Clinical trial NCT04525885
Conditions: Chronic Cough
Sponsor: Merck Sharp & Dohme LLC
Start date: 2019-05-17; Completion date: 2022-09-15
Enrollment: 161 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objective of this study will be to evaluate the efficacy of gefapixant (MK-7264) in reducing cough frequency as measured over a 24-hour period. It is hypothesized that at least one dose of gefapixant is superior to placebo in reducing coughs per hour (over 24 hours) at Week 24.

Detailed description:
This study will have a main 24-week treatment period and a 28-week extension period of treatment. Participants at selected sites and countries who complete the main and extension study periods may consent to participate in an observational, 3-month, Off-treatment Durability Study Period.

Arms: arm 1: Participants will receive a gefapixant 45 mg tablet BID during the main study period (24 weeks) and also during the extension period (28 weeks). arm 2: Participants will receive a gefapixant 15 mg tablet BID during the main study period (24 weeks) and also during the extension period (28 weeks). arm 3: Participants will receive a matching placebo tablet BID during the 24-week main study period and during the 28-week extension period.
Interventions: intervention 1: Gefapixant 45 mg twice daily (BID) intervention 2: Gefapixant 15 mg BID intervention 3: Placebo intervention 4: Gefapixant 45 mg BID
Intervention descriptions: intervention 1: Gefapixant 45 mg tablet to be administered orally BID intervention 2: Gefapixant 15 mg tablet to be administered orally BID intervention 3: Placebo tablet administered orally BID intervention 4: Gefapixant 45 mg tablet to be administered orally BID

Protocol documents:
Prot_SAP_000.pdf: 
Official Protocol Title: 
NCT number: 
NCT04525885  
Document Date: 
11-JAN-2021
A Phase 3, Randomized, Double-Blind, Placebo-Controlled, 12-Month Study
to Evaluate the Efficacy and Safety of MK-7264 in Adult Participants with 
Chronic Cough (PN030)


PRODUCT: MK-7264 
1
PROTOCOL/AMENDMENT NO.: 030-06
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11-JAN-2021
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., NJ, U.S.A. 
(MSD).
This protocol amendment is applicable only to China.
Protocol Title: A Phase 3, Randomized, Double-Blind, Placebo-Controlled, 12-Month Study 
to Evaluate the Efficacy and Safety of MK-7264 in Adult Participants with Chronic Cough 
(PN030)
Protocol Number: 030-06
Compound Number: MK-7264
Sponsor Name:
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
(hereafter referred to as the Sponsor or MSD)
Legal Registered Address:
One Merck Drive
P.O. Box 100
Whitehouse Station, New Jersey, 08889-0100, U.S.A.
Regulatory Agency Identifying Number(s):
IND
EudraCT
123007
2017-003559-49
Approval Date: 11 January 2021
 
 
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Sponsor Signatory
Typed Name:
Title:
Date
Protocol-specific Sponsor contact information can be found in the Investigator Study
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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DOCUMENT HISTORY
Document
Date of Issue
Overall Rationale
030-06
11-JAN-2021
This amendment is an amendment to P030-05 to remove the specialized urine 
collection for crystal assay as a study procedure, as well as clarify country 
specific study intervention administration after removal of the MK-7264 15 mg 
BID group.
030-05
08-JUL-2020
This amendment applies to the China extension period only and is an amendment 
to P030-03 to remove the MK-7264 15 mg BID group from the China extension 
period. 
030-04
26-APR-2019
The overall rationale for the country-specific amendment is to add a 3-month, 
Off-treatment Durability Study Period to explore the impact of withdrawing MK-
7264 therapy in participants who have been treated for 1 year.
030-03
18-OCT-2018
Amendment was created only for China. The purpose was to add a China 
extension period, in order to extend Chinese enrollment beyond the global study 
period to achieve the locally required sample size. (Note: Editorial changes were 
made to original rationale.)
030-02
18-SEP-2018
 
 
 
Based on the results of a study conducted in participants with severe renal 
impairment and moderate renal impairment, the expected increase in exposure to 
MK-7264 in participants with moderate renal impairment is not anticipated to 
 
 
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Document
Date of Issue
Overall Rationale
lead to an increased risk of clinically relevant adverse events. Therefore, another 
major update included in this amendment is that of the estimated glomerular 
filtration rate (eGFR) criterion for participant exclusion; updated from a cut-off 
of <50 mL/min/1.73 m2 to cut-off of <30 mL/min/1.73 m2. Participants with an 
eGFR of≥30 mL/min/1.73 m2 and <50 mL/min/1.73 m2 at Screening with 
unstable renal function (defined as a ≥50% increase of serum creatinine 
compared to a value obtained at least 6 months prior to the Screening Visit) were 
also excluded. 
Clarifications of certain sections and procedures, as detailed below, were also 
made in the protocol during the creation of this amendment.
030-01
13-DEC-2017
Removal of special characters in inclusion and exclusion criteria to support study 
database. Other clarifications required throughout including the schedule of 
assessments, study population, and formatting.
030-00
16-OCT-2017
Original protocol
 
 
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PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment: 06
Overall Rationale for the Amendments:
Based on preliminary results obtained from three Phase 3 studies with regards to findings of MK-7264 urine crystals, the sponsor has 
determined that it is not necessary to continue testing for MK-7264 urine crystals in ongoing clinical studies of MK-7264. Thus, this 
amendment removes the specialized urine collection for crystal assay as a study procedure.
Summary of Changes Table:
Section # and Name
Description of Change 
Brief Rationale 
Primary reason for this amendment
1.3 Schedule of Activities
Removed the specialized urine collection for 
crystal assay procedure row. 
Specialized urine collection for crystal assay was 
removed from the list of assessments performed during 
the study.
7.1 Discontinuation of Study 
Intervention
Updated text in 3rd bullet (deleted text with 
strikethrough):
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 
intervention (including recommendation to 
discontinue participant from study 
intervention as part of monitoring for 
crystalluria/urolithiasis, see Section 8.3.7).
To remove that participants should be discontinued 
from the study intervention if crystalluria/urolithiasis 
is detected.
 
 
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Section # and Name
Description of Change 
Brief Rationale 
8.1.11 Participant 
Blinding/Unblinding
Deleted last paragraph in section 
(strikethrough):
In the instance of identifying MK-7264
crystals in the urine, the participant will be 
discontinued from the study intervention (see 
Section 8.3.7 for further details). If a 
participant has confirmed MK-7264 crystals, 
it will be known that the participant was 
receiving MK-7264, but not which dose. In 
this circumstance, formal non-emergency 
unblinding should not be performed.
To remove that participants should be discontinued 
from the study intervention if MK-7264 crystalluria is 
detected.
8.3.7 Renal and Urological 
Safety Assessments
Updated last 2 paragraphs in section (new 
text in bold font, deleted text with 
strikethrough): 
If, after randomization, the participant has 
confirmed, unexplained hematuria and/or 
urinary crystals are identified and deemed to 
be clinically significant by the investigator,
the participant should be considered for 
further evaluation. per the central 
laboratory, an additional urine sample will 
need to be collected. One half of the sample 
will be sent to the central laboratory for 
reconfirmation of unexplained hematuria 
and/or urinary crystals. The other half of the 
sample will be collected via a specialized 
filter and shipped to Sponsor or designee and 
assessed for the presence of MK-7264 
To remove procedures/assessments for specialized 
urine crystal analysis.
 
 
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Section # and Name
Description of Change 
Brief Rationale 
urinary crystals via Raman spectroscopy. 
Raman spectroscopy is sensitive to the 
chemical structure of the molecule and MK-
7264 has a unique chemical structure 
compared to common urinary crystals. See 
vendor’ site manual for further procedural 
details.  
If an investigator deems it necessary to 
perform an unscheduled urinalysis at any 
time after randomization, the same 
procedures for collection/preparation of the 
urine sample and evaluation of hematuria 
(as explained or unexplained) described for 
post-randomization protocol-specified visits 
should be performed.
If a participant has confirmed MK-7264 
urinary crystals, the Sponsor will inform the 
investigator and require discontinuation of 
the participant from study intervention with 
the recommendation to follow-up at 
approximately 2-week intervals with 
additional specialized urine analyses 
performed until resolution of the MK-7264 
urinary crystals. Once a participant has 
confirmed MK-7264 crystals, it will be known 
that the participant was receiving MK-7264 
(formal unblinding should not be performed 
[see Section 8.1.11]).
 
 
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Section # and Name
Description of Change 
Brief Rationale 
Additional changes for this amendment:
5.2 Exclusion Criteria
Added note to Item # 20 (new text in bold 
font):
Note: Participants with cough (historic or 
ongoing) attributable to SARS-CoV-2 
(COVID-19) are ineligible to enroll in the 
study.
To clarify that participants with a known history or 
current evidence of SARS-CoV-2 (COVID-19) 
infection are ineligible to enroll in the study.
10.7 – Appendix 7: Country-
specific Requirements
Added the following to the Study Procedures 
section (new text in bold font):
The IRT system will be updated to allow 
dispensing of only one bottle. The IRT 
update only applies to new participants 
randomized. Following the IRT system 
updated, newly randomized participants will 
receive 1 study intervention bottle (ie, MK-
7264 45 mg OR placebo matched to MK 
7264 45 mg) for the duration of their 
participation in the study. All already 
randomized participants will continue to 
receive 2 study intervention bottles as 
described in protocol Section 8.1.9 for the 
duration of their participation in the study.
Considering double blind randomization in two groups 
can be achieved by dispensing only 1 study 
intervention bottle (MK-7264 45 mg OR placebo 
matched to MK 7264 45 mg), the IRT system will be 
updated to allow dispensing of only one bottle.  To 
clarify that participants randomized under P030-03 and 
P030-05 will receive either 1 or 2 bottles of study 
intervention, depending on IRT system update.
 
 
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Table of Contents
DOCUMENT HISTORY ........................................................................................................3
PROTOCOL AMENDMENT SUMMARY OF CHANGES...............................................5
1
PROTOCOL SUMMARY ............................................................................................17
1.1
Synopsis.................................................................................................................17
1.2
Schema ..................................................................................................................22
1.3
Schedule of Activities (SoA)................................................................................23
2
INTRODUCTION..........................................................................................................28
2.1
Study Rationale....................................................................................................29
2.2
Background ..........................................................................................................30
2.2.1
Pharmaceutical and Therapeutic Background .............................................30
2.2.2
Phase 3 Studies in Adults.............................................................................30
2.3
Benefit/Risk Assessment......................................................................................30
3
HYPOTHESIS, OBJECTIVES, AND ENDPOINTS .................................................31
4
STUDY DESIGN............................................................................................................33
4.1
Overall Design......................................................................................................33
4.2
Scientific Rationale for Study Design.................................................................34
4.2.1
Rationale for Endpoints ...............................................................................34
4.2.1.1
Efficacy Endpoints.............................................................................34
4.2.1.2
Safety Endpoints................................................................................36
4.2.1.3
Pharmacokinetic Endpoints ...............................................................37
4.2.1.4
Pharmacodynamic Endpoints.............................................................37
4.2.1.5
Planned Exploratory Biomarker Research.........................................37
4.2.1.5.1
Planned Genetic Analysis ........................................................37
4.2.1.6
Future Biomedical Research..............................................................37
4.2.2
Rationale for the Use of Comparator/Placebo .............................................38
4.3
Justification for Dose...........................................................................................38
4.3.1
Doses for This Study....................................................................................38
4.3.2
Maximum Dose/Exposure for This Study ...................................................38
4.3.3
Rationale for Dose Interval and Study Design ............................................38
4.4
Beginning and End of Study Definition .............................................................38
4.4.1
Clinical Criteria for Early Study Termination .............................................39
5
STUDY POPULATION ................................................................................................39
5.1
Inclusion Criteria.................................................................................................39
5.2
Exclusion Criteria................................................................................................40
5.3
Lifestyle Considerations......................................................................................42
 
 
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5.3.1
Meals and Dietary Restrictions....................................................................42
5.3.2
Caffeine, Alcohol, and Tobacco Restrictions ..............................................42
5.3.3
Activity Restrictions ....................................................................................43
5.4
Screen Failures.....................................................................................................43
5.5
Participant Replacement Strategy......................................................................43
6
STUDY INTERVENTION............................................................................................44
6.1
Study Intervention(s) Administered...................................................................45
6.1.1
Medical Devices...........................................................................................46
6.2
Preparation/Handling/Storage/Accountability .................................................46
6.2.1
Dose Preparation..........................................................................................46
6.2.2
Handling, Storage, and Accountability........................................................46
6.3
Measures to Minimize Bias: Randomization and Blinding..............................47
6.3.1
Intervention Assignment..............................................................................47
6.3.2
Stratification.................................................................................................47
6.3.3
Blinding........................................................................................................47
6.4
Study Intervention Compliance..........................................................................47
6.5
Concomitant Therapy..........................................................................................48
6.5.1
Rescue Medications and Supportive Care ...................................................50
6.6
Dose Modification ................................................................................................50
6.7
Intervention After the End of the Study............................................................50
6.8
Clinical Supplies Disclosure................................................................................50
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL............................................................................................................50
7.1
Discontinuation of Study Intervention...............................................................50
7.2
Participant Withdrawal From the Study...........................................................51
7.3
Lost to Follow-up .................................................................................................52
8
STUDY ASSESSMENTS AND PROCEDURES........................................................52
8.1
Administrative and General Procedures ...........................................................53
8.1.1
Informed Consent.........................................................................................53
8.1.1.1
General Informed Consent.................................................................53
8.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research.............................................................................................53
8.1.2
Inclusion/Exclusion Criteria ........................................................................54
8.1.3
Participant Identification Card.....................................................................54
8.1.4
Medical History ...........................................................................................54
8.1.5
Prior and Concomitant Medications Review...............................................54
8.1.5.1
Prior Medications...............................................................................54
8.1.5.2
Concomitant Medications..................................................................55
 
 
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8.1.6
Participant Comment Card...........................................................................55
8.1.7
Assignment of Screening Number...............................................................55
8.1.8
Assignment of Treatment/Randomization Number.....................................55
8.1.9
Study Intervention Administration ..............................................................55
8.1.9.1
Timing of Dose Administration.........................................................56
8.1.10
Discontinuation and Withdrawal .................................................................56
8.1.10.1
Withdrawal From Future Biomedical Research ................................56
8.1.11
Participant Blinding/Unblinding..................................................................57
8.1.12
Calibration of Equipment.............................................................................58
8.2
Efficacy Assessments ...........................................................................................58
8.2.1
Objective Cough Counts..............................................................................58
8.2.2
Electronic Patient-reported Outcomes .........................................................60
8.2.2.1
Leicester Cough Questionnaire..........................................................61
8.2.2.2
Cough Severity Diary ........................................................................61
8.2.2.3
Cough Severity Visual Analog Scale.................................................62
8.2.2.4
12-item Short Form Survey ...............................................................62
8.2.2.5
Work Productivity and Activity Impairment Questionnaire..............62
8.2.2.6
EuroQoL 5L Dimensions Questionnaire ...........................................63
8.2.2.7
Patient Global Impression of Change Questionnaire.........................63
8.2.2.8
Hull Airway Reflux Questionnaire....................................................63
8.3
Safety Assessments...............................................................................................63
8.3.1
Chest Radiography/Computed Tomography Thorax Scan..........................63
8.3.2
Physical Examinations.................................................................................64
8.3.3
Vital Signs and Weight and Height Measurements .....................................64
8.3.4
Electrocardiograms ......................................................................................64
8.3.5
Spirometry....................................................................................................64
8.3.6
Clinical Safety Laboratory Assessments .....................................................65
8.3.7
Renal and Urological Safety Assessments...................................................65
8.4
Adverse Events (AEs), Serious Adverse Events (SAEs), and Other 
Reportable Safety Events ....................................................................................66
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ..........................................................67
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events......69
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information...69
8.4.4
Regulatory Reporting Requirements for SAE .............................................69
8.4.5
Pregnancy and Exposure During Breastfeeding ..........................................69
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying 
as AEs or SAEs............................................................................................70
 
 
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8.4.7
Events of Clinical Interest (ECIs)................................................................70
8.5
Treatment of Overdose........................................................................................70
8.6
Pharmacokinetics.................................................................................................71
8.6.1
Blood Collection for Plasma MK-7264 .......................................................71
8.7
Pharmacodynamics..............................................................................................71
8.8
Biomarkers ...........................................................................................................71
8.8.1
Planned Genetic Analysis Sample Collection..............................................71
8.9
Future Biomedical Research Sample Collection...............................................72
8.10
Visit Requirements...............................................................................................72
8.10.1
Screening......................................................................................................72
8.10.2
Baseline........................................................................................................72
8.10.3
Main Study Period .......................................................................................73
8.10.4
Extension Study Period................................................................................73
8.10.5
Discontinued Participants Continuing to be Monitored in the Study ..........73
8.10.6
Poststudy......................................................................................................74
9
STATISTICAL ANALYSIS PLAN .............................................................................74
9.1
Statistical Analysis Plan Summary.....................................................................74
9.2
Responsibility for Analyses/In-house Blinding .................................................76
9.3
Hypotheses/Estimation ........................................................................................77
9.4
Analysis Endpoints...............................................................................................77
9.4.1
Efficacy Endpoints.......................................................................................77
9.4.2
Safety Endpoints..........................................................................................78
9.4.3
Derivations of Efficacy Endpoints...............................................................78
9.5
Analysis Populations............................................................................................80
9.5.1
Efficacy Analysis Populations.....................................................................80
9.5.2
Safety Analysis Population..........................................................................81
9.5.3
Pharmacokinetic Analysis Population .........................................................81
9.6
Statistical Methods...............................................................................................81
9.6.1
Statistical Methods for Efficacy Analyses...................................................81
9.6.2
Statistical Methods for Safety Analyses ......................................................83
9.6.3
Summaries of Baseline Characteristics, Demographics, and Other 
Analyses.......................................................................................................85
9.7
Interim Analyses ..................................................................................................85
9.7.1
Interim Efficacy Analysis ............................................................................86
9.7.2
Interim Safety Analyses...............................................................................86
9.8
Multiplicity ...........................................................................................................86
9.9
Sample Size and Power Calculations .................................................................87
9.10
Subgroup Analyses...............................................................................................89
 
 
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9.11
Compliance (Medication Adherence).................................................................90
9.12
Extent of Exposure...............................................................................................90
10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS.....................................................................................................91
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations........91
10.1.1
Code of Conduct for Clinical Trials.............................................................91
10.1.2
Financial Disclosure.....................................................................................93
10.1.3
Data Protection.............................................................................................93
10.1.3.1
Confidentiality of Data ......................................................................94
10.1.3.2
Confidentiality of Participant Records...............................................94
10.1.3.3
Confidentiality of IRB/IEC Information............................................94
10.1.4
Committees Structure...................................................................................94
10.1.4.1
Scientific Advisory Committee..........................................................94
10.1.4.2
Executive Oversight Committee........................................................94
10.1.4.3
External Data Monitoring Committee ...............................................95
10.1.5
Publication Policy........................................................................................95
10.1.6
Compliance with Study Registration and Results Posting Requirements ...95
10.1.7
Compliance with Law, Audit, and Debarmen .............................................96
10.1.8
Data Quality Assurance ...............................................................................96
10.1.9
Source Documents .......................................................................................97
10.1.10
Study and Site Closure.................................................................................97
10.2
Appendix 2: Clinical Laboratory Tests..............................................................98
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting.............................................................100
10.3.1
Definition of AE ........................................................................................100
10.3.2
Definition of SAE ......................................................................................101
10.3.3
Additional Events Reported.......................................................................102
10.3.4
Recording AE and SAE .............................................................................102
10.3.5
Reporting of AE, SAE, and Other Reportable Safety Events to the 
Sponsor ......................................................................................................106
10.4
Appendix 4: Medical Device Incidents: Definition and Procedures for 
Recording, Evaluating, Follow-up, and Reporting.........................................107
10.5
Appendix 5: Contraceptive Guidance and Pregnancy Testing......................108
10.5.1
Definitions..................................................................................................108
10.5.2
Contraception Requirements......................................................................108
10.5.3
Pregnancy Testing......................................................................................109
10.6
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research..........................................................................................110
10.7
Appendix 7: Country-specific Requirements..................................................115
 
 
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10.8
Appendix 8: Abbreviations ...............................................................................118
11
REFERENCES.............................................................................................................120
 
 
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LIST OF TABLES
Table 1
Study Interventions....................................................................................45
Table 2
Examples of Concomitant Treatments Permitted in the Study..................49
Table 3
Reporting Time Periods and Time Frames for Adverse Events and 
Other Reportable Safety Events.................................................................68
Table 4
Analysis Strategy for Primary and Key Secondary Efficacy Endpoints....83
Table 5
Analysis Strategy for Safety Parameters....................................................85
Table 6
Power for the Primary and Key Secondary Efficacy Endpoints................88
Table 7
Minimum Detectable Adverse Event Rate Differences in MK-7264 
Compared to Placebo .................................................................................89
Table 8
Protocol-required Safety Laboratory Assessments....................................99
Table 9
Contraceptive Methods ............................................................................109
 
 
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LIST OF FIGURES
Figure 1
Study Design..............................................................................................22
Figure 2
Cough Monitoring: Attachment Procedure................................................59
Figure 3
Cough Monitoring: Removal Procedure....................................................60
Figure 4
Study Design of China Extension Period.................................................116
Figure 5
China Enrollment Strategy.......................................................................116
 
 
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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A Phase 3, Randomized, Double-Blind, Placebo-Controlled, 12-Month Study 
to Evaluate the Efficacy and Safety of MK-7264 in Adult Participants with Chronic Cough 
(PN030)
Short Title: MK-7264 Phase 3 study in adult participants with chronic cough (PN030)
Acronym: COUGH-2
Hypotheses, Objectives, and Endpoints:
In this study, the objectives/hypotheses and endpoints below will be evaluated in adult 
participants with refractory or unexplained chronic cough as follows:
Primary Objectives
Primary Endpoints
- Objective: To evaluate the efficacy of 
MK-7264 in reducing cough frequency as 
measured over a 24-hour period
Hypothesis (H1): At least 1 MK-7264 dose is 
superior to placebo in reducing coughs per 
hour (over 24 hours) at Week 24
- 24-hour coughs per hour at Week 24
- Objective: To evaluate the safety and 
tolerability of MK-7264
- Number of participants experiencing an AE
- Number of participants discontinuing study 
intervention due to an AE
Secondary Objectives
Secondary Endpoints
- Objective: To evaluate the efficacy of 
MK-7264 in reducing cough frequency as 
measured while awake during a 24-hour 
period
Hypothesis (H2): At least 1 MK-7264 dose is 
superior to placebo in reducing coughs per 
hour (while awake during a 24-hour period) 
at Week 24
- Awake coughs per hour at Week 24
- Objective: To evaluate the ability of 
MK-7264 to provide a clinically significant 
improvement in cough specific quality of life
- Proportion of participants with a ≥1.3 point 
increase from baseline in LCQ total score at 
Week 24
 
 
05P73C
 
 
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PRODUCT: MK-7264 
18
PROTOCOL/AMENDMENT NO.: 030-06
MK-7264-030-06 FINAL PROTOCOL
11-JAN-2021
Hypothesis (H3): At least 1 MK-7264 dose is 
superior to placebo with respect to the 
proportion of participants with a ≥1.3-point 
increase from baseline in Leicester Cough 
Questionnaire (LCQ) total score at Week 24
- Objective: To evaluate the efficacy of 
MK-7264 based on the proportion of 
participants with a clinically significant 
reduction from baseline in 24-hour coughs 
per hour
Hypothesis (H4): At least 1 MK-7264 dose is 
superior to placebo with respect to the 
proportion of participants with a ≥30% 
reduction from baseline in 24-hour coughs 
per hour at Week 24
- Proportion of participants with a ≥30% 
reduction from baseline in 24-hour coughs 
per hour at Week 24
- Objective: To evaluate the efficacy of 
MK-7264 in improving self-rated cough 
severity
- Proportion of participants with a ≥1.3 point 
reduction from baseline in mean weekly 
Cough Severity Diary (CSD) total score at 
Week 24
- Proportion of participants with a ≥2.7 point 
reduction from baseline in mean weekly CSD 
total score at Week 24
- Proportion of participants with a ≥30 mm 
reduction from baseline in Cough Severity 
Visual Analog Scale (VAS) score at Week 24
 
 
05P73C
 
 
05PQGL


PRODUCT: MK-7264 
19
PROTOCOL/AMENDMENT NO.: 030-06
MK-7264-030-06 FINAL PROTOCOL
11-JAN-2021
Overall Design:
Study Phase
Phase 3
Primary Purpose
Treatment
Indication
Treatment of chronic cough
Population
Participants who are at least 18 years of age with refractory 
chronic cough or unexplained chronic cough
Study Type
Interventional
Intervention Model
Parallel
This is a multi-site study.
This study includes a 24-week Main study period, followed 
by a 28-week Extension study period.
Type of Control
Placebo
Study Blinding
Double-blind
Masking
Participant
Investigator
Estimated Duration of Study
The Sponsor estimates that the study will require 
approximately 37 months from the time the first participant 
signs the informed consent until the last participant’s last 
study-related telephone call or visit.
Number of Participants:
Approximately 1290 participants will be enrolled.
 
 
05P73C
 
 
05PQGL


PRODUCT: MK-7264 
20
PROTOCOL/AMENDMENT NO.: 030-06
MK-7264-030-06 FINAL PROTOCOL
11-JAN-2021
Intervention Groups and Duration:
Intervention 
Groups
Intervention 
Group Name
Dose 
Strength
Dose 
Frequency
Route of 
Admin.
Regimen/ Treatment 
Period
Use
MK-7264 45 mg
45 mg
1 tablet 
BID
Oral
Main Study Period: 24 weeks
Extension Study Period: 
28 weeks
Exp
0 mg 
matched to 
MK-7264 
15 mg
1 tablet 
BID
Oral
Main Study Period: 24 weeks
Extension Study Period: 
28 weeks
Pbo
MK-7264 15 mg
15 mg
1 tablet 
BID
Oral
Main Study Period: 24 weeks
Extension Study Period: 
28 weeks
Exp
0 mg 
matched to 
MK-7264 
45 mg
1 tablet 
BID
Oral
Main Study Period: 24 weeks
Extension Study Period: 
28 weeks
Pbo
Placebo
0 mg 
matched to 
MK-7264 
45 mg
1 tablet 
BID
Oral
Main Study Period: 24 weeks
Extension Study Period: 
28 weeks
Pbo
0 mg 
matched to 
MK-7264 
15 mg
Admin = administration; BID = twice daily; Exp = experimental; Pbo = placebo.
Total 
Number
3
Duration of 
Participation
Each participant will participate in the study for approximately 56 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 intervention for approximately 
52 weeks. Each participant will have a safety follow-up telephone call 14 
days after completion, discontinuation or withdrawal of the study 
intervention.
 
 
05P73C
 
 
05PQGL


PRODUCT: MK-7264 
21
PROTOCOL/AMENDMENT NO.: 030-06
MK-7264-030-06 FINAL PROTOCOL
11-JAN-2021
Study Governance Committees:
Steering Committee
No
Executive Oversight Committee
Yes
Data Monitoring Committee
Yes
Clinical Adjudication Committee
No
Scientific Advisory Committee
Yes
Study governance considerations are outlined in Appendix 1.
Study Accepts Healthy Volunteers: No
A list of abbreviations used in this document can be found in Appendix 8.
 
 
05P73C
 
 
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PRODUCT: MK-7264 
22
PROTOCOL/AMENDMENT NO.: 030-06
MK-7264-030-06 FINAL PROTOCOL
11-JAN-2021
1.2
Schema
The study design is depicted in Figure 1.
*Note: Visits 10, 12, and follow-up Visit 14 will be conducted by telephone.
BID = twice daily
Figure 1
Study Design
At study entry, participants will be randomized in a 1:1:1 ratio to 1 of 3 treatment groups: 
MK-7264 45 mg twice daily (BID), MK-7264 15 mg BID, or placebo. Participants will 
remain on their assigned intervention at Randomization throughout the study.
A safety follow-up telephone call will be conducted at a minimum of 14 days (with an 
allowed variance of up to + 7 days) after Visit 13 or after last dose of study intervention (for 
participants who discontinue from intervention). Please refer to details in Section 8.10.6.
 
 
05P73C
 
 
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PRODUCT: MK-7264
23
PROTOCOL/AMENDMENT NO.: 030-06
MK-7264-030-06 FINAL PROTOCOL
11-JAN-2021
1.3
Schedule of Activities (SoA)
Study Period
SCR
BL
Main Study Period
Extension Study Period
FU
Disc
Notes
Visit Number
Visit 1
Visit 
2
Visit 
3
Visit 4
Visit 5
Visit 6
Visit 7
Visit 8
Visit 9
Visit 
10 
(TC)
Visit 
11
Visit 
12 
(TC)
Visit 
13
Visit 
14 
(TC)
V10, 12, and 
Follow-up to be 
conducted by 
telephone
Scheduled Day
Dy
–14 
to 
Dy –
7
Dy
0
Dy
1
Dy 
27
Dy
28
Dy 
55
Dy
56
Dy 
83
Dy 
84
Dy 
111
Dy 
112
Dy 
139
Dy 
140
Dy 
167
Dy 
168
Dy
217
Dy
266
Dy
315
Dy
365
Dy
379
Scheduling 
Window
(Recommended)
NA
NA
NA
NA
±4 
dys
NA
±4 
dys
NA
±4 
dys
NA
±4 
dys
NA
±4 
dys
NA
±4 
dys
±4
dys
±4
dys
±4
dys
±4
dys
+7 
dys
Scheduled 
Week
Wk   
-2 to 
Wk   
-1
Wk
0
Wk
1
Wk
4
Wk
8
Wk
12
Wk
16
Wk
20
Wk
24
Wk
31
Wk
38
Wk
45
Wk
52
Wk
54
Administrative Procedures
Written 
Informed 
Consent
X
See Section 
8.1.1..
Participant 
Identification 
Card
X
Issue/Instruct 
the use of 
Participant 
Comment Card
X
X
X
X
X
X
X
X
See 
Section 8.1.6.
Collect/Review 
Participant 
Comment Card
X
X
X
X
X
X
X
X
X 
(MS/ES)
Informed 
Consent for 
Future 
Biomedical 
Research
X
Inclusion/
Exclusion 
Criteria
X
X
Demographics; 
Medical & 
Medication 
History
X
 
 
05P73C
 
 
05PQGL


PRODUCT: MK-7264
24
PROTOCOL/AMENDMENT NO.: 030-06
MK-7264-030-06 FINAL PROTOCOL
11-JAN-2021
Study Period
SCR
BL
Main Study Period
Extension Study Period
FU
Disc
Notes
Visit Number
Visit 1
Visit 
2
Visit 
3
Visit 4
Visit 5
Visit 6
Visit 7
Visit 8
Visit 9
Visit 
10 
(TC)
Visit 
11
Visit 
12 
(TC)
Visit 
13
Visit 
14 
(TC)
V10, 12, and 
Follow-up to be 
conducted by 
telephone
Scheduled Day
Dy
–14 
to 
Dy –
7
Dy
0
Dy
1
Dy 
27
Dy
28
Dy 
55
Dy
56
Dy 
83
Dy 
84
Dy 
111
Dy 
112
Dy 
139
Dy 
140
Dy 
167
Dy 
168
Dy
217
Dy
266
Dy
315
Dy
365
Dy
379
Scheduling 
Window
(Recommended)
NA
NA
NA
NA
±4 
dys
NA
±4 
dys
NA
±4 
dys
NA
±4 
dys
NA
±4 
dys
NA
±4 
dys
±4
dys
±4
dys
±4
dys
±4
dys
+7 
dys
Scheduled 
Week
Wk   
-2 to 
Wk   
-1
Wk
0
Wk
1
Wk
4
Wk
8
Wk
12
Wk
16
Wk
20
Wk
24
Wk
31
Wk
38
Wk
45
Wk
52
Wk
54
Prior/Con-
comitant 
Medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X 
(MS/ES)
Study 
intervention 
Distribution 
and/or 
Accountability
X
X
X
X
X
X
X
X
X
X 
(MS/ES)
See 
Section 8.1.9.
Contact IRT 
system
X
X
X
X
X
X
X
X
X
X
X 
(MS/ES)
Efficacy Procedures
Attach Cough 
Monitor
X
X
X
X
X
X
X
X (MS)
See 
Section 8.2.1.
Collect Cough 
Monitor
X
X
X
X
X
X
X
X (MS)
See 
Section 8.2.1.
Activate ePROs
X
X
X
X
X
X
X
X
X
X
(MS/ES)
See 
Section 8.2.2.
LCQ
X
X
X
X
X
X
X
X
X
X
(MS/ES)
See Sections 
8.2.2 and 8.2.2.1.
CSD
Daily
X
Daily
X
X
See 
Section 8.2.2.2.
Cough Severity 
VAS
Daily
X
Daily
X
X
See 
Section 8.2.2.3.
SF-12
X
X
X
X (MS)
See
Section 8.2.2.
WPAI
X
X
X
X (MS)
EQ5D-5L
X
X
X
X (MS)
PGIC
X
X
X (MS)
HARQ
X
See 
Section 8.2.2.8.
 
 
05P73C
 
 
05PQGL


PRODUCT: MK-7264
25
PROTOCOL/AMENDMENT NO.: 030-06
MK-7264-030-06 FINAL PROTOCOL
11-JAN-2021
Study Period
SCR
BL
Main Study Period
Extension Study Period
FU
Disc
Notes
Visit Number
Visit 1
Visit 
2
Visit 
3
Visit 4
Visit 5
Visit 6
Visit 7
Visit 8
Visit 9
Visit 
10 
(TC)
Visit 
11
Visit 
12 
(TC)
Visit 
13
Visit 
14 
(TC)
V10, 12, and 
Follow-up to be 
conducted by 
telephone
Scheduled Day
Dy
–14 
to 
Dy –
7
Dy
0
Dy
1
Dy 
27
Dy
28
Dy 
55
Dy
56
Dy 
83
Dy 
84
Dy 
111
Dy 
112
Dy 
139
Dy 
140
Dy 
167
Dy 
168
Dy
217
Dy
266
Dy
315
Dy
365
Dy
379
Scheduling 
Window
(Recommended)
NA
NA
NA
NA
±4 
dys
NA
±4 
dys
NA
±4 
dys
NA
±4 
dys
NA
±4 
dys
NA
±4 
dys
±4
dys
±4
dys
±4
dys
±4
dys
+7 
dys
Scheduled 
Week
Wk   
-2 to 
Wk   
-1
Wk
0
Wk
1
Wk
4
Wk
8
Wk
12
Wk
16
Wk
20
Wk
24
Wk
31
Wk
38
Wk
45
Wk
52
Wk
54
Safety Procedures
Chest 
Radiograph or 
CT Thorax
X
Not required if 
done in past 
5 years.
Physical 
Examination
X
X
X
X 
(MS/ES)
Complete 
physical exam 
performed only 
at V1; directed 
physical exam at 
all other 
scheduled visits.
Vital Signs
X
X
X
X
X
X
X
X
X
X
X
X 
(MS/ES)
Height
X
Weight
X
X
X
X
X
X 
(MS/ES)
ECG (12-lead)
X
Spirometry
X
Not required if 
done within past 
1 year and 
during a 
clinically stable 
period.
Hematology and 
Chemistry
X
X
X
X
X 
(MS/ES)
 
 
05P73C
 
 
05PQGL


PRODUCT: MK-7264
26
PROTOCOL/AMENDMENT NO.: 030-06
MK-7264-030-06 FINAL PROTOCOL
11-JAN-2021
Study Period
SCR
BL
Main Study Period
Extension Study Period
FU
Disc
Notes
Visit Number
Visit 1
Visit 
2
Visit 
3
Visit 4
Visit 5
Visit 6
Visit 7
Visit 8
Visit 9
Visit 
10 
(TC)
Visit 
11
Visit 
12 
(TC)
Visit 
13
Visit 
14 
(TC)
V10, 12, and 
Follow-up to be 
conducted by 
telephone
Scheduled Day
Dy
–14 
to 
Dy –
7
Dy
0
Dy
1
Dy 
27
Dy
28
Dy 
55
Dy
56
Dy 
83
Dy 
84
Dy 
111
Dy 
112
Dy 
139
Dy 
140
Dy 
167
Dy 
168
Dy
217
Dy
266
Dy
315
Dy
365
Dy
379
Scheduling 
Window
(Recommended)
NA
NA
NA
NA
±4 
dys
NA
±4 
dys
NA
±4 
dys
NA
±4 
dys
NA
±4 
dys
NA
±4 
dys
±4
dys
±4
dys
±4
dys
±4
dys
+7 
dys
Scheduled 
Week
Wk   
-2 to 
Wk   
-1
Wk
0
Wk
1
Wk
4
Wk
8
Wk
12
Wk
16
Wk
20
Wk
24
Wk
31
Wk
38
Wk
45
Wk
52
Wk
54
Urinalysis 
(w/Micro-
scopy)
X
X
X
X
X 
(MS/ES)
Dipstick 
performed for 
ALL 
participants. 
Samples are also 
collected and 
sent to central 
laboratory for 
ALL 
participants.
See Table 8.
Urine 
Pregnancy Test
X
See Appendix 5
for instructions 
on when 
pregnancy 
testing should be 
performed after 
Visit 1.
Serum 
Pregnancy Test
X
Only if urine 
pregnancy test is 
positive.
Adverse Event 
Monitoring
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X 
(MS/ES)
See Table 3 for 
further details.
 
 
05P73C
 
 
05PQGL


PRODUCT: MK-7264
27
PROTOCOL/AMENDMENT NO.: 030-06
MK-7264-030-06 FINAL PROTOCOL
11-JAN-2021
Study Period
SCR
BL
Main Study Period
Extension Study Period
FU
Disc
Notes
Visit Number
Visit 1
Visit 
2
Visit 
3
Visit 4
Visit 5
Visit 6
Visit 7
Visit 8
Visit 9
Visit 
10 
(TC)
Visit 
11
Visit 
12 
(TC)
Visit 
13
Visit 
14 
(TC)
V10, 12, and 
Follow-up to be 
conducted by 
telephone
Scheduled Day
Dy
–14 
to 
Dy –
7
Dy
0
Dy
1
Dy 
27
Dy
28
Dy 
55
Dy
56
Dy 
83
Dy 
84
Dy 
111
Dy 
112
Dy 
139
Dy 
140
Dy 
167
Dy 
168
Dy
217
Dy
266
Dy
315
Dy
365
Dy
379
Scheduling 
Window
(Recommended)
NA
NA
NA
NA
±4 
dys
NA
±4 
dys
NA
±4 
dys
NA
±4 
dys
NA
±4 
dys
NA
±4 
dys
±4
dys
±4
dys
±4
dys
±4
dys
+7 
dys
Scheduled 
Week
Wk   
-2 to 
Wk   
-1
Wk
0
Wk
1
Wk
4
Wk
8
Wk
12
Wk
16
Wk
20
Wk
24
Wk
31
Wk
38
Wk
45
Wk
52
Wk
54
Pharmacodynamics/Biomarkers
PK Sample 
(blood)
X
X
X
X
X
X
X
X
X
V3: pre-dose and 
2 hours post-
dose. 
V4-V9: pre-dose 
only.
V13: no dosing.
Blood for 
Genetic 
Analysis
X
Collected from 
randomized 
participants only; 
see Sections 8.8 
and 8.9.
AE = adverse event; BL = Baseline; CSD = Cough Severity Diary; CT = computed tomography; Disc = discontinuation; Dy = Day; dys = days; ECG = electrocardiogram; eDiary = electronic diary; 
ePRO = electronic patient-reported outcome; EQ5D-5L = EuroQoL5 Version 5L dimensions questionnaire; ES = Extension study period; ET = end of treatment; FBR = future biomedical research; FU =
follow-up; HARQ = Hull Airway Reflux Questionnaire; LCQ = Leicester Cough Questionnaire; MS = main study period; NA = not applicable; PGIC = Patient Global Impression of Change; PK =
pharmacokinetic; SCR = screening; SF-12 = 12-item Short Form Survey; SOP = standard operating procedure; TC = telephone contact; V = visit; VAS = Visual Analog Scale; Wk = Week; WPAI =
Work Productivity and Activity Impairment
 
 
05P73C
 
 
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PRODUCT: MK-7264 
28
PROTOCOL/AMENDMENT NO.: 030-06
MK-7264-030-06 FINAL PROTOCOL
11-JAN-2021
2
INTRODUCTION
Cough is one of the most common presenting symptoms for patients seeking care from 
primary care specialists, allergists, otolaryngologists, or pulmonologists worldwide. The 
importance of cough as a clinical problem globally has led to multiple societies publishing 
guidelines on the diagnosis and management of cough [Morice, A. H., et al 2004] [Chung, K. 
F., et al 2006] [Morice, A. H., et al 2006] [The committee for The Japanese Respiratory 
Society guidelines 2006] [Kardos, P., et al 2010]. In these clinical guidelines, cough is 
categorized based upon the duration of the cough; within each category 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. A cough 
that has been present longer than 3 weeks is either sub-acute (3 to 8 weeks) or chronic 
(> 8 weeks).
Chronic cough may affect up to approximately 12% of the adult population [Chamberlain, S. 
A., et al 2015]. For approximately two-thirds of these patients, a potential co-morbid 
condition can be identified and the cough effectively managed by optimizing therapy for the 
condition. A minority of patients with a potential 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 5% to 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 (FDA) or European Medicines Agency (EMA) for the 
treatment of chronic cough. Given the prolonged nature, significant morbidity, and 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 responsive, 
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. Adenosine 
triphosphate 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 hyper responsiveness through binding to P2X3 containing receptors and stimulating of 
C-fiber neurons [North, R. A. 2004] [Khakh, B. S. 2006]. Antagonism of P2X3-containing 
 
 
05P73C
 
 
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PRODUCT: MK-7264 
29
PROTOCOL/AMENDMENT NO.: 030-06
MK-7264-030-06 FINAL PROTOCOL
11-JAN-2021
receptors is predicted to normalize sensory neuron 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]. Adenosine triphosphate 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 stimuli that do not normally cause cough, increased cough sensitivity to inhaled stimuli, 
and cough paroxysms. A potential biologic explanation for cough hypersensitivity syndrome 
suggests an associated sensory neuropathy characterized by sensory nerve 
hyper-sensitization. Sensory nerves are susceptible to sensitization by neuroactive mediators 
and altered expression of ion channels which regulate sensory nerve excitability to many 
chemical stimuli. As described above, the action of ATP at sensory neurons may cause hyper
responsiveness 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 antagonism in the treatment of patients with 
refractory or unexplained chronic cough.
MK-7264 Development Program
MK-7264, a P2X3 receptor antagonist, is a clinical agent being developed for the treatment 
of cough.
The current MK-7264 cough development plan consists of two 12-month Phase 3 studies in 
participants with refractory or unexplained chronic cough: 1 study (Protocol 027) with a 
12-week Main study period and a 40-week Extension study period, and a second study 
(Protocol 030) with a 24-week Main study period and a 28-week Extension study period.
2.1
Study Rationale
The purpose of this study is to evaluate the efficacy and safety of MK-7264, an orally 
available P2X3 antagonist, in participants, at least 18 years of age, who have either refractory 
or unexplained chronic cough. 
Current therapies for acute and sub-acute cough (narcotic, non-narcotic, and over-the-counter 
medications) have limited and/or unproven efficacy and an undesirable side effect profile. 
There are currently no approved therapies for chronic cough. 
Previous Phase 2 studies have demonstrated dose-related efficacy and an acceptable safety 
and tolerability profile for MK-7264 in participants with refractory or unexplained chronic 
cough (see MK-7264 Investigator’s Brochure [IB]). This Phase 3 study will evaluate the 
efficacy and safety of MK-7264 in participants with refractory or unexplained chronic cough.
 
 
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2.2
Background
Refer to the IB for detailed nonclinical and clinical background information on MK-7264.
2.2.1
Pharmaceutical and Therapeutic Background
 
 
.
MK-7264 is an oral treatment provided as a film coated tablet. The MK-7264 tablets 
provided for this study contain either MK-7264 45 mg or 15 mg. The placebo tablets 
provided in this study are indistinguishable from the MK-7264 tablets, respectively, in 
appearance. The placebo tablets contain no MK-7264, but contain the same inactive 
excipients as those included in the active tablets.
2.2.2
Phase 3 Studies in Adults
The Sponsor intends to conduct a second Phase 3 study of MK-7264 (Protocol 027) in adult 
participants with refractory or unexplained chronic cough. The design of Protocol 027 will, 
in most aspects, be similar to Protocol 030. The main difference between the 2 studies will be 
the length of the Main study period which will be a total of 12 weeks in Protocol 027 
compared to 24 weeks in Protocol 030.
2.3
Benefit/Risk Assessment
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 AEs were the most frequent reported AEs. The rationale for taste 
disturbance 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 sensory 
nerves. The taste-related AEs are considered mechanism based non serious adverse drug 
reactions and are 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 other sections of the 
protocol 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.
 
 
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Additional details regarding specific benefits and risks for participants participating in this 
clinical study may be found in the accompanying IB and Informed Consent Form (ICF)
documents.
3
HYPOTHESIS, OBJECTIVES, AND ENDPOINTS
In this study, the objectives/hypotheses and endpoints below will be evaluated in adult 
participants with refractory or unexplained chronic cough as follows:
Objectives
Endpoints
Primary
•
Objective: To evaluate the efficacy of 
MK-7264 in reducing cough frequency as 
measured over a 24-hour period
Hypothesis (H1): At least 1 MK-7264
dose is superior to placebo in reducing 
coughs per hour (over 24 hours) at 
Week 24
•
24-hour coughs per hour at Week 24
•
Objective: To evaluate the safety and 
tolerability of MK-7264
•
Number of participants experiencing an 
AE
•
Number of participants discontinuing 
study intervention due to an AE
Secondary
•
Objective: To evaluate the efficacy of 
MK-7264 in reducing cough frequency as 
measured while awake during a 24-hour 
period
Hypothesis (H2): At least 1 MK-7264
dose is superior to placebo in reducing 
coughs per hour (while awake during a 
24-hour period) at Week 24
•
Awake coughs per hour at Week 24
 
 
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Objectives
Endpoints
•
Objective: To evaluate the ability of MK-
7264 to provide a clinically significant 
improvement in cough specific quality of 
life
Hypothesis (H3): At least 1 MK-7264
dose is superior to placebo with respect to 
the proportion of participants with a 
≥1.3-point increase from baseline in 
Leicester Cough Questionnaire (LCQ) 
total score at Week 24
•
Proportion of participants with a 
≥1.3 point increase from baseline in LCQ 
total score at Week 24
•
Objective: To evaluate the efficacy of 
MK-7264 based on the proportion of 
participants with a clinically significant 
reduction from baseline in 24-hour 
coughs per hour
Hypothesis (H4): At least 1 MK-7264
dose is superior to placebo with respect to 
the proportion of participants with a 
≥30% reduction from baseline in 24-hour 
coughs per hour at Week 24
•
Proportion of participants with a ≥30% 
reduction from baseline in 24-hour 
coughs per hour at Week 24
•
Objective: To evaluate the efficacy of 
MK-7264 in improving self-rated cough 
severity
•
Proportion of participants with a 
≥1.3 point reduction from baseline in 
mean weekly Cough Severity Diary 
(CSD) total score at Week 24
•
Proportion of participants with a 
≥2.7 point reduction from baseline in 
mean weekly CSD total score at Week 24
•
Proportion of participants with a ≥30 mm 
reduction from baseline in Cough 
Severity Visual Analog Scale (VAS) 
score at Week 24
 
 
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Objectives
Endpoints
Exploratory
•
Objective: To evaluate the efficacy of 
MK-7264 based on the proportion of 
participants with a clinically significant 
reduction from baseline in cough 
frequency
•
Proportion of participants with ≥50% and 
≥70% reduction from baseline in 24-hour 
coughs per hour
•
Proportion of participants with ≥30%, 
≥50%, and ≥70% reduction from baseline 
in awake coughs per hour
•
Objective: To evaluate the impact of MK-
7264 on generic health-related quality of 
life, work productivity, and global rating 
of change
•
12-Item Short Form Survey (SF-12)
•
Work Productivity and Activity 
Impairment (WPAI) questionnaire
•
EuroQoL Five Dimension Questionnaire 
(EQ5D-5L)
•
Patient Global Impression Change 
(PGIC)
•
Objective: To explore the relationship 
between genetic variation and response to 
the treatment(s) administered, and 
mechanisms of disease. Variation across 
the human genome may be analyzed for 
association with clinical data collected in 
the study
•
Germline genetic variation
4
STUDY DESIGN
4.1
Overall Design
Approximately 1290 participants who meet entry criteria will enter the study. The duration of 
intervention for each participant is as follows:

Screening Period: a minimum of 7 days and up to approximately 14 days (see 
Section 8.10.1)

Baseline: 1 day (including 24 hours of objective measurement of cough) (see 
Section 8.10.2)

Main study period (24-week treatment period after Baseline): 168 days (see 
Section 8.10.3)
 
 
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
Extension study period (28-week treatment period after the Main study period): 
197 days (see Section 8.10.4)

Follow-up period: 14 days (see Section 8.10.6)
During the Main study period, participants may be required to be seen by study site personnel 
for 2 consecutive days (eg, Visit 2 to Visit 3, the day before Visit 4 and Visit 4, the day 
before Visit 5 and Visit 5, the day before Visit 6 and Visit 6, the day before Visit 7 and 
Visit 7, the day before Visit 8 and Visit 8 and the day before Visit 9 and Visit 9) so that the 
cough monitor can be attached and removed (see Section 1.3). Study site staff or mobile 
research nurse services may be utilized (if locally available and approved for use), so 
participants have the opportunity to travel to the study site on 1 day instead of traveling to the 
study site for 2 consecutive days.
Individual participation is expected to be approximately 56 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 SoA in Section 1.3. Details of each procedure 
are provided in Section 8.
This study will use an adaptive design based on pre-specified criteria, using an independent, 
external Data Monitoring Committee (DMC) to monitor safety and efficacy. There will be 
1 planned interim efficacy analysis when approximately 40% of the total randomized 
participants have completed, or discontinued prior to completion of the Main study period. 
The study may be stopped for futility according to the results of the interim analysis.
Results of the interim analysis will be reviewed by the external DMC, which will make 
recommendations to the Executive Oversight Committee (EOC) of the Sponsor to continue, 
modify or stop the study according to the plan described in Section 9.
An initial database lock will occur after all participants have completed, or discontinued prior 
to completion of the Main study period, and a full analysis will be conducted.
The final database lock will be conducted when all participants have completed, or 
discontinued prior to the completion of, the Extension study period. Details of the blinding 
are in Section 9.2.
4.2
Scientific Rationale for Study Design
4.2.1
Rationale for Endpoints
4.2.1.1
Efficacy Endpoints
The primary efficacy endpoint is the 24-hour coughs per hour (ie, average hourly cough 
frequency based on 24-hour sound recordings) at Week 24. Cough counts will be measured 
using a digital recording device (VitaloJAK™, Vitalograph, Buckingham, United Kingdom; 
 
 
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hereafter referred to as cough monitor). Worn similar to a Holter monitor, with microphones 
affixed to the participant’s chest wall and attached to the participant’s clothing, the cough 
monitor 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.
The goal of this study is to demonstrate that MK-7264 is effective in the treatment of 
refractory or unexplained chronic cough, as evidenced by a change (reduction) from baseline 
at Week 24 in 24-hour coughs per hour in MK-7264 relative to placebo. Utilizing 2-hour 
coughs per hour as the primary endpoint is further supported with successful data from 
MK-7264 Protocol 012 (see MK-7264 IB). 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.
The first secondary endpoint of this study is awake coughs per hour at Week 24. As 
described above, the 24-hour period can be divided into periods of awake and asleep. In 
MK-7264 Protocol 012, awake baseline cough rates were numerically higher than 24-hour 
baseline cough rates and significantly higher than sleep cough rates. Based on these data, 
awake time may be a meaningful time period for participants with refractory or unexplained 
chronic cough. Therefore, awake coughs per hour will be evaluated as a secondary endpoint 
in this study.
The impact of chronic cough on health-related quality of life (HRQoL) as assessed by the 
LCQ is included as the second secondary endpoint. The goal is to demonstrate that a greater 
proportion of participants treated with MK-7264 relative to placebo achieve a clinically 
meaningful improvement from baseline in HRQoL defined as a ≥1.3-point increase in the 
LCQ total score at Week 24. The LCQ is a 19-item cough-specific HRQoL questionnaire 
which contains 3 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 2 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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Two additional patient reported outcome (PRO) measures specific to cough, the CSD and 
Cough Severity VAS are included as secondary endpoints to assess cough frequency, 
intensity, disruption due to cough and cough severity. 
The CSD is a 7-item, disease-specific PRO measure 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.
 
 
 
. 
The Cough Severity VAS is a single-item question asking the participant to rate the severity 
of their cough “today” using a 100 mm VAS anchored with “No Cough” at 0 and “Extremely 
Severe Cough” at 100. Similar to the well-established use of VAS scores 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.  
 
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].
4.2.1.2
Safety Endpoints
The safety data for MK-7264 to date has been described in detail in the MK-7264 IB. 
In support of the safety objective to evaluate the safety and tolerability profile of MK-7264, 
the safety and tolerability endpoints will be assessed by clinical evaluation of AEs and 
inspection of other study parameters including vital signs, physical examination, and 
standard laboratory safety tests at timepoints specified in the SoA. Adverse events are graded 
and recorded according to Section 8.4 and Appendix 3.
 
 
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4.2.1.3
Pharmacokinetic Endpoints
The relationship between MK-7264 plasma concentrations and cough frequencies/side 
effects will be explored. Population pharmacokinetic (PK) analyses will be conducted to 
understand the exposure-response relationships between MK-7264 and efficacy and safety 
data.
4.2.1.4
Pharmacodynamic Endpoints
No pharmacodynamic biomarkers that will require modeling are planned for this study.
4.2.1.5
Planned Exploratory Biomarker Research
4.2.1.5.1
Planned Genetic Analysis
Genetic variation may impact a participant’s response to therapy, susceptibility to, severity, 
and progression of disease. Variable response to therapy may be due to genetic determinants 
that impact drug absorption, distribution, metabolism, and excretion; mechanism of action of 
the drug; disease etiology; and/or molecular subtype of the disease being treated. Therefore, 
where local regulations and IRB/IEC allow, a sample will be collected for DNA analysis 
from consenting participants.
DNA samples will be used for research related to the study intervention(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 intervention(s). 
Genetic research may consist of the analysis of 1 or more candidate genes or the analysis of 
genetic markers throughout the genome [or analysis of the entire genome] (as appropriate).
DNA samples will be analyzed for variation across the entire genome. Analyses may be 
conducted if it is hypothesized that this may help further understand the clinical data.
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.
4.2.1.6
Future Biomedical Research
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 substudy are presented in Appendix 6.
 
 
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4.2.2
Rationale for the Use of Comparator/Placebo
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 intervention at any 
time. Given that there is no approved treatment for chronic cough, use of a placebo is 
justified.
4.3
Justification for Dose
4.3.1
Doses for This Study
The dose for this study will be either MK-7264 15 mg BID or MK-7264 45 mg BID as 
determined by the individual allocation per the assigned treatment group (see Section 6). 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. In order to allow patients and prescribers appropriate 
flexibility based upon individual clinical needs, the MK-7264 development program has 
targeted 2 different doses to study in the Phase 3 program.
4.3.2
Maximum Dose/Exposure for This Study
The maximum dose/exposure for this study will be at 45 mg BID. Participants who are 
administered MK-7264 (either 15 mg BID or 45 mg BID) will be exposed to MK-7264 for 
approximately 365 days (see Section 6).
4.3.3
Rationale for Dose Interval and Study Design
In this study, MK-7264 will be orally administered as MK-7264 45 mg BID and 15 mg BID 
based on the safety and PK efficacy results observed to date.
Based on PK studies, MK-7264 is rapidly absorbed with a median time to reach maximum 
plasma concentration of 1.0 to 2.0 hours. In addition, the half-life of MK-7264 is 
approximately 7 to 10 hours and consistent with a BID dosing schedule. 
For this study, 24 weeks duration of intervention for the Main study period was selected 
based on regulatory guidance regarding duration of therapy for symptomatic treatment in 
chronic diseases.
The study includes an extension for a total duration of intervention of up to 1 year, in order to 
provide a more robust assessment of the longer-term safety, tolerability and efficacy of 
MK-7264 in the treatment of refractory or unexplained chronic cough.
4.4
Beginning and End of Study Definition
The overall study begins when the first participant signs the ICF. The overall study ends 
when the last participant completes the last study-related telephone-call or visit, withdraws 
from the study, or is lost to follow-up (ie, the participant is unable to be contacted by the 
investigator).
 
 
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4.4.1
Clinical Criteria for Early Study Termination
Early study termination will be the result of the following specified criterion:
During the interim analysis, based on the interim data, if the futility criteria are met, then the 
study may be stopped for futility.
5
STUDY POPULATION
This study will enroll male and female participants with chronic cough ≥1 year and a 
diagnosis of refractory chronic cough or unexplained chronic cough according to the 
American College of Chest Physician (ACCP) guidelines [Irwin, R. S., et al 2006]. For the 
purposes of this study, refractory chronic cough is defined as participants who have had a 
clinical evaluation that suggested a co-morbid condition that may be associated with chronic
cough (eg, gastroesophageal reflux disease [GERD], asthma, or upper airway cough 
syndrome [UACS]), the participant has received appropriate diagnostic work-up and at least
2 months of therapy, prior to Screening, according to ACCP guidelines, and the participant 
continues to cough despite being on therapy. 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 co-morbid condition that may be 
associated with chronic cough. Participants with refractory chronic cough or unexplained 
chronic cough and who are at least 18 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.
5.1
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
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 (note: sub-investigator must be a physician).
2. Have chronic cough for ≥1 year and a diagnosis of refractory chronic cough or 
unexplained chronic cough as specified in Section 5.
3. Have a score of ≥40 mm on the Cough Severity VAS at both the Screening and Baseline 
visits, as specified in Section 8.2.2.
Demographics
4. Participant is Male or Female at least 18 years of age at the time of informed consent.
 
 
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Female Participants
5. A female participant is eligible to participate if she is not pregnant (Appendix 5), not 
breastfeeding, and at least 1 of the following conditions applies:
a.
Not a woman of childbearing potential (WOCBP) as defined in Appendix 5.
OR
b. A WOCBP who agrees to follow the contraceptive guidance in Appendix 5 from the 
time of signing the informed consent through at least 14 days after the last dose of 
study intervention.
Informed Consent
6. The participant (or legally acceptable representative if applicable) provides written 
informed consent for the study. The participant may also provide consent for future 
biomedical research. However, the participant may participate in the 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 and completion of the Cough Severity VAS, CSD, LCQ, and other 
protocol questionnaires) to the satisfaction of the investigator/qualified designee prior to 
randomization.
5.2
Exclusion Criteria
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.
 
 
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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) <30 mL/min/1.73 m2 at Screening OR eGFR
≥30 mL/min/1.73 m2 and <50 mL/min/1.73 m2 at Screening with unstable renal function 
(defined as a ≥50% increase of serum creatinine compared to a value obtained at least 
6 months prior to 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.
11. Screening systolic blood pressure >160 mm Hg or a diastolic blood pressure >90 mm Hg.
12. History of anaphylaxis or cutaneous adverse drug reaction (with or without systemic 
symptoms) to sulfonamide antibiotics or other sulfonamide-containing drugs.
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 pregnancy test at Visit 1. If the urine test is positive 
or cannot be confirmed as negative, a serum pregnancy test will be required.
Prior/Concomitant Therapy
16. Requiring treatment with a therapy that does not adhere to the guidance parameters 
specified in Section 6.5.
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
 
 
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Diagnostic Assessments
19. Significantly abnormal laboratory tests at Screening (see Sections 8.3.6 and 8.3.7),
including:
a.
alkaline phosphatase, 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 (<2.5 × 103/uL), 
neutrophil count <1500 mm3 (<1.5 × 103/uL), platelet count <100 × 103/mm3
(<100 × 103/uL).
For any of the above listed laboratory assessments, 1 repeat measurement will be allowed 
at the investigator’s discretion, before being considered a screen failure.
Other Exclusions 
20. Has a history or current evidence of any condition, therapy, lab abnormality, or other 
circumstance that may increase the risk associated with study participation or study 
intervention 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.
Note: Participants with cough (historic or ongoing) attributable to SARS-CoV-2 
(COVID-19) are ineligible to enroll in the 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.
5.3
Lifestyle Considerations
5.3.1
Meals and Dietary Restrictions
No restrictions are required.
5.3.2
Caffeine, Alcohol, and Tobacco Restrictions
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. For the purposes of the study, smoking is 
intended to include cigars, e-cigarettes, cigarettes, vapes, etc. Smoking of any kind is not 
permitted during the course of the study.
Based on known metabolism of MK-7264, there are no effects of alcohol and caffeine 
associated with the study intervention. However, participants will refrain from consumption 
of alcohol 24 hours prior to and after all study visits (including the PK sampling visits).
 
 
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On intermediate days, and at all other times, alcohol consumption per day is limited to no 
more than approximately 3 servings of alcoholic beverages or equivalent (1 serving is 
approximately equivalent to: beer [354 mL/12 ounces], wine [118 mL/4 ounces], or distilled 
spirits [29.5 mL/1 ounce]).
5.3.3
Activity Restrictions
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 cough 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 should also avoid allowing the cough monitor, microphone, or chest sensor to 
get 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.
See the VitaloJAK™site manual for further details.
5.4
Screen Failures
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 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 re-screened. 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 AEs or SAEs meeting reporting requirements as outlined in the 
data entry guidelines.
5.5
Participant Replacement Strategy
Participants who discontinue from study intervention or withdraw from the study will not be 
replaced.
 
 
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6
STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to 
the study protocol.
Clinical supplies of MK-7264 and placebo will be packaged to support enrollment and 
replacement participants as required. Clinical supplies will be affixed with a clinical label in 
accordance with regulatory requirements.
 
 
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6.1
Study Intervention(s) Administered
The study interventions to be used in this study are outlined in Table 1.
Table 1
Study Interventions
Arm 
Name
Arm 
Type
Intervention 
Name
Type
Dose 
Formulation
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Admin.
Regimen/
Treatment Period
Use
IMP/
NIMP
Sourcing
MK-7264
Experi-
mental
MK-7264
Drug
Tablet
45 mg
1 tablet 
BID
Oral
Main Study Period: 
24 weeks
Extension Study 
Period: 28 weeks
Experimental
IMP
Central
Placebo
Placebo 
Com-
parator
Placebo matched 
to MK-7264 
45 mg
Other
Tablet
0 mg
1 tablet 
BID
Oral
Main Study Period: 
24 weeks
Extension Study 
Period: 28 weeks
Placebo
IMP
Central
MK-7264
Experi-
mental
MK-7264 
Drug
Tablet
15 mg
1 tablet 
BID
Oral
Main Study Period: 
24 weeks
Extension Study 
Period: 28 weeks
Experimental
IMP
Central
Placebo
Placebo 
Com-
parator
Placebo matched 
to MK-7264 
15 mg
Other
Tablet
0 mg
1 tablet 
BID
Oral
Main Study Period: 
24 weeks
Extension Study 
Period: 28 weeks
Placebo
IMP
Central
Admin. = administration; BID = twice daily; IMP = investigational medicinal product; NIMP = non-investigational medicinal product.
 
 
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All supplies indicated in Table 1 will be provided per the "Sourcing" column depending upon 
local country operational requirements. Every attempt should be made to source these 
supplies from a single lot/batch number. The study site is responsible for recording the lot 
number, manufacturer, and expiry date for any locally purchased product (if applicable) as 
per local guidelines unless otherwise instructed by the Sponsor.
Refer to Section 8.1.9 for details regarding administration of the study intervention.
All placebos were created by the Sponsor to match the active product.
6.1.1
Medical Devices
Not applicable.
6.2
Preparation/Handling/Storage/Accountability
6.2.1
Dose Preparation
There are no specific calculations or evaluations required to be performed in order to 
administer the proper dose to each participant. The rationale for selection of doses to be used 
in this study is provided in Section 4.3. 
6.2.2
Handling, Storage, and Accountability
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received, and any discrepancies are 
reported and resolved before use of the study intervention.
Only participants enrolled in the study may receive study intervention, and only authorized 
site staff may supply or administer study intervention. All study interventions 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 intervention accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records).
For all study sites, the local country Sponsor personnel or designee will provide appropriate 
documentation that must be completed for drug accountability and return, or local discard 
and destruction if appropriate. Where local discard and destruction is appropriate, the 
investigator is responsible for ensuring that a local discard/destruction procedure is 
documented.
The study site is responsible for recording the lot number, manufacturer, and expiry date for 
any locally purchased product (if applicable) as per local guidelines unless otherwise 
instructed by the Sponsor.
 
 
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The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution, and usage of study 
interventions in accordance with the protocol and any applicable laws and regulations.
6.3
Measures to Minimize Bias: Randomization and Blinding
6.3.1
Intervention Assignment
Allocation or randomization to study intervention will occur centrally using an interactive 
response technology (IRT) system. There are 3 study intervention arms. Participants will be 
assigned randomly in a 1:1:1 ratio to MK-7264 45 mg BID, MK-7264 15 mg BID, or placebo. 
Study sites should contact the IRT system for the purposes of enrollment tracking and study 
intervention dispensation as outlined in Section 1.3. Participants will be assigned to 
treatments based on a randomization scheme. The details of the randomization scheme and 
identification for each participant will be included in the clinical study report (CSR). 
Randomization data will be kept strictly confidential, filed securely by an appropriate group 
in Merck or contract research organization, and accessible only to authorized persons per 
standard operating procedures until the time of unblinding.
6.3.2
Stratification
Treatment allocation/randomization will be stratified according to the following factors:

Gender (Male, Female)

Geographical Region (North America, Europe, Asia-Pacific, Others)
6.3.3
Blinding
A double-blinding technique with in-house blinding will be used. MK-7264 and placebo will 
be packaged identically, respectively, during the study. The participant, the investigator, and 
Sponsor personnel or delegate(s) who are involved in the study intervention administration or 
clinical evaluation of the participants are unaware of the group assignments.
Details on the analysis and in-house blinding are provided in Section 9.2.
See Section 8.1.11 for a description of the method of unblinding a participant during the 
study, should such action be warranted.
6.4
Study Intervention Compliance
Records of intervention compliance for each participant will be kept during the study. The 
clinical research associates will review intervention 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.
 
 
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Interruptions from the protocol specified intervention 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.
6.5
Concomitant Therapy
Medications specifically prohibited in the exclusion criteria are not allowed during the 
ongoing study unless stated otherwise in this section. If there is a clinical indication for any 
medication or vaccination specifically prohibited, discontinuation from study intervention 
may be required. The investigator should discuss any questions regarding this with the 
Sponsor Clinical Director. The final decision on any supportive therapy rests with the 
investigator and/or the participant’s primary physician. However, the decision to continue the 
participant on study intervention requires the mutual agreement of the investigator, the 
Sponsor, and the participant.
For participants who receive study intervention, 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 will also be recorded. The investigator(s) will 
record any AE on the AEs CRF for which a concomitant medication/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 the Main and Extension 
study periods. 
Opioids (including codeine) for indications other than chronic cough are 
permitted provided the participant is receiving a stable treatment regimen for at 
least 1 week prior to Screening/Visit 1 and in the opinion of the investigator, is 
likely to remain on the stable treatment regimen through completion of the Main 
and Extension study periods.
2. Pregabalin, gabapentin, amitriptyline, or nortriptyline 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, amitriptyline, or nortriptyline for the treatment of cough from 
Randomization/Visit 3 through completion of the Main and Extension study 
periods.  
Pregabalin, gabapentin, amitriptyline, or nortriptyline for indications other than 
chronic cough are permitted provided the participant is receiving a stable 
 
 
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treatment regimen for at least 2 weeks prior to Screening/Visit 1 and in the 
opinion of the investigator, is likely to remain on the stable treatment regimen
through completion of the Main and Extension study periods.
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. Furthermore, participants 
should not initiate therapy with dextromethorphan, guaifenesin, benzonatate, or 
any over the counter or prescription treatments for cough from 
Randomization/Visit 3 through completion of the Main and Extension study 
periods. Lozenges/drops, teas/drinks, natural/herbal remedies, and other similar 
treatments which do not contain an active antitussive or expectorant are allowed, 
provided they have been used on a regular basis for at least 2 weeks prior to 
Screening/Visit 1. Lozenges/drops, teas/drinks, and natural/herbal remedies 
should not be initiated during the study. The Sponsor needs to be consulted for 
further information.
4. Treatments for conditions associated with chronic cough, such as GERD, asthma, 
UACS (formerly called post-nasal drip), or non-asthmatic eosinophilic bronchitis, 
are permitted provided that participants have been treated for at least 2 months for 
these co-morbid conditions associated with chronic cough and are receiving a 
stable treatment regimen for at least 2 weeks prior to Screening/Visit 1 and in the 
opinion of the investigator, are likely to remain on the stable treatment regimen
through completion of the Main and Extension study periods. 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
Examples 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
UACS (formerly 
post-nasal drip)
Antihistamine/decongestant therapy with a first-generation 
antihistamine
Non-asthmatic 
eosinophilic bronchitis
Inhaled/oral corticosteroids
GERD = gastroesophageal reflux disease; UACS = upper airway cough syndrome
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 the Main and Extension study periods.
 
 
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6. Angiotensin converting enzyme inhibitors are not allowed from 3 months prior to 
Screening/Visit 1 through completion of the Main and Extension study periods.
6.5.1
Rescue Medications and Supportive Care
No rescue or supportive medications are specified to be used in this study.
6.6
Dose Modification
No dose modification is allowed in this study.
6.7
Intervention After the End of the Study
There is no study-specified intervention following the end of the study.
6.8
Clinical Supplies Disclosure
The emergency unblinding call center will use the intervention/randomization schedule for 
the study to unblind participants and to unmask study intervention identity. The emergency 
unblinding call center should only be used in cases of emergency (see Section 8.1.11). In the 
event that the emergency unblinding call center is not available for a given site in this study, 
the central electronic intervention allocation/randomization system (IRT) should be used to 
unblind participants and to unmask study intervention identity. The Sponsor will not provide 
random code/disclosure envelopes or lists with the clinical supplies.
See Section 8.1.11, for a description of the method of unblinding a participant during the 
study, should such action be warranted.
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL
7.1
Discontinuation of Study Intervention
Discontinuation of study intervention does not represent withdrawal from the study.
As certain data on clinical events beyond study intervention 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 intervention. Therefore, all participants 
who discontinue study intervention prior to completion of the protocol-specified treatment 
period will still continue to participate in the study as specified in Sections 1.3 and 8.10.5.
Participants may discontinue study intervention at any time for any reason or be discontinued 
from the study intervention at the discretion of the investigator should any untoward effect 
occur. In addition, a participant may be discontinued from study intervention by the 
investigator or the Sponsor if study intervention is inappropriate, the study plan is violated, or 
for administrative and/or other safety reasons. Specific details regarding procedures to be 
performed at study intervention discontinuation are provided in Section 8.10.5.
 
 
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A participant must be discontinued from study intervention but continue to be monitored in 
the study for any of the following reasons:
•
The participant or participant’s legally acceptable representative requests to discontinue 
study intervention.
•
The participant’s treatment assignment has been unblinded by the investigator, Merck 
Sharp & Dohme Inc. subsidiary, or through the emergency unblinding call center.
•
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 intervention.
•
The participant has a confirmed positive serum pregnancy test.
•
In case of clinically significant and potentially drug-related rash or signs and/or 
symptoms consistent with allergic drug reaction or anaphylaxis to study intervention.
•
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 intervention but continue to be monitored 
in the study, all visits and procedures, as outlined in the SoA, should be completed. Also see
Section 8.10.5.
Discontinuation from study intervention is “permanent.” Once a participant is discontinued, 
he/she shall not be allowed to restart study intervention.
7.2
Participant Withdrawal From the Study
A participant must be withdrawn from the study if the participant or participant’s legally 
acceptable representative withdraws consent from the study.
If a participant withdraws from the study, they will no longer receive study intervention 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 8.1.10. 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 7.3.
 
 
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7.3
Lost to Follow-up
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, telephone 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 
prespecified statistical data handling and analysis guidelines.
8
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 ensuring 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 study-related medical decisions must be made by an investigator who is a qualified 
physician.
•
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), 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.
 
 
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The maximum amount of blood collected from each participant over the duration of the 
study, including any extra assessments that may be required will be approximately 75 mL.
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with 
the samples.
8.1
Administrative and General Procedures
8.1.1
Informed Consent
The investigator or medically qualified designee (consistent with local requirements) must 
obtain documented consent from each potential participant or each participant’s legally 
acceptable representative prior to participating in a clinical study or future biomedical 
research. If there are changes to the participant’s status during the study (eg, health or age of 
majority requirements), the investigator or medically qualified designee must ensure the 
appropriate consent is in place.
8.1.1.1
General Informed Consent
Consent must be documented by the participant’s dated signature or by the participant’s 
legally acceptable representative’s dated signature on a consent form along with the dated 
signature of the person conducting the consent discussion.
A copy of the signed and dated consent form should be given to the participant before 
participation in the study.
The initial ICF, any subsequent revised written ICF, and any written information provided to 
the participant must receive the Institutional Review Board/Independent Ethics Committee’s 
(IRB/IEC’s) approval/favorable opinion in advance of use. The participant or his/her legally 
acceptable representative should be informed in a timely manner if new information becomes 
available that may be relevant to the participant’s willingness to continue participation in the 
study. The communication of this information will be provided and documented via a revised 
consent form or addendum to the original consent form that captures the participant’s dated 
signature or by the participant’s legally acceptable representative’s dated signature.
Specifics about a study and the study population will be added to the consent form template 
at the protocol level.
The informed consent will adhere to IRB/IEC requirements, applicable laws and regulations, 
and Sponsor requirements.
8.1.1.2
Consent and Collection of Specimens for Future Biomedical Research
The investigator or medically 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 substudy. 
A copy of the informed consent will be given to the participant.
 
 
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8.1.2
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator who is a qualified 
physician to ensure that the participant qualifies for the study. Inclusion and exclusion 
criteria for this study are defined in Section 5.1 and Section 5.2, respectively.
For inclusion criterion 2, which states that eligible participants are to have chronic cough for 
≥1 year and a diagnosis of refractory chronic cough of unexplained cough (Section 5.1), a
combination of medical records and/or verbal history from participant/parent/legal guardian 
may be elicited at Screening/Visit 1 and can be used to fulfill this criterion if documented in 
the participant study file by the investigator.
Source documentation for all eligibility criteria needs to be maintained at the site. For 
participants with eGFR ≥30 mL/min/1.73 m2 and <50 mL/min/1.73 m2 at Screening with 
stable renal function (unstable renal function is defined as a ≥50% increase of serum 
creatinine compared to a value obtained at least 6 months prior to the Screening Visit),
documentation of stable serum creatinine must be retained as source documentation at the 
study site.
8.1.3
Participant Identification Card
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 used 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 intervention
allocation/randomization, site personnel will add the intervention/randomization number to 
the participant identification card.
The participant identification card also contains contact information for the emergency 
unblinding call center so that a healthcare provider can obtain information about study 
intervention in emergency situations where the investigator is not available.
8.1.4
Medical History
A medical history will be obtained by the investigator or qualified designee (refer to
electronic case report form (eCRF) entry guidelines).
8.1.5
Prior and Concomitant Medications Review
8.1.5.1
Prior Medications
The investigator or qualified designee will review prior medication use prior to Screening
(see Section 6.5 and refer to eCRF entry guidelines).
 
 
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8.1.5.2
Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the participant 
during the study.
8.1.6
Participant Comment Card
Participants randomized into the study will be provided a separate participant comment card 
to capture any AEs that occur and any concomitant medications used between scheduled 
study site visits. The investigator or study site staff personnel will train the participant on the 
use of the participant comment card prior to dispensing study intervention to the participant 
at Visit 3.The participant comment card should be dispensed and collected/reviewed as 
outlined in Section 1.3. 
Any AE data from the participant comment card will be entered into the eCRF with 
appropriate assessments made by the investigator. Any concomitant therapy data from the 
participant comment card will be entered as appropriate into the eCRF.
8.1.7
Assignment of Screening Number
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 1 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/rescreening visit 
requirements are provided in Section 8.10.1.
8.1.8
Assignment of Treatment/Randomization Number
All eligible participants will be randomly allocated and will receive a 
treatment/randomization number. The treatment/randomization number identifies the 
participant for all procedures occurring after treatment allocation/randomization. Once a 
treatment/randomization number is assigned to a participant, it can never be re-assigned to 
another participant.
A single participant cannot be assigned more than 1 treatment/randomization number.
8.1.9
Study Intervention Administration
The distribution of study intervention will be witnessed by the investigator and/or study staff 
at the study site visits. Since MK-7264 45 mg and 15 mg will differ in appearance and have 
corresponding matching placebos, participants will receive 2 study intervention bottles (ie, 
either MK-7264 45 mg and placebo matched to MK-7264 15 mg OR MK-7264 15 mg and 
placebo matched to MK-7264 45 mg OR placebos matched to MK-7264 45 mg and 15 mg). 
Participants should be instructed to take 1 tablet from each bottle BID.
 
 
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Study intervention should begin on the day of intervention allocation/randomization and will 
be administered at the study site at Visit 3. This first dose of study intervention at Visit 3 
should be administered after the cough monitor is removed, after the pre-dose PK sample 
collection, and before approximately 11 AM. As dosing is BID, the next dose should be 
taken orally in the evening, approximately 12 hours later. 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, on the day of a study site visit, the 
morning dose should not be taken at home and instead will be given as a witnessed dose at 
the study site, after the cough monitor is removed, after the pre-dose PK sample collection, 
and before approximately 11 AM (see Section 8.2.1 for further details). 
On the day before Visits 4, 5, 6, 7, 8, and 9, the morning dose should not be taken at home 
and instead will be given as a witnessed dose at the study site. If the attachment of the cough 
monitor is to be managed by study site staff or a mobile nurse (where locally available and 
approved per regulations), the morning dose will be a witnessed dose with the study site staff 
or mobile nurse, at the participant’s home. The cough monitor should be attached prior to 
dosing and TURNED ON immediately AFTER dosing, before approximately 11 AM (see 
Section 8.2.1 for further details). 
Following the last Main study period visit (ie, Visit 9), participants will continue their 
assigned intervention in the Extension study period. The last dose of study intervention will 
be on the evening prior to Visit 13. Study intervention supplies will be collected at Visit 13
or Discontinuation.
8.1.9.1
Timing of Dose Administration
Study intervention will be administered orally, BID, approximately 12 hours apart for 
approximately 168 days (24 weeks) during the Main study period and then administered 
orally, BID, approximately 12 hours apart for approximately another 28 weeks during the 
Extension study period.
8.1.10
Discontinuation and Withdrawal
Participants who discontinue study intervention prior to completion of the study 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/early withdrawal visit as described in Section 1.3 should be 
performed (at the time of withdrawal). Any AEs that are present at the time of withdrawal 
should be followed in accordance with the safety requirements outlined in Section 8.4.
8.1.10.1
Withdrawal From Future Biomedical Research
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). 
 
 
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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. 
8.1.11
Participant Blinding/Unblinding
STUDY INTERVENTION 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.
For emergency situations where the investigator or medically qualified designee (consistent 
with local requirements) needs to identify the study intervention used by a participant and/or
the dosage administered, he/she will contact the emergency unblinding call center by 
telephone and make a request for emergency unblinding. As requested by the investigator or 
medically qualified designee, 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 intervention
assignment, the investigator who is a qualified physician should make reasonable attempts to 
enter the intensity of the AEs observed, the relation to study intervention, the reason thereof, 
etc., in the medical chart. If it is not possible to record this assessment in the chart prior to the 
unblinding, the unblinding should not be delayed.
In the event that unblinding has occurred, the circumstances around the unblinding (eg, date, 
reason, and person performing the unblinding) must be documented promptly, and the 
Sponsor Clinical Director notified as soon as possible.
Once an emergency unblinding has taken place, the principal investigator, site personnel, and 
Sponsor personnel may be unblinded so that the appropriate follow-up medical care can be 
provided to the participant.
Participants whose treatment assignment has been unblinded by the investigator or medically 
qualified designee and/or nonstudy treating physician must be discontinued from study 
intervention, but should continue to be monitored in the study.
Additionally, the investigator or medically qualified designee must go into the IRT system 
and perform the unblind in the IRT system to update drug disposition. In the event that the 
emergency unblinding call center is not available for a given site in this study, the IRT 
 
 
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system should be used for emergency unblinding in the event that this is required for 
participant safety.
8.1.12
Calibration of Equipment
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.
8.2
Efficacy Assessments
Compliance with the efficacy and safety assessments (along with study intervention 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.
8.2.1
Objective Cough Counts
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 device (Premarket Notification per the US Food, Drug and Cosmetic Act) that has 
been implemented successfully in clinical studies of potential cough therapies, including 
2 Phase 2 studies of MK-7264.
The VitaloJAK™ cough monitor is a digital recording device that uses 2 input channels: 
biometric sensor and air microphone. The first records sounds from the lungs and trachea 
through a chest contact biometric sensor, which is attached to the skin at the top of the 
sternum. The second channel captures ambient sounds through a lapel air microphone. The 
device will be carried in a cloth belt bag worn around the participants’ waist, and all sounds 
the participant makes during cough monitoring will be recorded on the compact flash (CF) 
card. The CF card contains the full, raw, sound recording data that is the output from the 
validated cough monitor and is the source for the recording data. The sound recordings on the 
CF cards are uploaded to the Vitalograph Web Portal for storage and analysis to generate 
cough data per Vitalograph standard operating procedures, and the Web Portal is the source 
for the cough counts data.
Sites will be uploading the CF card recordings to the Vitalograph Web Portal; however, if 
after troubleshooting the sites are unsuccessful, the site will securely ship the CF card to 
Vitalograph for uploading. Long-term storage of the CF cards may be done by Vitalograph 
for those sites unable to provide long-term storage of the cards. 
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 
 
 
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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 for the 24-hour period from the 
annotated audio file. Awake cough counts are tallied only during the time the participant is 
determined to be awake for the awake coughs per hour assessment. 
The cough monitor will be attached to the participant at Visit 2 and the day before for Visit 
4-9 and Discontinuation during the Main study period (see Section 1.3). Attachment should 
occur before approximately 11 AM and the cough monitor should be 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 during the actual visit, at the 
clinic, by site staff the next day. The first dose of study intervention administered is at Visit 3 
after the cough monitor is removed, after the pre-dose PK sample collection, and before 
approximately 11 AM.
Attachment of the cough monitor may be managed by study site staff or mobile nurses if 
available and approved. On the day of a study site visit after Visit 3 (or mobile nurse visit 
where applicable) when the cough monitor will be attached, study intervention dosing should 
occur prior to the cough monitor being turned on. Therefore, the cough monitor should first 
be attached, the participant should then be dosed, and then the cough monitor should 
immediately be turned on (see Figure 2).
V = Visit.
Figure 2
Cough Monitoring: Attachment Procedure
Removal of the cough monitor will occur at the study site and be managed by study site staff. 
On the day of a study site visit when the cough monitor will be removed, the morning dose 
should not be taken at home and instead will be given as a witnessed dose at the study site. 
Therefore, dosing will occur after the cough monitor is removed (once 24-hour recording has 
completed), after the pre-dose PK sample collection, and before approximately 11 AM (see 
Figure 3). 
 
 
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PK = Pharmacokinetic; V = Visit.
Figure 3
Cough Monitoring: Removal Procedure
It is recommended that the monitor first be removed (once the 24-hour recording has 
completed) to avoid any interference. Pre-dose PK should then be collected, prior to study 
intervention dosing.
All visits, where the cough monitor will be attached/removed, should be scheduled prior to 
11 AM to meet the attachment/removal timeframes as well as the PK sample collection(s), 
and study site dosing requirements.  
If cough data is not usable and patient is required to return to the clinic to repeat, it should 
only be repeated upon Sponsor approval.
Participants who discontinue study intervention 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 for the remaining visits (as outlined in the SoA) through the end of the study.
8.2.2
Electronic Patient-reported Outcomes
At Screening (Visit 1), each participant will be properly trained and instructed on the use of 
an electronic diary (eDiary) for completing the ePRO measures. Participants should bring 
their eDiary device for all study visits, and should be contacted and reminded to do so (eg, by 
telephone or text) before each study site visit.
Compliance with daily completion of the eDiaries must be monitored by the investigator or 
designee. Each investigator site will contact individual participants who are non-compliant in 
order to retrain and/or remind them to complete their assessments as per Section 1.3 (SoA).
Participants will be instructed to complete daily ePRO measures (CSD and Cough Severity 
VAS) at approximately the same time in the evening as outlined in the SoA. If a participant 
fails to complete the CSD and/or Cough Severity VAS ePRO measure(s), the eDiary will 
 
 
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allow the participant, based on recall, to complete measures at any time in the next 24 hours
(also see vendor’s site manual for further details). 
Participants will also be asked to complete visit ePRO measures (Hull Airway Reflux 
Questionnaire [HARQ], LCQ, SF-12, EQ5D 5L, WPAI and/or PGIC) on the day of the visits 
as outlined in the SoA (also see vendor’s site manual for further details). If a participant fails 
to complete the HARQ, LCQ, SF-12, EQ5D 5L, WPAI and/or PGIC ePRO measure(s), the 
eDiary will allow the participant, based on recall, to complete these measures at any time in 
the next 48 hours. If these visit ePROs are not completed, based on recall, within the 48 
hours, participants may be asked to complete them at a later date. All Visit 2 ePRO 
measures MUST be activated and completed prior to the first dose of study 
intervention/Randomization (also see vendor’s site manual for further details).
Electronic PRO measures must be activated as outlined in the SoA. Visit 8, Visit 11, Visit 13,
and the Discontinuation Visit ePROs are “activated” by entering actual visit/event dates in 
the vendor portal (Engage). All other visit ePROs are activated at the clinic visit using the 
site menu on the device or remotely using a PIN if the participant forgets to bring the device 
to the clinic visit.
Participants who discontinue study intervention early will continue to be monitored in the 
study and should be encouraged to continue to complete the ePRO measures (along with the 
assessment of 24-hour coughs per hour) for the remaining visits (as outlined in the SoA) 
through the end of the study.
Data collection for all ePRO measures will be dependent on ePRO device and software 
availability.
8.2.2.1
Leicester Cough Questionnaire
Participants will be asked to complete the 19-item LCQ to assess the impact of their cough 
severity on physical, social and psychological functioning. 
8.2.2.2
Cough Severity Diary
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 at approximately the same time daily, beginning at
Visit 1 until Visit 9 (with a minimum requirement of 7 days of completion prior to first dose 
of study intervention/Randomization). 
During the Extension study period, completion of the CSD will be required daily, at 
approximately the same time for a 1 week period, beginning 1 week prior to Visit 11 and 
beginning 1 week prior to Visit 13. Participants should be contacted (eg, by telephone or 
text) during the Extension study period to remind them to complete the CSD during these 
weeks.
 
 
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8.2.2.3
Cough Severity Visual Analog Scale
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 approximately the same time daily, 
beginning at Visit 1 until Visit 9 (with a minimum requirement of 7 days of completion prior 
to first dose of study intervention/Randomization).
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 on the day of Visit 1 (or from the next day, if the evening measure was missed).

Participant met the Baseline Cough Severity VAS criteria from the measurement 
done on the day prior to Visit 2 prior to conducting any other Visit 2 procedures (or 
from the morning of Visit 2, prior to conducting any Visit 2 procedures, if the 
evening measure was missed).
A score of ≥40 mm on the Cough Severity VAS, at both the Screening and Baseline visits is 
required for randomization into the study.
During the Extension study period, completion of the Cough Severity VAS will be required 
daily, at approximately the same time for a 1 week period beginning 1 week prior to Visit 11 
and beginning 1 week prior to Visit 13. Participants should be contacted (eg, by telephone or 
text) during the Extension study period to remind them to complete the Cough Severity VAS 
during these weeks.
8.2.2.4
12-item Short Form Survey
The SF-12 is a validated, 12-item questionnaire designed to assess general health-related 
quality of life. It is a widely used instrument that has been shown to be responsive to changes 
in disease severity following intervention. The SF-12 is scored such that a total score and 
8 domain scores can be calculated with higher scores indicating better functioning: Physical 
Functioning, Role-Physical, Role-Emotional, Bodily Pain, General Health, Social 
Functioning, Mental Health, and Vitality. Data obtained from the SF-12 will be used in 
health economic analyses.
8.2.2.5
Work Productivity and Activity Impairment Questionnaire
The WPAI questionnaire yields four types of scores as follows: (1) absenteeism (work time 
missed); (2) presenteeism (impairment at work / reduced on-the-job effectiveness); (3) work 
productivity loss (overall work impairment / absenteeism plus presenteeism); and (4) activity 
impairment. The WPAI outcomes are expressed as impairment percentages, with higher 
numbers indicating greater impairment and less productivity, ie, worse outcomes. 
 
 
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Participants will be asked to indicate if they are currently employed and to respond to the 
following questions referring to “the past 7 days”: work hours missed due to health problems, 
work hours missed for other reasons, hours actually worked, the degree to which their health 
has affected productivity while working, and the degree to which their health affected 
productivity in regular unpaid activities.
8.2.2.6
EuroQoL 5L Dimensions Questionnaire
The EQ5D-5L is a standardized instrument for measuring generic health status used for 
estimating preference weights for that health status. By combining the weight with time, 
quality adjusted life years can be computed. The EQ5D-5L descriptive system comprises the 
following 5 dimensions: mobility, self-care, usual activities, pain/discomfort and 
anxiety/depression. Each dimension has 5 levels and the participant will be asked to indicate 
their health state using a 5-level rating scale. The EQ VAS records the participant’s self-rated 
health on a vertical VAS where the endpoints are labeled ‘best imaginable health state’ and 
“worst imaginable health state”. This information can be used as a quantitative measure of 
health outcome as judged by the individual participant.
8.2.2.7
Patient Global Impression of Change Questionnaire
Participants will be asked to rate the change in their chronic cough compared to the start of 
the study using the PGIC with response options ranging from “ very much improved” to 
“very much worse”. 
8.2.2.8
Hull Airway Reflux Questionnaire
Unlike the other cough questionnaires used in this study (ie, LCQ, CSD, and Cough Severity 
VAS), the HARQ was designed as an aid to diagnosis rather than assess quality of life 
impacts or cough severity. The HARQ has demonstrated good psychometric properties and 
no redundant items. The HARQ consists of 14 questions with responses on a numeric scale 
from 0 to 5. A score of ‘‘0’’ means that no problems are caused by the cough symptom and 
‘‘5’’ means severe/frequent problems. The HARQ will be used to more completely 
characterize the patient population.
8.3
Safety Assessments
Details regarding specific safety procedures/assessments to be performed in this study are 
provided. The total amount of blood/tissue to be drawn/collected over the course of the study 
(from prestudy to poststudy visits), including approximate blood/tissue volumes 
drawn/collected by visit and by sample type per participant, can be found in Section 8.
Planned timepoints for all safety assessments are provided in the SoA.
8.3.1
Chest Radiography/Computed Tomography Thorax Scan
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 
 
 
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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 5.1).
8.3.2
Physical Examinations
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. 
Any clinically significant abnormalities in physical examinations noted after Visit 1 will be 
recorded as AEs in the eCRF.
A brief directed physical exam 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.
8.3.3
Vital Signs and Weight and Height Measurements
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 
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 noted after Visit 1 will be recorded as 
AEs in the eCRF.
8.3.4
Electrocardiograms
A 12-lead ECG will be performed at Screening using local standard procedures. Clinically 
significant abnormal findings should be recorded in the AE eCRF.
8.3.5
Spirometry
A spirometry assessment will be performed locally at Screening using a calibrated 
spirometer. Assessments will include FEV1, FVC, and FEV1/FVC ratio.
Spirometry should be performed in accordance with guidelines established by the ATS/ERS 
(Available from: http://www.thoracic.org/statements/). For safety reasons, spirometry should 
be performed with the participant sitting, using a chair with arms and without wheels; 
 
 
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however, if necessary to undertake the testing with the participant standing or in another 
position, this should be noted in the participant’s study file.
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).
8.3.6
Clinical Safety Laboratory Assessments
•
Refer to Appendix 2 for the list of clinical laboratory tests to be performed and to the 
SoA for the timing and frequency.
•
The investigator or medically qualified designee (consistent with local requirements) 
must review the laboratory report, document this review, and record any clinically 
relevant changes occurring during the study in the AE section of the case report form 
(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 2, must be 
conducted in accordance with the laboratory manual and the SoA.
•
If laboratory values from nonprotocol specified laboratory assessments performed at the 
institution’s local laboratory require a change in study participant management or are 
considered clinically significant by the investigator (eg, SAE or AE or dose 
modification), then the results must be recorded in the appropriate CRF (eg, SLAB).
•
For any laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 7 days after the last dose of study intervention, 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.
8.3.7
Renal and Urological Safety Assessments
Safety assessments will be performed in all participants in order to monitor renal and 
urological safety during the course of the study. Participants will be monitored for hematuria 
using urinary dipstick (performed at the study site) and urinary crystals and hematuria 
through urinalysis (performed at the central laboratory). Dipstick and urinalyses (including 
microscopy) will be collected as outlined in the SoA.
If during screening, a participant has crystalluria and/or unexplained hematuria (defined as, 
for example, participants without a history of recent menses, urinary tract infection, or recent 
procedure/instrumentation that would explain the hematuria. Note: Any other explanation for 
hematuria finding must be reviewed with the Sponsor), the investigator should:
 
 
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
Review and confirm if the finding is a new finding or a previously documented 
finding.

Evaluate the participant’s medical history to identify conditions (ie, prior renal 
disease, prior history of kidney stones, medications, gastrointestinal conditions) and 
make a clinical determination if the participant is at high or low risk of potential 
complications/worsening due to an associated renal/urinary condition or its treatment, 
or requires a change in therapy for that condition that may interfere with 
interpretation of safety data collected during the study.

If high risk, the participant should not be enrolled and should be considered for 
further evaluation.

If low risk, the participant may continue with screening.
If after randomization, unexplained hematuria and/or urinary crystals are identified and 
deemed to be clinically significant by the investigator, the participant should be considered 
for further evaluation.
If an investigator deems it necessary to perform an unscheduled urinalysis at any time after 
randomization, the same procedures for collection/preparation of the urine sample and 
evaluation of hematuria (as explained or unexplained) described for post-randomization 
protocol-specified visits should be performed.
8.4
Adverse Events (AEs), Serious Adverse Events (SAEs), and Other Reportable 
Safety Events
The definitions of an AE or 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 3.
Adverse events, SAEs, and other reportable safety events will be reported by the participant 
(or, when appropriate, by a caregiver, surrogate, or the participant's legally authorized 
representative).
The investigator and any designees are responsible for detecting, 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 8.4.3.
The investigator, who is a qualified physician, will assess events that meet the definition of 
an AE or SAE as well as other reportable safety events with respect to seriousness, 
intensity/toxicity and causality.
 
 
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8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other Reportable 
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 cause 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 last study-related intervention 
safety follow-up telephone call, all AEs, SAEs and other reportable safety events must be 
reported by the investigator; however, for those participants who discontinued from the study 
intervention but continuing to be monitored only the adverse events and other reportable 
safety events as shown in Table 3  need to be reported from completion of the safety follow-
up telephone call/visit following cessation of intervention to the last study-related off-
intervention telephone call/visit.
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 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 intervention 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 time frames as indicated in Table 3.
 
 
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Table 3
Reporting Time Periods and Time Frames 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 alla
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
Reporta
- 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
Reporta
- non-DILI ECIs 
and those not 
requiring regulatory 
reporting
Not required
Within 5 
calendar days 
of learning of 
event
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 alla
Not required
Within 5 
calendar days 
of learning of 
event
DILI = drug-induced liver injury; ECI = event of clinical interest
a Participants who discontinue study intervention and are continuing to be monitored in the study do not require the 
reporting of ECIs, pregnancy/lactation exposure, and overdose. Previously reported pregnancies/lactations exposure need to 
be followed for completion/termination; report outcome.
 
 
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8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events
Care will be taken not to introduce bias when detecting AE and/or SAE and other reportable 
safety events. Open-ended and nonleading verbal questioning of the participant is the 
preferred method to inquire about AE occurrence.
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information
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, events of clinical interest (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 7.3). In 
addition, the investigator will make every attempt to follow all nonserious AEs that occur in 
randomized participants for outcome. Further information on follow-up procedures is given 
in Appendix 3.
8.4.4
Regulatory Reporting Requirements for SAE
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 intervention 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 intervention under clinical investigation. All 
AEs will be reported to regulatory authorities, IRB/IECs, and investigators in accordance 
with all applicable global laws and regulations (ie, per ICH Topic E6 (R2) Guidelines for 
Good Clinical Practice [GCP]).
Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSARs) 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 IB and will notify the IRB/IEC, if appropriate according to local requirements.
8.4.5
Pregnancy and Exposure During Breastfeeding
Although pregnancy and infant exposure during breastfeeding are not considered AEs, 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 
 
 
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serious events (Important Medical Events). If the pregnancy continues to term, the outcome 
(health of infant) must also be reported.
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying as 
AEs or SAEs
There are no disease-related events and/or disease-related outcomes not qualifying as AEs or 
SAEs.
8.4.7
Events of Clinical Interest (ECIs)
Selected nonserious and SAEs are also known as ECIs and must be reported to the Sponsor.
Events of clinical interest for this study include:

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 Study 
File Binder (or equivalent).
8.5
Treatment of Overdose
In this study, an overdose is any dose higher than the amount of study intervention taken 
outside the intervention assignment (Section 4.3.2). Study intervention should be taken once 
in the morning and once in the evening. If more than the protocol-specified intervention is 
taken within a 1-day period (ie, >2 tablets/day from either bottle) this is regarded as an 
overdose.
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 (see MK-7264 IB). Overdose should be treated according to the participant’s 
clinical signs and symptoms.
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the Sponsor Clinical Director based on the clinical evaluation of the 
participant.
 
 
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8.6
Pharmacokinetics
The date and time for the last dose of study intervention 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.
8.6.1
Blood Collection for Plasma MK-7264
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 (ie, the morning dose of study intervention will be taken after the PK sample is 
collected). Only at Visit 3, there will be 2 PK sample collections: 1 at pre-dose and the other 
at 2 hours (±30 minutes) post-dose. Scheduled PK sample collections for all other visits, as 
outlined in the SoA, will be predose only. There will not be any dosing at Visit 13, but PK 
sample collection will be done.
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.
8.7
Pharmacodynamics
Pharmacodynamic parameters will not be evaluated in this study.
8.8
Biomarkers
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 randomized 
participants as specified in the SoA:
•
Blood for genetic analysis
8.8.1
Planned Genetic Analysis Sample Collection
The planned genetic analysis sample should be drawn for planned analysis of the association 
between genetic variants in DNA and drug response. This sample will not be collected at the 
site if there is either a local law or regulation prohibiting collection, or if the IRB/IEC does 
not approve the collection of the sample for these purposes. If the sample is collected, 
leftover extracted DNA will be stored for future biomedical research if the participant signs 
the future biomedical research consent. If the planned genetic analysis is not approved, but 
future biomedical research is approved and consent is given, this sample will be collected for 
the purpose of future biomedical research.
Sample collection, storage, and shipment instructions for planned genetic analysis samples 
will be provided in the operations/laboratory manual.
 
 
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8.9
Future Biomedical Research Sample Collection
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
8.10
Visit Requirements
Visit requirements are outlined in Section 1.3. Specific procedure-related details are provided 
in Section 8.
8.10.1
Screening
Potential participants will be evaluated at Screening to determine if they fulfill the entry 
requirements as set forth in Sections 5.1 and 5.2. If any participant fails to meet the study 
entry criteria, screening procedures may be repeated once 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.
Participants who are consented and then are considered for washout of prohibited therapy 
(see Section 6.5), should complete the washout prior to completing other screening
procedures. For these individuals, the screening period would begin after the completion of 
washout and when the participant returns to the clinic. Participants who washout of 
prohibited therapy should return to the clinic after washout to complete the remaining Visit 1 
procedures.
Participants who are consented may, at the investigator’s discretion, consider beginning the 
completion of daily ePROs (CSD and VAS) on the day of Visit 1 prior to completing other 
screening procedures (in order to first determine if the participant meets the Visit 1 VAS 
entry criterion). For participants who meet the Visit 1 VAS criterion, the screening period is 
noted as starting when the participant has provided consent. Participants who meet the Visit 1 
VAS inclusion criterion should return to the clinic as soon as possible (within the 
recommended scheduling windows) after availability of the Visit 1 VAS score to complete 
the remaining Visit 1 procedures.
8.10.2
Baseline
The Baseline visit must be scheduled between 7 days and approximately 14 days after 
Screening.
Blood for PK assessments will be collected during Visit 2, and should be collected before 
attachment of the cough monitor (to avoid interference) as cough assessments will begin at 
Visit 2. The cough monitor should be attached before approximately 11 AM and worn for 
24 hours.
 
 
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8.10.3
Main Study Period
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. Additionally, 1 day prior to Visits 4, 5, 6, 7, 8 9, and 
Discontinuation (from the Main study period) participants should return to the clinic to have 
the cough monitor attached. Attachment of the cough monitor at these visits, may be 
managed by study site staff or mobile nurses (if locally available and approved for use), who 
will attach the cough monitor at the home of the participant. Cough monitors will be removed 
at study site Visits 4, 5, 6, 7, 8, 9, and Discontinuation (from the Main study period). Refer to 
the vendor’s site manual for additional details.
For all study site visits, participants are to be reminded to bring their eDiary device with 
them to the visit.
8.10.4
Extension Study Period
Participants will continue their assigned treatments during the 28-week Extension study 
period. Cough counts will not be collected during this period. Electronic PRO measures will 
continue to be completed as outlined in the SoA.
8.10.5
Discontinued Participants Continuing to be Monitored in the Study
If a participant is discontinued from the study intervention early, the Discontinuation Visit 
assessments are to be performed at the final study site visit. 
It is intended that all participants should be followed through completion of the study, 
regardless of premature discontinuation of intervention, unless the participant withdraws 
consent. Thus, participants who discontinue from study intervention prior to completion of 
the study should continue to be monitored to obtain relevant information through the end of 
the study. Study site visits/telephone 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 eDiary 
assessments as outlined in Section 1.3. 
Concomitant therapies specifically prohibited (see Section 6.5) while the patient was on 
study intervention are no longer prohibited after discontinuation of study intervention.
For these participants who have discontinued study intervention 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 telephone, 
work telephone, mobile telephone). 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 7.1), the 
participant should be encouraged to accept a telephone contact at least at the final visit date 
(at the end of Main study period if they discontinue intervention during the Main study or at 
the end of the Extension study period if they discontinue intervention during the Extension).
 
 
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Additionally, the ICF will explain the importance of continued data collection from 
participants, including the use of continued contact by telephone.
8.10.6
Poststudy
All participants will be required to complete the safety follow up telephone call 
approximately 14 days (+ 7 days) after the last dose of study intervention to determine if any 
AEs have occurred since discontinuing study intervention.  
If the safety follow-up telephone contact occurs less than 14 days after the last dose of study 
intervention, a subsequent follow-up telephone call should be made at approximately 14 days 
(+ 7 days) post the last dose of study intervention.
9
STATISTICAL ANALYSIS PLAN
This section outlines the statistical analysis strategy and procedures for the study. If, after the 
study has begun, but prior to any unblinding, there are changes made to the primary and/or 
key secondary hypotheses, or the statistical methods related to those hypotheses, then the 
protocol will be amended (consistent with ICH Guidance for Industry E9). Changes to 
exploratory or other non-confirmatory analyses made after the protocol has been finalized, 
but prior to unblinding, will be documented in a supplemental Statistical Analysis Plan 
(sSAP) and referenced in the CSR for the study. Post-hoc exploratory analyses will be clearly 
identified in the CSR. Separate analysis plans (ie, separate documents from the sSAP) will be 
developed to detail other planned analyses including those specific to the analysis of PK data 
and ePROs.
9.1
Statistical Analysis Plan Summary
Key elements of the statistical analysis plan are summarized below. The comprehensive plan 
is provided in Sections 9.2 through 9.12.
Study Design Overview
A Phase 3, Randomized, Double-blind, Placebo-Controlled, 
12-month Study to Evaluate the Efficacy and Safety of 
MK-7264 in Adult Participants with Chronic Cough (PN030)
Treatment Assignment
Participants will be randomized in a 1:1:1 ratio to 1 of 
3 treatment groups: MK-7264 45 mg BID, MK-7264 15 mg 
BID, or placebo.
 
 
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Analysis Populations
Efficacy: Full Analysis Set (FAS) population which consists of 
all randomized participants who have taken at least 1 dose of 
study intervention and have at least 1 Baseline and at least 
1 post-Baseline endpoint observation during the treatment 
period; and Per-protocol (PP) population which excludes 
participants due to important deviations from the protocol from 
the FAS population. 
Safety: All Participants as Treated (APaT) population, which 
consists of all randomized participants who received at least 
1 dose of study intervention.
Primary Endpoint
24-hour coughs per hour at Week 24
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 
longitudinal analysis of covariance (ANCOVA) model. In this 
model, the response vector consists of the change from baseline 
in log-transformed 24-hour coughs per hour at each 
post-Baseline visit. The model will include factors for treatment
group, visit, the interaction of treatment group by visit, gender, 
and region; and the log-transformed baseline value and the 
interaction of log-transformed baseline value by visit as 
covariates. The model will use all available 24-hour coughs per 
hour data at Baseline and on Week 4, 8, 12, 16, 20 and 24. 
Contrasts will be constructed to compare each of the 2 MK-7264 
treatment groups to the placebo group at each post-Baseline
visit. The least squares mean change from baseline (in log scale) 
with the associated standard errors will be displayed for each 
treatment group. Estimated treatment differences (MK-7264 − 
placebo) along with corresponding 95% confidence intervals 
(CIs) will also be presented for each MK-7264 treatment group. 
In addition, the geometric mean of the 24-hour coughs per hour 
will be presented by treatment group 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.
Statistical Methods for 
Key Safety Analyses
The analysis of safety endpoints will follow a tiered approach. 
The tiers differ with respect to the analyses that will be 
performed. Tier 1 safety endpoints will be subject to inferential 
testing for statistical significance with p-values and 95% CIs 
provided for between-group comparisons. Tier 2 safety 
endpoints will be evaluated via point estimates and 95% CIs for 
between-group comparisons. Tier 3 safety endpoints will be 
evaluated via point estimates only.
 
 
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Interim Analyses
One planned interim efficacy analysis will be performed in this 
study. Results will be reviewed by an external DMC. The 
interim analysis is summarized below. Details are provided in 
Section 9.7.
a.
Timing: To be performed when approximately 40% of 
participants have either completed, or discontinued prior 
to completion of the Main study period.
b. Testing: Futility analysis based on the primary endpoint 
of 24-hour coughs per hour at Week 24 will be provided.
 
Additional interim safety reviews will also be conducted at 
regular intervals.
Multiplicity
The Type-I error rate over the multiple treatment group
comparisons and multiple endpoints will be controlled by a step 
down testing procedure in a pre-specified order (details are 
described in Section 9.8).
Sample Size and Power
Calculations
The planned sample size is 1290 participants. Table 6 in 
Section 9.9 provides power for the primary and key secondary 
efficacy endpoints. All calculations are based on 2-sided 
α=0.0499 significance level.
9.2
Responsibility for Analyses/In-house Blinding
The statistical analysis of the data obtained from this study will be the responsibility of the 
Sponsor.
This study (both the Main study period and the Extension study period) will be conducted as 
a double-blind study under in-house blinding procedures. At the end of the Main study 
period, a copy of the database will be locked after medical/scientific review has been 
completed, and data have been declared final and complete. The study team will be 
unblinded in order to perform and review the full analysis of data from the Main study 
period, as well as author a CSR for regulatory submission. A separate, blinded Sponsor team 
(ie, blinded to participant-level intervention assignment) will then be assigned to continue the 
conduct of the Extension study period. All personnel who are unblinded for the Main study 
period will be excluded from any future data review at the individual participant level.
At the end of the Extension study period, the CSR from the Main study period will be 
updated to include analyses of the additional data acquired from the completion of the 
Extension study period. The investigator site personnel and the participants will be blinded to 
intervention assignment until the entire study completion.
 
 
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The Clinical Biostatistics department will generate the randomized allocation schedule(s) for 
study intervention assignment.
Unblinding for Interim Efficacy and Safety Analyses
Planned interim analyses are described in Section 9.7. Study enrollment is likely to be 
ongoing at the time of any interim analyses. Blinding to intervention assignment will be 
maintained at all investigational sites. The results of interim analyses will not be shared with 
the investigators prior to the completion of the study.
Results of the interim efficacy and safety analyses will be provided by the external unblinded 
statistician to the DMC. Limited additional Sponsor personnel may be unblinded to the 
treatment-level results of the interim analyses, if required, in order to act on the 
recommendations of the DMC. The extent to which individuals are unblinded with respect to 
results of interim analyses will be documented by the unblinded statistician.
The DMC will serve as the primary reviewer of the results of the interim efficacy and safety 
analyses and will make recommendations for discontinuation of the study or modification to 
an EOC of the Sponsor. If the DMC recommends modifications to the design of the protocol 
or discontinuation of the study, the EOC may be unblinded to the results at the 
treatment-level in order to act on these recommendations. Additional logistical details will be 
provided in the DMC Charter. Key aspects of the interim analyses are described in 
Section 9.7.
The external unblinded statistician will not be involved in any discussions regarding 
modifications to the protocol, statistical methods, identification of protocol deviations, or 
data validation efforts after the interim analyses.
9.3
Hypotheses/Estimation
The primary and secondary hypotheses for this study are stated in Section 3.
9.4
Analysis Endpoints
Efficacy and safety endpoints for evaluation are listed below, followed by the descriptions of 
the derivations of selected endpoints.
9.4.1
Efficacy Endpoints
Primary Efficacy Endpoint

24-hour coughs per hour at Week 24
Secondary Efficacy Endpoints

Awake coughs per hour at Week 24
 
 
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
Proportion of participants with a ≥1.3-point increase from baseline in LCQ total score 
at Week 24

Proportion of participants with a ≥30% reduction from baseline in 24-hour coughs per 
hour at Week 24

Proportion of participants with a ≥1.3-point reduction from baseline in mean weekly 
CSD total score at Week 24

Proportion of participants with a ≥2.7-point reduction from baseline in mean weekly 
CSD total score at Week 24

Proportion of participants with a ≥30 mm reduction from baseline in Cough Severity 
VAS score at Week 24
Exploratory Efficacy Endpoints
Exploratory efficacy endpoints are stated in Section 3.
9.4.2
Safety Endpoints
Safety endpoints are stated in Section 3.
9.4.3
Derivations of Efficacy Endpoints
Baseline for efficacy variables is defined as the last non-missing value prior to the first study 
intervention.
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 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 a 
duration of recording <20 hours will be considered as missing. If a session has a 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.
 
 
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24-hour Coughs per Hour
The 24-hour coughs per hour at Baseline and each 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 hours (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 the primary endpoint. For each post-Baseline visit, the primary 
efficacy variable of analysis is defined as follows:
Change from baseline in log-transformed 24-hour coughs per hour
= Log (24-hour coughs per hour at post-Baseline visit) – Log (24-hour coughs per hour at 
Baseline)
The primary analysis of the primary endpoint will be on the natural log scale of the cough 
rate data.
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 primary efficacy variable, change from baseline in 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 visit) – Log (Awake coughs per hour at 
Baseline)
 
 
 
 
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9.5
Analysis Populations
9.5.1
Efficacy Analysis Populations
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 1 dose of study intervention and provided at least 1 Baseline and at least 1 post-Baseline
endpoint observation during the treatment period. 
The PP population excludes participants due to important deviations from the protocol that 
may substantially affect the results of the primary efficacy endpoint. Potential deviations that 
may result in the exclusion of a participant from the PP population will be specified in the 
sSAP. The final determination on important protocol deviations, and thereby the composition 
of the PP population, will be made prior to the first unblinding of the database and will be 
documented in a separate memo. A supportive analysis using the PP population may be 
performed for the primary efficacy endpoint if the proportion of the participants with 
important protocol deviations is >10%. 
 
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Participants will be included in the treatment group to which they are randomized for the 
analysis of efficacy data using both the FAS and PP populations. Details on the approach to 
handling missing data are provided in Section 9.6.
9.5.2
Safety Analysis Population
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 1 dose of study 
intervention. Participants will be included in the treatment group corresponding to the study 
intervention 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. 
Participants who take incorrect study intervention for the entire treatment period will be 
included in the treatment group corresponding to the study intervention actually received.
At least 1 laboratory or vital sign measurement obtained subsequent to at least 1 dose of 
study intervention is required for inclusion in the analysis of each specific parameter. To 
assess change from baseline, a Baseline measurement is also required.
9.5.3
Pharmacokinetic Analysis Population
The evaluable PK population for PK data analysis is defined as all participants with 
1 measurable PK sample.
9.6
Statistical Methods
This section describes the statistical methods that address the primary and secondary 
objectives. Methods related to exploratory objectives and supportive analyses will be 
described in the sSAP.
Statistical testing and inference for efficacy and safety analyses are described in 
Sections 9.6.1 and 9.6.2, respectively. Controlling of family-wise Type I error rate is 
described in Section 9.8. Unless otherwise stated, all statistical tests will be conducted at 
α=0.0499 (2-sided) level.
9.6.1
Statistical Methods for Efficacy Analyses
The analysis of efficacy endpoints will be based on the FAS population. Unless otherwise 
specified, all efficacy data, regardless of participant exposure to study intervention, will be 
included in efficacy analyses.
Primary Efficacy Analysis
Cough monitoring is conducted for baseline and 24 hours after administration of the study 
intervention on Weeks 4, 8, 12, 16, 20, and 24. The primary efficacy endpoint of this study is 
24-hour coughs per hour at Week 24. As the change from baseline in 24-hour coughs per 
hour may have a skewed and wide distribution, the data will be log-transformed prior to 
analysis for the primary approach. The primary analysis of the primary endpoint will be on 
the natural log scale of the cough rate data. The variable of change from baseline in 
 
 
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log-transformed 24-hour coughs per hour will be used in the analysis of the primary 
endpoint. A negative result indicates a decrease in cough rate, while a positive result 
indicates an increase in cough rate.
The primary analysis approach will be conducted utilizing the longitudinal ANCOVA model. 
In this model, the response vector consists of the change from baseline in log-transformed 
24-hour coughs per hour at each post-Baseline visit. The model will include factors for 
treatment group, visit, the interaction of treatment group by visit, gender, and region; and the 
log-transformed baseline value and the interaction of log-transformed baseline value by visit 
as covariates. The model will use all available 24-hour coughs per hour data at baseline on 
Weeks 4, 8, 12, 16, 20, and 24. Contrasts will be constructed to compare each of the 
2 MK-7264 treatment groups to the placebo group at each post-Baseline visit. The least 
squares mean change from baseline (in log scale) with the associated standard errors will be 
displayed for each treatment group. Estimated treatment differences (MK-7264 − placebo) 
along with corresponding 95% CIs will also be presented for each MK-7264 treatment group. 
In addition, the geometric mean of the 24-hour coughs per hour will be presented by 
treatment group 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.
Further details of the model specification, assumptions, and SAS implementation codes will 
be provided in the sSAP.
Secondary Efficacy Analysis
The continuous secondary efficacy endpoints will be analyzed using a similar longitudinal 
ANCOVA model as used for the primary efficacy 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.
Responder endpoints will be analyzed by the logistic regression model. The model will 
include terms for treatment group, visit, the interaction of treatment group by visit, gender, 
region, baseline, and the interaction of baseline by visit for the underlying continuous 
response. Log odds ratio will be back transformed into odds ratio for final reporting. 
Table 4 summarizes the analysis strategy of the primary and key secondary efficacy 
endpoints.
 
 
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Table 4
Analysis Strategy for Primary and Key Secondary Efficacy Endpoints
Endpoint/Variable
(At Week 24)
Statistical Method
Missing Data 
Approach
Primary
24-hour coughs per hour
Longitudinal ANCOVA
Model-baseda
Secondary
Awake coughs per hour
Longitudinal ANCOVA
Model-baseda
Proportion of participants with a ≥1.3 point 
increase from baseline in LCQ total score
Logistic Regression
Model-baseda
Proportion of participants with a ≥30% 
reduction from baseline in 24-hour coughs per 
hour
Logistic Regression
Model-baseda
Proportion of participants with a ≥1.3 point 
reduction from baseline in mean weekly CSD 
total score
Logistic Regression
Model-baseda
Proportion of participants with a ≥2.7 point 
reduction from baseline in mean weekly CSD 
total score
Logistic Regression
Model-baseda
Proportion of participants with a ≥30 mm 
reduction from baseline in Cough Severity 
VAS score
Logistic Regression
Model-baseda
a
Includes data collected after intervention discontinuation.
ANCOVA = analysis of covariance; CSD = Cough Severity Diary; LCQ = Leicester Cough Questionnaire; 
VAS = Visual Analogue Scales.
The strategy to address multiplicity issues with regard to multiple treatment comparisons, 
multiple efficacy endpoints, multiple timepoints, and interim analyses is described in 
Sections 9.7 and 9.8.
Handling of Missing Data
The missing data approach is specified in the above mentioned primary and secondary 
efficacy endpoints analysis sections. All other analyses will be conducted based on the 
observed data only. Additional sensitivity analyses with respect to the handling of missing 
data will be specified in the sSAP.
9.6.2
Statistical Methods for Safety Analyses
The safety endpoints will be analyzed based on the data collected in the Main study period, 
as well as based on the cumulative data collected across both the Main and Extension study 
periods.
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
AEs, laboratory tests, and vital signs.
 
 
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The analysis of safety results will follow a tiered approach (Table 5). The tiers differ with 
respect to the analyses that will be performed. Tier 1 safety endpoints will be subject to 
inferential testing for statistical significance with p-values and 95% CIs provided for 
between-group comparisons. Tier 2 safety endpoints will be evaluated via point estimates 
and 95% CIs for between-group comparisons. Tier 3 safety endpoints will be evaluated via 
point estimates only.
Taste-related AEs (including dysgeusia, ageusia, and hypogeusia, as well as other related 
terms) will be classified as belonging to “Tier 1”. The unadjusted p-values and point 
estimates with 95% CIs from the pairwise comparison between each of MK-7264 dose 
versus placebo will be provided. The definition of taste-related AEs will be finalized and 
documented before the database lock of the Main study period.
The frequency of taste-related AEs across pre-defined time intervals will be provided, where 
the time intervals will be defined as: >0 to ≤1 week, >1 to ≤4 weeks, >4 to ≤8 weeks, >8 to 
≤12 weeks, >12 to 16 weeks, >16 to 20 weeks, and >20 to 24 weeks in the Main study 
period; and >24 to ≤38 weeks, and >38 to ≤52 weeks in Extension study period. In each time 
interval, the denominator for calculation of percentage will be the number of participants 
exposed at the beginning of the time interval and the numerator will be the number of
participants with at least 1 taste related AE occurring in this time interval. Only the first 
event will be counted and all recurrent events will not be included.
The broad clinical and laboratory AE categories consisting of the percentage of participants 
with any AE, a drug related AE, a serious AE, an AE which is both drug-related and serious, 
an oral paresthesia AE, an oral hypoesthesia AE, and who discontinued due to an AE will be 
classified as belonging to “Tier 2”.
Adverse experiences (specific terms as well as system organ class terms) and predefined 
limits of change in laboratory, and vital signs will be classified as belonging to “Tier 2” or 
“Tier 3”, based on the number of events observed. Membership in Tier 2 requires that at least 
4 participants in any treatment group exhibit the event; all other adverse experiences and 
predefined limits of change will belong to Tier 3.
The threshold of at least 4 events was chosen because the 95% CI for the between-group 
difference in percent incidence will always include zero when treatment groups of equal size 
each have less than 4 events and thus would add little to the interpretation of potentially 
meaningful differences. Because many 95% CIs may be provided without adjustment for 
multiplicity, the CIs should be regarded as a helpful descriptive measure to be used in 
review, not a formal method for assessing the statistical significance of the between-group 
differences in adverse experiences and predefined limits of change.
The Tier 1 and Tier 2 safety endpoints will be analyzed using the Miettinen & Nurminen 
method [Miettinen, O. and Nurminen, M. 1985]. 
Continuous measures such as changes from baseline in laboratory and vital signs will be 
considered Tier 3 safety parameters.
 
 
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Summary statistics for baseline, on treatment, and change from baseline values will be 
provided by treatment group in table format.
Table 5
Analysis Strategy for Safety Parameters
Safety 
Tier
Safety Endpointa
p-value
95% CI for 
Treatment 
Comparison
Descriptive 
Statistics
Tier 1
Any taste-related AE
X
X
X
Tier 2
Any oral paresthesia AE
X
X
Any oral hypoesthesia AE
X
X
Any AE
X
X
Any Serious AE
X
X
Any Drug-related AE
X
X
Any Serious and Drug-related AE
X
X
Discontinuation due to AE
X
X
Specific AEs, SOCs, or PDLCsb
(incidence ≥4 participants in 1 of the 
treatment groups)
X
X
Tier 3
Specific AEs, SOCs, or PDLCsb
(incidence <4 participants in all the 
treatment groups)
X
Change from baseline results (Labs, Vital 
Signs)
X
a
Adverse experience references refer to both clinical and laboratory AEs.
b
Includes only those endpoints not pre-specified as Tier 1 or not already pre-specified as Tier 2 endpoints.
AE = adverse event; CI = confidence interval; PDLC = Pre-defined Limit of Change; SOC = System Organ Class; 
X = results will be provided.
9.6.3
Summaries of Baseline Characteristics, Demographics, and Other Analyses
Demographic and Baseline Characteristics
The number and percentage of participants screened, randomized, the primary reasons for 
screening failure, and the primary reason for discontinuation will be displayed. 
Demographic variables (including age, gender, race, weight, and height), baseline 
characteristics, primary and co-morbid conditions, and prior and concomitant therapies will 
be summarized by treatment group either by descriptive statistics or categorical tables. The 
comparability of the treatment groups for each relevant characteristic will be assessed by the 
summary tables. No statistical hypothesis tests will be performed on these characteristics.
 
 
 
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9.7.2
Interim Safety Analyses
Interim safety analyses will be performed periodically (determined either by calendar date or 
enrollment milestones, to be specified separately in the DMC charter). For these interim 
analyses, a general review of safety results will be performed based on review of AEs, 
laboratory safety parameters, and other safety endpoints.
9.8
Multiplicity
Primary and Key Secondary Endpoints
Due to the interim analysis for futility, an α-spending of 0.0001 will be applied to the 2-sided 
Type I error rate of 0.05 for the primary and secondary hypotheses based on the 
 
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Haybittle Peto method [Haybittle, J. L. 1971] [Peto, R., et al 1976]. Multiplicity adjustment 
will be made for testing 2 doses on the primary and the key secondary endpoints for the 
analysis, ie, for testing a family of the following hypotheses:

H11: MK-7264 45 mg BID is superior to placebo in reducing 24hour coughs per hour 
at Week 24

H12: MK-7264 15 mg BID is superior to placebo in reducing 24-hour coughs per 
hour at Week 24

H21: MK-7264 45 mg BID is superior to placebo in reducing awake coughs per hour 
at Week 24

H22: MK-7264 15 mg BID is superior to placebo in reducing awake coughs per hour 
at Week 24

H31: MK-7264 45 mg BID is superior to placebo on the proportion of participants 
with a ≥1.3-point increase from baseline in LCQ total score at Week 24

H32: MK-7264 15 mg BID is superior to placebo on the proportion of participants 
with a ≥1.3-point increase from baseline in LCQ total score at Week 24

H41: MK-7264 45 mg BID is superior to placebo with respect to the proportion of 
participants with a ≥30% reduction from baseline in 24-hour coughs per hour at 
Week 24

H42: MK-7264 15 mg BID is superior to placebo with respect to the proportion of 
participants with a ≥30% reduction from baseline in 24-hour coughs per hour at 
Week 24
To strongly control the Type I error rate for this family, a step down testing procedure will be 
applied in the order specified above. Each hypothesis will be formally tested only if the 
preceding one is significant at α=0.0499 level.
 
 
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, Table 6 provides power for the primary and key secondary 
efficacy endpoints with a total of 1290 participants (430 participants per treatment group). 
All calculations are based on 2-sided α=0.0499 significance level. The dropout rate is
expected to be 20% at Week 24.
Table 6
Power for the Primary and Key Secondary Efficacy Endpoints
Endpoints
(At Week 24)
Power in
MK-7264 45 mg
BID Group
Power in
MK-7264 15 mg
BID Group
24-hour coughs per hour
>99%
98%
Awake coughs per hour
98%
97%
Proportion of participants with ≥1.3-point 
increase from baseline in LCQ total score
81%
56%
Proportion of participants with ≥30% 
reduction from baseline in 24-hour coughs per 
hour
55%
50%
BID = twice daily; LCQ = Leicester Cough Questionnaire
 
 
 
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Note: details of the concomitant medications will be provided in a separate sSAP.
A similar longitudinal ANCOVA model as the primary efficacy endpoint will be performed.
For each subgroup, summary statistics including mean, SD, and 95% CIs will be provided for 
each treatment group.
 
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9.11
Compliance (Medication Adherence)
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 study intervention as instructed in Section 8. When a participant takes less than or 
more than the required study intervention 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 intervention day to the 
last scheduled intervention 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 intervention day to the last dose day.
Summary statistics will be provided on percent compliance by treatment group for the APaT 
population.
9.12
Extent of Exposure
The duration of intervention for each participant will be evaluated by calculating the number 
of days on therapy. Exposure to study intervention will be summarized using descriptive 
statistics (mean, SD, median, minimum, and maximum) for the APaT population.
 
 
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10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1
Code of Conduct for Clinical Trials
Merck Sharp and Dohme Corp., a subsidiary of Merck & Co., Inc. (MSD)
Code of Conduct for Interventional Clinical Trials
I. Introduction
A. Purpose
MSD, 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 participants in clinical trials is the 
overriding concern in the design of clinical trials. In all cases, MSD clinical trials will be conducted in compliance 
with local and/or national regulations (eg, International Council for Harmonisation Good Clinical Practice [ICH-
GCP]) and in accordance with the ethical principles that have their origin in the Declaration of Helsinki.
B. Scope
Highest ethical and scientific standards shall be endorsed for all clinical interventional investigations sponsored by 
MSD 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 that are observational in nature, or 
which are retrospective. Further, this Code does not apply to investigator-initiated trials, which are not under the 
full control of MSD.
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 MSD or comparator products. 
Alternatively, MSD may conduct outcomes research trials, trials to assess or validate various endpoint 
measures, or trials to determine patient preferences, etc.
The design (ie, participant population, duration, statistical power) must be adequate to address the specific
purpose of the trial. Participants must meet protocol entry criteria to be enrolled in the trial. 
2. Site Selection
MSD selects investigative sites based on medical expertise, access to appropriate participants, adequacy of 
facilities and staff, previous performance in clinical trials, as well as budgetary considerations. Prior to trial 
initiation, sites are evaluated by MSD personnel to assess the ability to successfully conduct the trial.
3. Site Monitoring/Scientific Integrity
Investigative trial sites are monitored to assess compliance with the trial protocol and general principles of 
Good Clinical Practice (GCP). MSD reviews clinical data for accuracy, completeness, and consistency. Data 
are verified versus source documentation according to standard operating procedures. Per MSD policies and 
procedures, if fraud, scientific/research misconduct, or serious GCP-noncompliance is suspected, the issues 
 
 
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are investigated. When necessary, the clinical site will be closed, the responsible regulatory authorities and 
ethics review committees notified.
B. Publication and Authorship
Regardless of trial outcome, MSD commits to publish primary and secondary results of its registered trials of 
marketed products in which treatment is assigned, according to the prespecified plans for data analysis. To the 
extent scientifically appropriate, MSD seeks to publish the results of other analyses it conducts that are important 
to patients, physicians, and payers. 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 such as multiplicity.
MSD’s policy on authorship is consistent with the recommendations published by the International Committee of 
Medical Journal Editors (ICMJE). 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. MSD funding of a trial will be acknowledged in 
publications.
III. Participant Protection
A. Ethics Committee Review (Institutiona Review Board [IRB]/Independent Ethics Committee [IEC])
All clinical trials will be reviewed and approved by an IRB/IEC before being initiated at each site. Significant 
changes or revisions to the protocol will be approved by the ethics committee prior to implementation, except 
changes required urgently to protect participant safety that may be enacted in anticipation of ethics committee 
approval. For each site, the ethics committee and MSD 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.
All participation in MSD clinical trials is voluntary. Participants enter the trial only after informed consent is 
obtained. Participants may withdraw from an MSD 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
MSD is committed to safeguarding participant confidentiality, to the greatest extent possible. Unless required by 
law, only the investigator, Sponsor (or representative), ethics committee, and/or regulatory authorities will have 
access to confidential medical records that might identify the participant by name.
D. Genomic Research
Genomic research will only be conducted in accordance with a protocol and informed consent authorized by an 
ethics committee.
IV. Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive. It is MSD’s policy to compensate investigators (or the sponsoring 
institution) in a fair manner for the work performed in support of MSD trials. MSD 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.
MSD does not pay for participant referrals. However, MSD may compensate referring physicians for time spent 
on chart review to identify potentially eligible participants.
 
 
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B. Clinical Research Funding
Informed consent forms will disclose that the trial is sponsored by MSD and that the investigator or sponsoring 
institution is being paid or provided a grant for performing the trial. However, the local ethics committee may 
wish to alter the wording of the disclosure statement to be consistent with financial practices at that institution. As 
noted above, all publications resulting from MSD trials will indicate MSD 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.
V. Investigator Commitment
Investigators will be expected to review MSD’s Code of Conduct as an appendix to the trial protocol, and in signing the 
protocol, agree to support these ethical and scientific standards.
10.1.2
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.
10.1.3
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 that 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.
 
 
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10.1.3.1
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 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.
10.1.3.2
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 to 
verify worksheet/CRF 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/CRF 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.
10.1.3.3
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.
10.1.4
Committees Structure
10.1.4.1
Scientific Advisory Committee
This study was developed in collaboration with a Scientific Advisory Committee (SAC). The 
SAC is comprised of both Sponsor and non-Sponsor scientific experts who provide input 
with respect to study design, interpretation of study results, and subsequent peer-reviewed 
scientific publications.
10.1.4.2
Executive Oversight Committee
The Executive Oversight Committee (EOC) is comprised of members of Sponsor Senior 
Management. The EOC will receive and decide upon any recommendations made by the
DMC regarding the study.
 
 
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10.1.4.3
External Data Monitoring Committee
To supplement the routine study monitoring outlined in this protocol, an external DMC will 
monitor the interim data from this study. The voting members of the committee are external 
to the Sponsor. The members of the DMC must not be involved with the study in any other 
way (eg, they cannot be study investigators) and must have no competing interests that could 
affect their roles with respect to the study.
The DMC will make recommendations to the EOC regarding steps to ensure both participant 
safety and the continued ethical integrity of the study. Also, the DMC will review interim 
study results, consider the overall risk and benefit to study participants (Section 9.7) and 
recommend to the EOC whether the study should continue in accordance with the protocol.
Specific details regarding composition, responsibilities, and governance, including the roles 
and responsibilities of the various members and the Sponsor protocol team; meeting 
facilitation; the study governance structure; and requirements for and proper documentation 
of DMC reports, minutes, and recommendations will be described in the DMC charter that is 
reviewed and approved by all the DMC members.
10.1.5
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.
10.1.6
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 study 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. 
10.1.7
Compliance with Law, Audit, and Debarmen
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 GCP
(eg, International Conference on Harmonization of Technical Requirements for Registration 
of Pharmaceuticals for Human Use GCP: 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 Code of 
Conduct for Clinical Studies.
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.
10.1.8
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 any regulatory authorities as a result of an audit or inspection to 
cure deficiencies in the study documentation and worksheets/CRFs.
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.
10.1.9
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.
10.1.10
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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10.2
Appendix 2: Clinical Laboratory Tests
•
The tests detailed in Table 8 will be performed at the study site or by the central 
laboratory.
•
Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5 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.
 
 
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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
AST/ SGOT
ALT/ SGPT
Alkaline phosphatase
Total bilirubin (and direct bilirubin, if total bilirubin is elevated 
above the upper limit of normal)
Renal function tests
Blood Urea Nitrogen (BUN)
Creatinine
eGFR calculation:
eGFR will be calculated with each serum creatinine 
measurement (using the Chronic Kidney Disease Epidemiology 
Collaboration [CKD EPI] formula [http://mdrd.com/])
Other
Glucose (non-fasting)
Albumin
Total Protein
Urine Dipstick/ 
Routine 
Urinalysis

Specific gravity, pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, 
nitrite, leukocyte esterase by dipstick

Microscopic examination (crystals will be characterized)
Note: Dipstick performed at the site for ALL participants. Urine samples are also 
collected and sent to central laboratory for ALL participants.
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 Section 1.3.
ALT/SGPT = alanine aminotransferase (SGPT); AST/SGOT = aspartate aminotransferase (SGOT); eGFR = estimated 
glomerular filtration rate; MCH = mean corpuscular hemoglobin; MCV = mean corpuscular volume; RBC = red blood cell; 
SGOT = serum glutamic-oxaloacetic transaminase; SGPT = serum glutamic-pyruvic transaminase; WBC = white blood cell.
The investigator (or medically qualified designee) must document their review of each 
laboratory safety report.
 
 
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10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
10.3.1
Definition of AE
AE definition
•
An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of study intervention, whether or not considered related to the 
study intervention.
•
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 intervention.
•
NOTE: For purposes of AE definition, study intervention (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, 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 intervention 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 
intervention or a concomitant medication.
•
For all reports of overdose (whether accidental or intentional) with an associated AE, the 
AE term should reflect the clinical symptoms or abnormal test result. An overdose 
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 8.4.6 for protocol-specific exceptions.
10.3.2
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.
An 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 an SAE. A pre-existing condition is a clinical condition that is 
diagnosed prior to the use of an MSD product and is documented in the participant’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, 
 
 
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and accidental trauma (eg, sprained ankle) that may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
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 1 
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.
10.3.3
Additional Events Reported
Additional events that require reporting
In addition to the above criteria, AEs 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
10.3.4
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 AE 
CRFs/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 
 
 
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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.
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 sufficient discomfort to interfere 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 used 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 AE?
•
The determination of the likelihood that the Sponsor’s product caused the AE 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 AE 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 AE:
-
Exposure: Is there evidence that the participant was actually exposed to the 
Sponsor’s product such as: reliable history, acceptable compliance assessment (pill 
 
 
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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.
-
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 1 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 1 time.)
NOTE: IF A RECHALLENGE IS PLANNED FOR AN AE THAT WAS SERIOUS AND 
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 
IRB/IEC.
•
Consistency with study intervention profile: Is the clinical/pathological presentation of 
the AE consistent with previous knowledge regarding the Sponsor’s product or drug class 
pharmacology or toxicology?
 
 
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•
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 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 1 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.
 
 
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10.3.5
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 8.4.1  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 EDC tool will be taken off-line to prevent 
the entry of new data or changes to existing data.
•
If a site receives a report of a new SAE from a study participant or receives updated data 
on a previously reported SAE after the EDC 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 Study File Binder (or 
equivalent).
SAE reporting to the Sponsor via paper CRF
•
If the EDC 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 Study File Binder (or equivalent).
 
 
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10.4
Appendix 4: Medical Device Incidents: Definition and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
Not applicable.
 
 
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10.5
Appendix 5: Contraceptive Guidance and Pregnancy Testing
10.5.1
Definitions
Women of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile.
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 
hormone replacement therapy (HRT). However, in the absence of 12 months of 
amenorrhea, confirmation with 2 FSH measurements in the postmenopausal range is 
required.
-
Females on HRT and whose menopausal status is in doubt will be required to use 1 of 
the nonhormonal 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.
10.5.2
Contraception Requirements
Male Participants
Male participants are not required to use a form of contraception.
 
 
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Female Participants
Female participants of childbearing potential are eligible to participate if they agree to use 
one of the contraception methods described in Table 9 consistently and correctly during the 
protocol-defined time frame in Section 5.1.
Table 9
Contraceptive Methods
Highly Effective Contraceptive Methods That Are User Dependenta
Failure rate of <1% per year when used consistently and correctly.
●Combined (estrogen- and progestogen- containing) hormonal contraceptionb
○
Oral
○
Intravaginal
○
Transdermal
○
Injectable
●Progestogen only hormonal contraceptionb
○
Oral
○
Injectable
Highly Effective Methods That Have Low User Dependency
Failure rate of <1% per year when used consistently and correctly.
●Progestogen- only contraceptive implantb
●Intrauterine hormone-releasing system (IUS)b
●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 intervention. The reliability of sexual 
abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual lifestyle 
of the participant.
Notes:
Use should be consistent with local regulations regarding the use of contraceptive methods for participants of clinical 
studies.
a
Typical use failure rates are higher than perfect-use failure rates (ie, when used consistently and correctly).
b
If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) guidelines, acceptable hormonal 
contraceptives are limited to those which inhibit ovulation.
WOCBP = women of childbearing potential
10.5.3
Pregnancy Testing
WOCBP should only be included after a negative highly sensitive urine or serum pregnancy 
test.
Pregnancy testing will be performed at Visit 1 (in WOCBP) and after Visit 1 whenever an 
expected menstrual cycle is missed or when pregnancy is otherwise suspected. Testing can 
also be performed as necessary based on local requirements.
 
 
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10.6
Appendix 6: Collection and Management of Specimens for Future Biomedical 
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 8.9 will 
be used in various experiments to understand:
•
The biology of how drugs/vaccines work
•
Biomarkers responsible for how a drug/vaccine enters and is removed by the body
•
Other pathways drugs/vaccines may interact with
•
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.
 
 
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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 substudy
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 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 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 
 
 
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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 substudy. 
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. 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 
 
 
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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.
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.
 
 
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12. Questions
Any questions related to the future biomedical research should be emailed directly to 
clinical.specimen.management@merck.com.
13. References
1.
National Cancer Institute [Internet]: Available from 
https://www.cancer.gov/publications/dictionaries/cancer-terms?cdrid=45618
2.
International Conference on Harmonization [Internet]: E15: Definitions for 
Genomic Biomarkers, Pharmacogenomics, Pharmacogenetics, Genomic Data 
and Sample Coding Categories. 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 [Internet]: 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 [Internet]: Pharmacogenomics 
Informational Brochure for IRBs/IECs and Investigational Site Staff. 
Available at http://i-pwg.org/
 
 
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10.7
Appendix 7: Country-specific Requirements
The China Extension Period
The China extension period is designed to extend China enrollment beyond the global study 
period to achieve locally required sample size and to evaluate the efficacy and safety of MK-
7264 in Chinese participants with refractory or unexplained chronic cough.
Top line results from the Phase 3 studies (P027 and P030) announced that treatment with 
MK-7264 15 mg twice daily did not meet the primary efficacy endpoint. Thus, removing the 
MK-7264 15 mg BID group applies to participants allocated after the protocol amendment. 
Those participants randomized to MK-7264 15 mg BID group will continue in their assigned 
treatment allocation for the duration of the study.
1. Overall study design of China Extension Study Period: 
This amendment removes the MK-7264 15 mg BID group. Others of the overall study design 
remain the same as the Global Cohort (i.e., inclusion and exclusion criteria, study endpoints, 
study assessments and procedures, safety assessments and reporting, and statistical methods). 
Study Objectives
The objectives of the China Cohort are to evaluate the efficacy and safety of MK-7264 45 mg 
BID in Chinese participants with refractory or unexplained chronic cough.
Efficacy evaluation of the MK-7264 15 mg BID group will be removed from the study 
objectives of the China Cohort. Safety evaluation of participants that have already been 
randomized to the  MK-7264 15 mg BID group will be kept consistent with the Global 
Cohort.
Study Procedures
Eligible participants under the current protocol amendment will be randomized in a 1:1 ratio 
to 1 of 2 treatment groups: MK-7264 45 mg BID or placebo (Figure 4).  There will be no 
changes to the participants randomized prior to the Protocol Amendment 05 approval (i.e., all 
participants randomized under P030-03 will continue in the same treatment group they were 
randomized to for the duration of the study). 
The IRT system will be updated to allow dispensing of only one bottle. The IRT update only 
applies to new participants randomized. Following the IRT system updated, newly 
randomized participants will receive 1 study intervention bottle (ie, MK-7264 45 mg OR 
placebo matched to MK 7264 45 mg) for the duration of their participation in the study. All 
already randomized participants will continue to receive 2 study intervention bottles as 
described in protocol Section 8.1.9 for the duration of their participation in the study. 
 
 
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Note: Figure 4 applies to participants allocated after P030-05 implementation.
Figure 4
Study Design of China Extension Period
China Sample Size and Enrollment Strategy
It is planned to enroll approximately 160 Chinese participants in the China Cohort. This will 
include participants enrolled in China during the global enrollment period as well as the 
China extension period. When enrollment of the Global Cohort is closed, participants from 
China will be enrolled in the China extension period until approximately 130 Chinese 
participants are randomized into the MK-7264 45 mg BID and placebo groups combined, 
which will account for 15% of sample size in global corresponding groups per local authority 
request (Figure 5).
*Note: Total sample size of the China Cohort include all participants randomized under P030-03 and P030-05, including 
approximately 130 participants randomized into the MK-7264 45 mg BID and placebo groups combined, as originally 
planned.
Figure 5
China Enrollment Strategy
 
 
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2. Estimated Duration of China Extension Period:
The sponsor estimates the China extension study period will require approximately 2.5 years 
from the time the first participant signs the informed consent until the last participant’s last 
visit in the China extension study period.
3. Statistical Analysis Plan for China Extension Period: 
All objectives for the China Cohort are considered as exploratory and there are no associated 
testing hypotheses. The evaluation of treatment effect will be estimated in the China Cohort.
Eligible participants under the current protocol amendment will be randomized in a 1:1 ratio 
to MK-7264 45 mg BID group or placebo group for a total sample size of approximately 
160 (including approximately 130 participants in the MK-7264 45 mg BID and placebo 
groups combined to meet local authority requirements that at least 15% of participants in the 
global study are Chinese). All participants enrolled in the China Cohort will be analyzed
separately.
The FAS population that includes the Chinese participants randomized into the MK-7264 
45 mg BID group or placebo group will serve as the primary population for the analysis of 
efficacy data in the China Cohort.
The APaT population (including Chinese participants in MK-7264 15 mg BID group, where 
appropriate) will be used for the safety analysis in the China Cohort.
Details of the statistical analysis will be provided in a supplemental SAP.
 
 
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10.8
Appendix 8: Abbreviations
Abbreviation
Expanded Term
ACCP
American College of Chest Physician
AE
Adverse event 
ALT (SGPT)
Alanine aminotransferase (serum glutamic pyruvic transaminase)
ANCOVA
Analysis of covariance
APaT
All participants as treated
ATP
Adenosine triphosphate
AST (SGOT)
Aspartate aminotransferase (serum glutamic oxaloacetic transaminase)
ATS
American Thoracic Society
BID
Twice daily
CF
Compact flash
CFR
Code of Federal Regulations
CI
Confidence interval
CKD EPI
Chronic Kidney Disease Epidemiology Collaboration
CP
Conditional power
CRF
Case report form
CSD
Cough Severity Diary
CSR
Clinical study report
DMC
Data Monitoring Committee 
DNA
Deoxyribonucleic acid 
ECG
Electrocardiogram 
ECI
Event of clinical interest
eCRF
Electronic case report form
eGFR
Estimated glomerular filtration rate
EMA
European Medicines Agency
EOC
Executive Oversight Committee 
ePRO
Electronic patient-reported outcome
EQ5D-5L
EuroQoL 5 Dimensions Questionnaire
ERS
European Respiratory Society
FAS
Full analysis set
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Amendments Act
FEV1
Forced expiratory volume in 1 second
FVC
Forced vital capacity
GCP
Good Clinical Practice 
GERD
Gastroesophageal reflux disease
HARQ
Hull Airway Reflux Questionnaire
HRQoL
Health-related quality of life
IB
Investigator’s Brochure 
ICF
Informed Consent Form 
ICH
International Conference on Harmonization
IEC
Independent Ethics Committee
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
PP
Per-protocol
PRO
Patient-reported outcome
RBC
Red blood cell (count)
 
 
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Abbreviation
Expanded Term
RNA
Ribonucleic acid
SAE
Serious adverse event
SD
Standard deviation
SF-12
12-item short form survey
SoA
Schedule of Activities
SOP
Standard operating procedure
sSAP
Supplemental Statistical Analysis Plan
UACS
Upper airway cough syndrome
VAS
Visual analog scale
WBC
White blood cell (count)
WOCBP
Woman/women of childbearing potential 
WPAI
Work productivity and activity impairment
 
 
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11
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