Withdrawal/Discontinuation. The procedures to be performed 
should a participant repeatedly fail to return for scheduled visits and/or if the study site is 
unable to contact the participant are outlined in Section 8.3 – Lost to Follow Up.
 
 
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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. 
●
Procedures conducted as part of the participant’s routine clinical management (eg, 
blood count) and obtained before signing of ICF may be utilized for screening or 
baseline purposes provided the procedure met the protocol-specified criteria and were 
performed within the time frame defined in the SoA.
●
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
40 mL.
 
 
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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 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 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 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.
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.
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 
to ensure that the participant qualifies for the study. Inclusion and exclusion criteria for this 
study are defined in Sections 6.1 – Inclusion Criteria and 6.2 – Exclusion Criteria, 
respectively.
 
 
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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 (refer to 
electronic CRF [eCRF] entry guidelines).
Prior and Concomitant Medications Review
9.1.5
Prior Medications
9.1.5.1
The investigator or qualified designee will review prior medication use prior to screening 
(see Section 7.7 – Concomitant Therapy and refer to eCRF entry guidelines).  
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 
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.
 
 
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A single participant cannot be assigned more than 1 treatment/randomization number.
Treatment Administration
9.1.8
Study treatment will be administered at the study site at Visit 3. This first dose of study 
treatment at Visit 3 should be administered as a witnessed dose after the cough counter is 
removed, after the pre-dose PK sample collection. Subsequent dosing will be performed by 
the participant (ie, unsupervised at his/her home) BID, approximately 12 hours apart at 
approximately the same time each day. However, at Visit 4, the morning dose should not be 
taken at home and instead will be administered as a witnessed dose at the study site, after the 
pre-dose PK sample collection, and before approximately 11 AM. The cough monitor should 
be attached prior to dosing and TURNED ON immediately AFTER dosing. The last dose of 
study treatment will be administered at the evening of Visit 4 (Day 28).
Timing of Dose Administration
9.1.8.1
Study treatment will be administered orally, BID, approximately 12 hours approximately 28
days (4 weeks) during the treatmentperiod.
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.
When a participant withdraws from participation in the study, all applicable activities 
scheduled for the discontinuation visit 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 - Adverse Events, Serious Adverse 
Events, and Other Reportable Safety Events..
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.
 
 
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Participant Blinding/Unblinding
9.1.10
When the investigator or delegate needs to identify the drug used by a participant and the 
dosage administered in case of emergency eg, the occurrence of serious adverse events, 
he/she will contact the emergency unblinding call center by telephone and make a request for 
emergency unblinding.  As requested by the investigator or delegate the emergency 
unblinding call center will provide the information to him/her promptly and report unblinding 
to the sponsor.  Prior to contacting the emergency unblinding call center to request 
unblinding of a participant’s treatment assignment, the investigator or delegate must enter the 
intensity of the adverse events observed, the relation to study drug, the reason thereof, etc., in 
the medical chart etc.
Participants whose treatment assignment has been unblinded by the investigator/delegate 
and/or non-study treating physician must be discontinued from study drug, but should 
continue to be monitored in the study.
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.
Calibration of Equipment
9.1.11
The investigator or qualified designee has the responsibility to ensure that any device or 
instrument used for a clinical evaluation/test during a clinical study that provides information 
about inclusion/exclusion criteria and/or safety or efficacy parameters shall be suitably 
calibrated and/or 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 trial includes:

VitaloJAK™cough monitor. Operational and maintenance instructions are 
provided separately in a study site manual. Use should be performed according to 
the manufacturer’s specifications. No calibration required.

Spirometer – performed locally. The spirometer must be calibrated according to 
the American Thoracic Society (ATS)/European Respiratory Society (ERS)
guidelines. Calibration checks should be performed (ie, with a 3-liter syringe) at a 
minimum of each day that a study participant performs a spirometry assessment. 

ECG device – sourced locally; use and calibration should be performed according 
to the manufacturer’s specifications.
 
 
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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.
24-Hour Coughs Per Hour
9.2.1
The assessment of 24-hour coughs per hour (ie, average hourly cough frequency based on 
24-hour sound recordings) will be evaluated using the VitaloJAK™ cough monitor, a 510k 
approved (Premarket Notification per the US 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 is a digital recording device that uses two input channels. 
The first records sounds from the lungs and trachea through a chest contact sensor, which is 
attached to the skin at the top of the sternum. The second channel captures ambient sounds 
through a lapel air microphone. Sounds are stored on a high-capacity compact flash card. The 
device will be carried in a cloth belt bag worn around the participants’ 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 
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 software built for analysis and annotation of sound recordings (Vitalograph Web 
Portal). Cough counts are then tallied automatically from the annotated audio file. 
The cough monitor will be attached to the participant before approximately 11 AM and worn 
for 24 hours (see VitaloJAK site manual for further details). The participant should not 
remove the cough monitor during the 24 hour period; the monitor will be removed at the 
clinic, by site staff the next day. Attachment of the monitor will be managed by study site 
staff.
At Visit 3, the first dose of study treatment is to be administered after the cough monitor is 
removed, after the pre-dose PK sample collections.
At Visit 4, the dose of study treatment is to be administered after the pre-dose PK sample 
collections, and before approximately 11 AM. The cough monitor should be attached prior to 
dosing and TURNED ON immediately AFTER dosing.
If cough data is not usable, it may be repeated upon consultation with the Sponsor.
Participants who discontinue study treatment early will continue to be monitored in the study 
and should be encouraged to continue to complete the assessment of 24-hour coughs per hour 
at Day 28 (Visit 4) and Day 29 (Visit 5) as outlined in the SoA.
 
 
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Patient-reported Outcomes
9.2.2
At Screening (Visit 1) and Baseline (Visit 2), each participant will be properly trained and 
instructed on the PRO measures. Participants should be contacted and reminded to do so (eg, 
by phone) before the next study site visit.
Participants who discontinue study treatment early will continue to be monitored in the study 
and should be encouraged to continue to complete the PRO measures as outlined in the SoA.
Leicester Cough Questionnaire
9.2.2.1
Participants will be asked to complete the 19-item LCQ to assess the impact of their cough 
severity on physical, social and psychological functioning. 
Participants will complete the LCQ at the study site visits outlined in the SoA.
Cough Severity Diary
9.2.2.2
Participants will be asked to record their cough frequency, intensity, and disruption due to 
cough 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.
Participants will complete the CSD, daily, at the same time every evening on Screening visit 
and during treatment period (beginning in the evening on the day of Visit 1 until the evening 
on the day of Visit 4). 
Cough Severity Visual Analog Scale
9.2.2.3
Participants will be asked to rate the severity of their cough over the past 24 hours using a 
100 mm Cough Severity VAS single-item questionnaire with the response ranging from 0 
(“No Cough”) to 100 (“Extremely Severe Cough”).
Participants will complete the Cough Severity VAS at the study site visit at Screening, 
Baseline and Visit 4.
In order to confirm participant eligibility, study site staff will be required to review/confirm 
the:

Participant met the Screening Cough Severity VAS criteria from the measurement 
done at Visit 1.

Participant met the Baseline Cough Severity VAS criteria from the measurement 
done at Visit 2
A score of ≥40 mm on the Cough Severity VAS, at both the Screening and Baseline visits is 
required for randomization into the study.
 
 
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Adverse Events (AE), Serious Adverse Events (SAE) and Other Reportable 
9.3
Safety 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 or surrogate). 
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.
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 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 higher than the amount of study treatment taken 
outside the treatment assignment (Section 5.5.1 – Starting Dose for This Trial)
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 (refer to IB Edition 16, 2017). Overdose should be treated according to the 
participant’s clinical signs and symptoms.
Decisions regarding dose interruptions 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. The total amount of blood to be drawn over the course of the study, 
including approximate blood/ volumes drawn can be found in Section 9.
Planned time points for all safety assessments are provided in the SoA.
Chest Radiography/Computed Tomography Thorax Scan
9.5.1
A chest radiograph or computer tomography scan of the thorax should be performed locally 
for participants, at Screening, if this has not been done within the last 5 years and after the
onset of chronic cough. The chest radiograph or computer tomography scan of the thorax 
should not demonstrate any abnormality considered to be significantly contributing to the 
chronic cough or any other clinically significant lung disease in the opinion of the principal 
investigator (or sub-investigator, see inclusion criterion 1, Section 6.1 – Inclusion Criteria).
Physical Examinations
9.5.2
A complete physical examination will include assessments of the following general 
appearance; skin and lymphatic; eyes, ears, nose, throat; cardiovascular system; respiratory 
system; abdomen/gastrointestinal system; urological system; musculoskeletal and 
neurological systems. Other body systems may be examined.
Clinically significant changes after Screening will be recorded as AEs.
A brief directed physical examination may be performed at any study site visit that does not 
already include a physical exam if deemed necessary by the investigator due to 
signs/symptoms. A physical exam (complete or directed) can be performed at any 
unscheduled visit if deemed necessary by the investigator.
Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
 
 
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Vital Signs and Weight and Height Measurements
9.5.3
Vital sign measurements, including systolic blood pressure (mm Hg), diastolic blood 
pressure (mm Hg), heart rate (beats per minute), respiratory rate (breaths per minute), and 
oral or tympanic body temperature (in centigrade) will be collected as outlined in the SoA. 
All blood pressure measurements should be performed on the same arm, preferably by the 
same person.
Height (cm) and weight (kg) will also be collected as per the SoA 
Any clinically significant abnormalities in vital signs and changes in weight noted after Visit 
1 will be recorded as AEs in the eCRF.
Electrocardiograms
9.5.4
A 12-lead ECG will be performed at Screening and Visit 5 or Discontinuation Visit using 
local standard procedures. Any clinically significant abnormal findings after Visit 1 should 
be recorded in the AE eCRF. 
Spirometry 
9.5.5
A spirometry assessment will be performed locally at Screening using a calibrated spirometer. 
Assessments will include FEV1, FVC and FEV1/FVC ratio.
Spirometry performed within the past year of Screening is acceptable if the investigator 
confirms that spirometry was done during a period where the participant was clinically stable 
(eg, not during an upper respiratory infection)
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 laboratory manual and the SoA.

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).
 
 
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
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. 
Renal and Urological Safety Procedures
9.5.7
Additional safety assessments will be performed in all participants in order to monitor renal 
and urological safety. Urinalysis (including microscopy) will be collected as outline in the 
SoA. Participants will be monitored for hematuria using urinary dipstick (performed at the 
study site). In addition, participants will simultaneously be evaluated further for urinary 
crystals.
Participants who have either crystals or unexplained hematuria will be further evaluated.
Hematuria detected in the context of menstrual bleeding or urinary tract infection, for 
example, would not be considered “unexplained”, and would not warrant an evaluation. The 
decision regarding continuing treatment with MK-7264 and/or continued participation in the 
study will be made on a case by case basis in consultation with Sponsor.
Pharmacokinetics
9.6
The date and time for the last dose of study treatment taken prior to the study visit on which 
the PK sample was collected should be recorded in the eCRF. In addition, the date and time 
of the PK sample collection should also be recorded in the eCRF.
Blood Collection for Plasma MK-7264
9.6.1
Blood samples will be collected at several visits during the study for determination of 
MK-7264 as outlined in the SoA. Samples will be collected pre-dose at the specified study 
site visits. At Visit 4 (Day 28), the morning dose of study treatment will be taken after the PK 
sample is collected. The last dose of study treatment will be administered at the evening of 
Visit 4 (Day 28).
MK-7264 plasma concentrations will be determined using a validated LC-MS/MS assay.
Sample collection, storage and shipment instructions for plasma samples will be provided in 
the operations/laboratory manual for the study.
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:

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.
The blood for genetic analysis sample should be collected only once per randomized 
participant, at pre-dose.
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:
Leftover 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.
Screening
9.10.1
Potential participants will be evaluated at Screening to determine if they fulfill the entry 
requirements as set forth in Section 6.1 – Inclusion Criteria and Section 6.2 – Exclusion 
Criteria. If any participant fails to meet the study entry criteria, screening procedures may be 
repeated within 7 to 45 days or based on investigator judgment after initial screening, and
after consultation with the Sponsor. However, participants will not be permitted to rescreen if 
inclusion criteria for the Cough Severity VAS was not met at Visit 1.
Baseline
9.10.2
The Baseline visit must be scheduled between 7 days and 14 days after Screening.
Cough assessments will begin at Visit 2. The cough monitor should be attached before 
approximately 11 AM and worn for 24 hours.
Treatment Period
9.10.3
Participants will be required to be seen in the clinic at Visit 3 to have the cough monitor 
removed that was attached at Visit 2. Blood for PK assessments will also be collected during 
Visit3. Additionally, at Visits 4, participants should return to the clinic to have the cough 
monitor attached. Cough monitors will be removed at study site at Visits 5. Refer to the 
vendor’s site manual for additional details. Patient-reported outcome measures will be 
completed as outlined in the SoA.
 
 
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Discontinued Participants Continuing to be Monitored in the Study
9.10.4
If a participant is discontinued from the study treatment early, all applicable activities 
scheduled for the Discontinuation Visit should be performed (at the time of discontinuation 
of study treatment).
It is intended that all participants should be followed through completion of the study, 
regardless of premature discontinuation of treatment, unless the participant withdraws 
consent. Thus, participants who discontinue from study treatment prior to completion of the 
study should continue to be monitored to obtain relevant information through the end of the 
study. Clinic visits/phone calls should be made at timepoints that correspond to each 
remaining study visit. Such contacts will allow collection of follow-up information, limited 
to AEs, concomitant medication use, objective cough counting and PROs assessments as 
outlined in the SoA (Section 2).
Concomitant therapies specifically prohibited (see Section 7.7 – Concomitant Therapy) while 
the patient was on study treatment are no longer prohibited after discontinuation of study 
treatment.
For these participants who have discontinued study treatment early, sites will be instructed to 
exert diligent efforts to continue to contact them. To enable sites to reach participants, the 
participants should provide primary and secondary contact information (eg, home phone, 
work phone, mobile phone). Sites must document the outcome of the telephone contact(s), to 
demonstrate diligent efforts have been made. If a participant does not agree to be 
contacted for follow-up for each of the remaining visits (as described in 
Section 8.1 -Discontinuation of Study Treatment), the participant should be encouraged to 
accept a telephone contact at least at the date of Visit 5.
Additionally, the ICF will explain the importance of continued data collection from 
participants, including the use of continued contact by phone.
Post-Study
9.10.5
All participants will be required to clinic approximately 14 days (+ 3 days) after the last dose 
of study treatment for the post-study visit to determine if any AEs have occurred since 
discontinuing 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 SAP (sSAP) and referenced in the Clinical Study Report 
(CSR) for the study.  Post-hoc exploratory analyses will be clearly identified in the CSR.
 
 
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Statistical Analysis Plan Summary
10.1
Key elements of the SAP are summarized below. The comprehensive plan is provided in 
Sections 10.2-10.12. This is an estimation/exploratory study, no hypothesis testing will be 
performed (and therefore no multiplicity adjustments will be made).
Study Design Overview
Phase II study, Parallel, randomized, double-blind, placebo-
controlled, 4-week clinical study, to evaluate the efficacy and 
safety of MK-7264 in adult Japanese participants with 
unexplained or refractory chronic cough
Treatment Assignment
Participants will be randomized in a 1:1 ratio to either MK-7264 
45 mg BID or placebo treatment group, stratified by gender.
Analysis Populations
Efficacy: Full Analysis Set (FAS) population.  
Safety: All Participants as Treated (APaT) population
Primary Endpoint

Number of participants experiencing adverse events (AEs)

Number of participants discontinuing study treatment due 
to AEs
Statistical Methods for 
Key Efficacy Analyses
The primary analysis will be based on the FAS population. The 
primary analysis approach will be conducted utilizing the 
analysis of covariance (ANCOVA) model. In this model, the 
response vector consists of the change from baseline in (natural) 
log-transformed 24-hour coughs per hour at post-baseline. The 
model will include factors for treatment, gender, and the log-
transformed baseline value as a covariate. The model will use 
all available 24-hour coughs per hour data at baseline and on 
Week 4. The least-squares (LS) mean change from baseline (in 
log scale) with the associated standard errors (SEs) will be 
displayed for each treatment group. Estimated treatment 
differences (MK-7264 − placebo) along with corresponding 
95% confidence intervals (CIs) (no multiplicity adjustment) will 
also be presented for MK-7264 45 mg BID treatment group.
The percent difference change between MK-7264 and placebo 
will be estimated by 100*(ediff - 1), where diff is the difference 
provided by the analysis of the log transformed variable.
Statistical Methods for 
Key Safety Analyses
AEs will be summarized by the number and percentage of the 
subjects who experienced respective events. Taste-related AEs 
and Oral paraesthesia/hypoesthesia will be evaluated 95% CIs 
within treatment group. Change from baseline in laboratory 
tests, vital signs and ECG will be summarized by descriptive 
statistics.
Interim Analyses
No interim analysis is planned in this trial.
Multiplicity
No multiplicity adjustment is planned in this Phase II trial.
 
 
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Sample Size and Power The planned sample size is 20 participants. Assuming 5% 
dropout rate, this will provide approximately 9 evaluable 
participants per treatment group.
With 9 evaluable participants per treatment group, the precision 
of the point estimate in terms of half-width of the 95% 
confidence interval (CI) is summarized for a range of relative 
reduction and common standard deviations (SDs) of difference 
in 24-hr coughs per hour between MK-7264 45 mg BID and 
placebo groups in section 10.9.
Responsibility for Analyses/In-House Blinding
10.2
The statistical analysis of the data obtained from this study will be the responsibility 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.
The Clinical Biostatistics department will generate the randomized allocation schedule(s) for 
study treatment assignment.
Hypotheses/Estimation
10.3
There is no hypotheses for this study.
Analysis Endpoints
10.4
Efficacy and safety endpoints that will be evaluated for are presented in Section 4 followed 
by the descriptions of the derivations of selected endpoints.
Efficacy Endpoints
10.4.1
Secondary Efficacy Endpoint

24-hour coughs per hour at Week 4.

Awake coughs per hour at Week 4
Exploratory Efficacy Endpoints

LCQ total score at Week 4

Mean weekly CSD total score at Week 4

Cough Severity VAS score at Week 4
 
 
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Safety Endpoints
10.4.2
Safety endpoints are stated in Section 4.
Derivations of Efficacy Endpoints
10.4.3
Baseline for efficacy variable is defined as the last non-missing value prior to the first study 
treatment.
Data Handling Rules for Cough Data
In general, each 24-hour session starts with awake status and is composed of an awake 
monitoring period and a sleep monitoring period. If a participant did not have a sleep time 
available before the end of the recording session, it will be considered that the participant
was awake during the entire the session. The last monitoring period of a session will be 
censored after the end time of the session.
The cough data will contain all cough events occurring during that 24-hour monitoring 
period as well as the information about “sleep time” and “awake time”.  Any session with 
duration of recording <20 hours will be considered as missing. If a session has duration less 
than 24 hours but no less than 20 hours, the 24-hour coughs per hour will be based on the 
actual duration of the session.
On each collection day, the cough counts, the actual cough monitoring duration (in hours), 
and the coughs per hour will be derived for the total 24-hour period, the awake period, and 
the sleep period, respectively.
24-hour Coughs Per Hour
The 24-hour coughs per hour at baseline and post-baseline visit are calculated as follows:
24-hour coughs per hour = (Total number of cough events during the monitoring period (24-
hour interval))/24 (where the denominator may be different, as noted above, if the recording 
period is actually <24 hours but ≥20 hours).
As the change from baseline in 24-hour coughs per hour may have a skewed and wide 
distribution, the data will be (natural) log-transformed prior to analysis for the primary 
approach. The variable of change from baseline in log-transformed 24-hour coughs per hour 
will be used in the analysis of this endpoint. For post-baseline, the efficacy variable of 
analysis is defined as following:
Change from baseline in log-transformed 24-hour coughs per hour
= Log (24-hour coughs per hour at post-baseline) – Log (24-hour coughs per hour at 
baseline).
The primary analysis of this endpoint will be on the natural log scale of the cough rate data.
 
 
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Awake Coughs Per Hour
Awake is time between waking up and sleep during the 24-hour monitoring period. The 
awake coughs per hour are defined as follows:
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.
Similar to the 24-hour coughs per hour variable, change from baseline in (natural) log-
transformed awake coughs per hour will be used in the analysis and defined as below:
Change from baseline in log-transformed awake coughs per hour
= Log (Awake coughs per hour at post-baseline) – Log (Awake coughs per hour at baseline).
PRO Endpoints

LCQ total score
Change from baseline in LCQ total score = LCQ total score at post-baseline – LCQ total 
score at baseline.

Mean weekly CSD total score
Change from baseline in mean weekly CSD total score = mean weekly CSD total score at 
each post-baseline week – mean weekly CSD total score at baseline.

Cough Severity VAS score
Change from baseline in Cough Severity VAS score = Cough Severity VAS score at post-
baseline – Cough Severity VAS score at baseline.
Analysis Populations
10.5
Efficacy Analysis Population
10.5.1
The FAS population will serve as the primary population for the analysis of efficacy data in 
this study. The FAS population consists of all randomized participants who have taken at 
least one dose of study medication and provided at least one baseline and one post-baseline 
endpoint observations during the treatment period. Participants will be analyzed according to 
the treatment group to which they are randomized. 
Participants will be included in the treatment group to which they are randomized for the 
analysis of efficacy data using the FAS populations.  Details on the approach to handling 
missing data are provided in Section 10.6 Statistical Methods.
Safety Analysis Population
10.5.2
The 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. 
For most participants this will be the treatment group to which they are randomized. 
 
 
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Participants who take incorrect study treatment for the entire treatment period will be 
included in the treatment group corresponding to the study treatment actually received.
At least one laboratory or vital sign measurement obtained subsequent to at least one dose of 
study treatment is required for inclusion in the analysis of each specific parameter. To assess 
change from baseline, a baseline measurement is also required.
Pharmacokinetic Analysis Population
10.5.3
The evaluable PK population for PK data analysis is defined as all participants with one 
measurable PK sample.
Statistical Methods
10.6
Statistical testing and inference for efficacy and safety analyses are described in Sections 
10.6.1 and 10.6.2.
Statistical Methods for Efficacy Analyses
10.6.1
The analysis of efficacy endpoints will be based on the FAS population.
Secondary Efficacy Analysis
Cough monitoring is conducted for baseline and 24 hours after administration of the study 
treatment on Week 4. As the change from baseline in 24-hour coughs per hour may have a 
skewed and wide distribution, the data will be (natural) log-transformed prior to analysis for 
the primary approach.
The primary analysis will be based on the FAS population. The primary analysis approach 
will be conducted utilizing the ANCOVA model. In this model, the response vector consists 
of the change from baseline in log-transformed 24-hour coughs per hour at post-baseline. The 
model will include factors for treatment, gender, and the log-transformed baseline value as a 
covariate. The model will use all available 24-hour coughs per hour data at baseline and on
Week 4. The least-squares (LS) mean change from baseline (in log scale) with the associated 
standard errors (SEs) will be displayed for each treatment group.  Estimated treatment 
differences (MK-7264 − placebo) along with corresponding 95% CIs (no multiplicity
adjustment) will also be presented for MK-7264 45 mg BID treatment group. 
In addition, the geometric mean of the 24-hour coughs per hour will be presented by 
treatment and by visit.  The percent difference in the change from baseline between MK-
7264 and placebo will be estimated by 100*(ediff − 1), where diff is the difference provided 
by the analysis of the log-transformed variable.
An observation of zero coughs per hour will be replaced by a cough rate of 0.1/hour for the 
calculation of geometric means. If this rule is used, the table will have a footnote detailing 
the participant(s) and treatment group(s) that had observations of zero coughs per hour.
Awake coughs per hour will be analyzed using the same ANCOVA model as used for the 24-
hour coughs per hour primary analysis. 
As the change in awake coughs per hour may have a skewed and wide distribution, the data 
will be log-transformed (natural log) prior to analysis. The variable of change from baseline 
in log-transformed awake coughs per hour will be used in the analysis.
 
 
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Table 4 summarizes key analysis strategy of the secondary efficacy endpoints.
Table 4
Analysis Strategy for Secondary Efficacy Endpoints
Endpoint/Variable
(At Week 4)
Approach
Statistical 
Method
Analysis 
Population
Missing Data 
Approach
Secondary
24-hour coughs per hour
P
ANCOVA
FAS
Observed 
data only
Awake coughs per hour
P
ANCOVA
FAS
Observed 
data only
ANCOVA = Analysis of covariance; FAS = Full Analysis set.; P = Primary
Handling of Missing Data
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 electrocardiogram (ECG) measurements.
All safety analyses will be based on APaT population. 
AEs and other safety events will be summarized using the number and percentage of the
subjects who experienced respective events.
Taste-related AEs (including dysgeusia, ageusia, and hypogeusia, as well as other related 
terms) and Oral paraesthesia/hypoesthesia are considered as interested AEs, which will be 
evaluated via point estimates and 95% CIs using the exact binomial method proposed by 
Clopper and Pearson (1934) since there are small number of participants. Any AE, Any 
Serious AE, Any Drug-Related AE, Any Serious and Drug-Related AE and predefined limits 
of change will be also evaluated via point estimates and 95% CIs.
Continuous measures such as changes from baseline in laboratory, vital signs, and ECG 
parameters will be summarized using descriptive statistics.
Summary statistics for baseline, on treatment, and change from baseline values will be 
provided by treatment group in table format.
Table 5 summarizes analysis strategy for safety parameters.
 
 
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Table 5
Analysis Strategy for Safety Parameters
Safety Endpoint†
95% CI within 
Treatment group
Descriptive 
Statistics
Taste-related AE
X
X
Oral paraesthesia/hypoesthesia 
X
X
Any AE
X
X
Any Serious AE
X
X
Any Drug-Related AE
X
X
Any Serious and Drug-Related AE
X
X
PDLCs
X
X
Discontinuation due to AE
X
Specific AEs by preferred term
X
SOCs
X
Change from baseline results (Labs, ECGs, 
Vital Signs)
X
†
Adverse Experience references refer to both Clinical and Laboratory adverse events.
AE = adverse event; ECG = electrocardiogram; SOC=System Organ Class; PDLC=Pre-Defined Limit of 
Change; X = results will be provided.
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, weight, and height), 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.
Interim Analyses
10.7
No interim analysis is planned in this trial.
Multiplicity
10.8
No multiplicity adjustment is planned in this Phase II trial.
Sample Size and Power Calculations
10.9
A total of 20 participants (10 per treatment group) will be randomized in a 1:1 ratio to either 
MK-7264 45 mg BID or placebo. Assuming 5% dropout rate, this will provide approximately 
9 evaluable participants per treatment group.
 
 
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With 9 evaluable participants per treatment group, the precision of the point estimate in terms 
of half-width of the 95% confidence interval (CI) is summarized for a range of relative 
reduction and common standard deviations (SDs) of difference in 24-hr coughs per hour 
between MK-7264 45 mg BID and placebo groups in Table 6. Assumption is based on 
Protocol 012 data.
Table 6
Half-width of the 95% CI for Different Common Standard Deviations (SDs)
Expected 
Common SD
(Log scale)
Expected Relative Reduction
(MK-7264 45 mg BID vs. Placebo)
30%
25%
0.7
53%
57%
0.8
62%
67%
0.9
72%
77%
Subgroup Analyses
10.10
Analysis for 24-hour coughs per hour will be provided for the following subgroups of 
baseline factors:

Gender (Male, Female);

Age group (<60 years, ≥60 years);

Duration of cough (in years) (<10 years, ≥10 years);

Baseline Cough Severity VAS (<60 mm, ≥60 mm);

Baseline 24-hour coughs per hour (<20 coughs/hr, ≥20 coughs/hr).
For each subgroup, summary statistics including mean, SD will be provided for each 
treatment group.
Compliance (Medication Adherence)
10.11
For each participant, percent compliance will be calculated using the following formula:
%
100
Therapy
on 
Be
Should
  
Days
of
Number 
Therapy
on 
Days
of
Number 
Compliance
Percent 


A day within the study will be considered an “On-Therapy” day if the participant takes all 
required medication as instructed in Section 9 – Study Assessments and Procedures. When a 
participant takes less than or more than the required medication on a day, that day is not 
considered an On-Therapy day.
For participants who are followed for the entire study period, the “Number of Days Should 
be on Therapy” is the total number of days from the first scheduled treatment day to the last 
scheduled treatment day. For participants who discontinue from the study permanently, the 
“Number of Days Should Be on Therapy” is the total number of days from the first scheduled 
treatment day to the last dose day.
 
 
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Summary statistics will be provided on percent compliance by treatment group 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 medication will be summarized using descriptive statistics 
(mean, SD, median, minimum, and maximum) for the APaT population.
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. 2014]
Chung KF. Approach to chronic cough: the neuropathic 
basis for cough hypersensitivity syndrome. J Thorac 
Dis. 2014 Oct;6(Suppl 7):S699-707.
04R3SD
[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
[Dworkin, R. H., et al 
2009]
Dworkin RH, Turk DC, McDermott MP, Peirce-
Sandner S, Burke LB, Cowan P, et al. Interpreting the 
clinical importance of group differences in chronic pain 
clinical trials: IMMPACT recommendations. Pain. 
2009 Dec;146(3):238-44.
03Z3YR
[Gibson, P., et al 2016]
Gibson P, Wang G, McGarvey L, Vertigan AE, Altman 
KW, Birring SS. Treatment of Unexplained Chronic 
Cough: CHEST Guideline and Expert Panel Report. 
Chest. 2016 Jan;149(1):27-44.
04MMZ9
[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
[Kanemitsu, Y., et al 
2016]
Kanemitsu Y, Niimi A, Matsumoto H, Iwata T, Ito I, 
Oguma T, et al. Gastroesophageal dysmotility is 
associated with the impairment of cough-specific 
quality of life in patients with cough variant asthma. 
Allergol Int. 2016 Jul;65(3):320-6.
04SV2L
 
 
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[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
[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
[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.
 
 
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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 
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.
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.  
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 subject
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.  
 
 
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By signing this protocol, the investigator acknowledges that the statutory obligations under 
FDAAA, the EMA clinical trials directive or other locally mandated registries are that of the 
Sponsor and agrees not to submit any information about this 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 
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. 
 
 
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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. 
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 –
Future Biomedical Research Sample Collection 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 
withdraw consent at any time by contacting the principal investigator for the main study. 
 
 
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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
○
A 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 Table 7 consistently and correctly during the 
protocol-defined time frame in Section 6.1.
 
 
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Table 7
Contraceptive Methods
Highly Effective Contraceptive Methods That Are User Dependent a 
Failure rate of <1% per year when used consistently and correctly.
●
Combined (estrogen- and progestogen- containing ) hormonal contraception 
○
Oral 
●
Progestogen-only hormonal contraception 
○
Oral 
Highly Effective Methods That Have Low User Dependency 
Failure rate of <1% per year when used consistently and correctly.
●
Intrauterine hormone-releasing system (IUS)  
●
Intrauterine device (IUD)
●
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). 
Pregnancy Testing
WOCBP should only be included after a negative highly sensitive urine or serum pregnancy 
test.
Pregnancy testing will be performed 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)?
●
Likely Cause:  Is the AE not reasonably explained by another etiology such as 
underlying disease, other drug(s)/vaccine(s), or other host or environmental 
factors
 
 
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●
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 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 
 
 
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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 
●
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.
 
 
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●
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 8 will be performed

Protocol-specific requirements for inclusion or exclusion of participants are detailed 
in Section 6 – Study Population 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 8
Protocol-Required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet Count 
RBC Indices:
MCV
MCH
%Reticulocytes
WBC count with 
Differential:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
RBC Count
Hemoglobin
Hematocrit
Chemistry
Electrolytes
Sodium
Potassium
Chloride
Bicarbonate
Calcium
Phosphorous
Liver function 
tests
Aspartate Aminotransferase (AST)/ Serum Glutamic-
Oxaloacetic Transaminase (SGOT)
Alanine Aminotransferase (ALT)/ Serum Glutamic-
Pyruvic Transaminase (SGPT)
Alkaline phosphatase
Total bilirubin (and direct bilirubin, if total bilirubin is 
elevated above the upper limit of normal)
Renal function 
parameters
Blood Urea Nitrogen
Creatinine
eGFR calculation
eGFR will be calculated with each serum creatinine 
measurement (using the Japanese Equation for 
Estimating GFR [Japanese Society of Nephrology])
Other
Glucose (nonfasting)
Albumin
Total Protein
 
 
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Laboratory 
Assessments
Parameters
Routine 
Urinalysis
Specific gravity, pH, glucose, protein, blood, ketones, bilirubin, 
urobilinogen, nitrite, leukocyte esterase by dipstick (performed at 
site) 
Microscopic examination (all crystals will be characterized)
Other Screening 
Tests

Serum or urine β human chorionic gonadotropin (β hCG) pregnancy 
test (as needed for women of childbearing potential)
a. Urine pregnancy test will be performed at site in women of 
child-bearing potential. Refer to SoA in Section 2.
Investigators must document their review of each laboratory safety report.
 
 
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Appendix 6: Abbreviations and Trademarks
12.6
Abbreviation
Term
ACCP
American College of Chest Physican
AE
adverse event
ALT (SGPT)
alanine aminotransferase (serum glutamic pyruvic 
transaminase)
ANCOVA
analysis of covariance
APaT
all participants as treated
ATP
adenosine triphosphate
ATS
American Thoracic Society
AST (SGOT)
aspartate aminotransferase (serum glutamic oxaloacetic 
transaminase) 
BID
twice daily
CFR
Code of Federal Regulations
CI
confidence interval
CRF
case report form 
CSD
Cough Severity Diary
CSR
clinical study report
DNA
deoxyribonucleic acid
ECG
electrocardiogram
ECI
event of clinical interest
EMA
European Medicines Agency
ERS
European Respiratory Society
eCRF
electronic case report form
eGFR
estimated glomerular filtration rate
FDAAA
Food and Drug Administration Amendments Act
FEV1
forced expiratory volume in 1 second
FVC
forced vital capacity
GERD
gastroesophageal reflux disease
GCP
Good Clinical Practice(s)
HIV
human immunodeficiency virus
IB
Investigator’s brochure
ICH
International Council on Harmonisation 
IEC
independent ethics committee
 
 
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Abbreviation
Term
IRB
institutional review board
IRT
interactive response technology
LCQ
Leicester Cough Questionnaire
NSAE
non-serious adverse event
PGIC
Patient Global Impression of Change
PK
pharmacokinetic
PRO
patient reported outcome
RBC
red blood cell (count)
RNA
ribonucleic acid
SAE
serious adverse event
SD
standard deviation
SoA
Schedule of Activities
sSAP
supplemental Statistical Analysis Plan
UACS
upper airway cough syndrome
VAS
visual analog scale
WBC
white blood cell (count)
WOCBP
women of child bearing potential
 
 
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