Clinical trial NCT03696108
Conditions: Chronic Cough
Sponsor: Merck Sharp & Dohme LLC
Start date: 2018-10-31; Completion date: 2020-10-07
Enrollment: 175 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objective of this study is to evaluate the safety of two doses of gefapixant (MK-7264) in Japanese adult participants with refractory or unexplained chronic cough.

Detailed description:

Arms: arm 1: Participants will receive gefapixant 15 mg tablet and placebo tablet to match gefapixant 45 mg twice daily (BID) during the study period (52 weeks). arm 2: Participants will receive gefapixant 45 mg tablet and placebo tablet to match gefapixant 15 mg BID during the study period (52 weeks).
Interventions: intervention 1: Gefapixant intervention 2: Placebo
Intervention descriptions: intervention 1: Gefapixant 15 mg or 45 mg tablet administered orally BID intervention 2: Placebo matched to gefapixant 15 mg or 45 mg administered orally BID

Protocol documents:
Prot_SAP_000.pdf: 
Official Protocol Title: 
NCT number: 
NCT03696108 
Document Date: 
26-SEP-2018
A Phase 3, Randomized, Double-blind Clinical Study to Evaluate the 
Longterm Safety and Efficacy of MK-7264 in Japanese Adult Participants 
with Refractory or Unexplained Chronic Cough


PRODUCT: MK-7264
1
PROTOCOL/AMENDMENT NO.: 038-01
MK-7264-038-01 FINAL PROTOCOL
26-SEP-2018
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).
Protocol Title: A Phase 3, Randomized, Double-blind Clinical Study to Evaluate the Long-
term Safety and Efficacy of MK-7264 in Japanese Adult Participants with Refractory or 
Unexplained Chronic Cough
Protocol Number: 038-01
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):
Approval Date: 26-SEP-2018
 
 
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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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PROTOCOL AMENDMENT SUMMARY OF CHANGES 
Amendment: 01
Overall Rationale for the Amendments:
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 lead to an increased risk of 
clinically relevant adverse events. Therefore, a major update included in this amendment is to change the estimated glomerular 
filtration (eGFR) rate criterion for participant exclusion 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 Visit 1 with unstable renal function (defined as a ≥50% 
increase of serum creatinine compared to a value obtained at least 6 months prior to Visit 1) are also excluded.
Clarifications of certain sections and procedures, as detailed below, were also made in the protocol during the creation of this 
amendment. 
Summary of Changes Table:
Section # and Name
Description of Change 
Brief Rationale 
1.3 – Schedule of Activities
Removed explanatory text in the notes 
column.
Explanatory text is found in the protocol 
body and is now cross-referenced in the 
Schedule of Activities. 
Added row for contact to participant 
enrollment center.
For reference
Added weight measurements to be 
conducted at Visit 3 and Visit 6.
Included additional visits for weight 
measures to better assess any changes in 
weight throughout the trial.
Added specialized urine collection for 
crystal assay to be performed at Visits 5, 6, 
8, and discontinuation. 
This assessment was included to highlight 
the visits where specialized urine 
collection is required.
 
 
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Section # and Name
Description of Change 
Brief Rationale 
5.2 – Exclusion Criteria
Exclusion #7 was updated to change the 
estimated glomerular filtration (eGFR) rate 
for participant exclusion from a cut-off of 
<50 mL/min/1.73 m2 to cut-off of <30 
mL/min/1.73 m2 OR ≥30 mL/min/1.73 m2 
and <50 mL/min/1.73 m2 at Visit 1 with 
unstable renal function (defined as a ≥50% 
increase of serum creatinine compared to a 
value obtained at least 6 months prior to 
Visit1).
To allow enrollment of participants with
moderate to severe renal impairment in the 
study.
Exclusion #18 was updated to include text 
indicating that laboratory assessments can 
be repeated once at the investigator’s 
discretion.
To provide more flexibility during the 
screening process.
5.3.2 – Caffeine, Alcohol, and Tobacco 
Restrictions
Added text specifying that smoking of any 
kind is not permitted during the study. 
Examples of smoking are provided. 
To better clarify that all tobacco and non-
tobacco smoking items are not permitted 
during the study. 
6.8 – Clinical Supplies Disclosure
Added cross reference for unblinding a 
participant during the study
For reference.
8.1.2 – Inclusion/Exclusion Criteria
Added the instruction for source 
documentation regarding eGFR criterion.
The source documentation of stable serum 
creatinine must be retained to enroll the 
participant with eGFR ≥30 mL/min/1.73 
m2 and <50 mL/min/1.73 m2 at Visit 1 
with stable renal function.
 
 
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Section # and Name
Description of Change 
Brief Rationale 
8.1.10 – Participant Blinding/Unblinding
Removed the description for returning 
random code/disclosure envelops or lists 
and unblinding log to the Sponsor or 
designee.
This process is not applied to this study.
8.2.1– Parient-reported Outcomes (PRO)
Text updated describing training on CSD 
will be needed at Visit 1 and instruction on 
the PRO measurments at each visits.
PRO training at Visit 2 is not necessarily 
needed when training on CSD is conducted 
properly at Visit 1.
8.3.3– Vital Signs and Weight and Height 
Measurements
Removed the method of collection for 
temperature.
To allow flexibility for temperature to be 
collected according to local clinical 
practice
8.3.7 – Renal and Urological Safety 
Assessments
Text updated describing how participants 
with urinary crystals and/or hematuria 
should be assessed by the investigator for 
participation in the study and how a 
participant with MK-7264 crystal should 
be followed .
To adjust the description and and to update 
follow-up procedure for a participant with 
MK-7264 crystal.
10.5 – Appendix 5: Contraceptive 
Guidance and Pregnancy Testing
Added clarification that pregnancy testing 
will be performed at Visit 1 for women of 
childbearing potential (WOCBP) and after 
Visit 1 whenever an expected menstrual 
cycle is missed or when pregnancy is 
otherwise suspected.
To provide better clarification of timing of 
pregnancy testing.
Added text that male participants are not 
required to use a form of contraception.
To clarify contraception use in male 
participants during the study.
Throughout
Minor editorial and document formatting 
revisions.
Minor, therefore have not been 
summarized.
 
 
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Table of Contents
PROTOCOL AMENDMENT SUMMARY OF CHANGES...............................................3
1
PROTOCOL SUMMARY ............................................................................................13
1.1
Synopsis.................................................................................................................13
1.2
Schema ..................................................................................................................16
1.3
Schedule of Activities (SoA) ................................................................................17
2
INTRODUCTION..........................................................................................................20
2.1
Study Rationale....................................................................................................21
2.2
Background ..........................................................................................................21
Pharmaceutical and Therapeutic Background .............................................22
2.2.1
Clinical Studies in Chronic Cough Patients.................................................22
2.2.2
2.3
Benefit/Risk Assessment......................................................................................22
3
HYPOTHESIS, OBJECTIVES, AND ENDPOINTS .................................................23
4
STUDY DESIGN............................................................................................................24
4.1
Overall Design ......................................................................................................24
4.2
Scientific Rationale for Study Design.................................................................25
Rationale for Endpoints ...............................................................................25
4.2.1
4.2.1.1
Safety Endpoints ................................................................................25
4.2.1.2
Efficacy Endpoints.............................................................................25
4.2.1.3
Planned Exploratory Biomarker Research.........................................26
4.2.1.3.1
Planned Genetic Analysis ........................................................26
4.2.1.4
Future Biomedical Research..............................................................27
Rationale for the Use of Comparator/Placebo .............................................27
4.2.2
4.3
Justification for Dose ...........................................................................................27
Doses for This Study....................................................................................27
4.3.1
Maximum Dose/Exposure for This Study ...................................................28
4.3.2
Rationale for Dose Interval and Study Design ............................................28
4.3.3
4.4
Beginning and End of Study Definition .............................................................28
Clinical Criteria for Early Study Termination .............................................28
4.4.1
5
STUDY POPULATION ................................................................................................28
5.1
Inclusion Criteria.................................................................................................29
5.2
Exclusion Criteria ................................................................................................30
5.3
Lifestyle Considerations ......................................................................................32
Meals and Dietary Restrictions....................................................................32
5.3.1
Caffeine, Alcohol, and Tobacco Restrictions ..............................................32
5.3.2
Activity Restrictions ....................................................................................32
5.3.3
 
 
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5.4
Screen Failures.....................................................................................................32
5.5
Participant Replacement Strategy......................................................................32
6
STUDY INTERVENTION............................................................................................32
6.1
Study Intervention(s) Administered...................................................................33
Medical Devices...........................................................................................34
6.1.1
6.2
Preparation/Handling/Storage/Accountability .................................................34
Dose Preparation..........................................................................................34
6.2.1
Handling, Storage, and Accountability........................................................34
6.2.2
6.3
Measures to Minimize Bias: Randomization and Blinding..............................35
Intervention Assignment..............................................................................35
6.3.1
Stratification.................................................................................................35
6.3.2
Blinding........................................................................................................35
6.3.3
6.4
Study Intervention Compliance..........................................................................35
6.5
Concomitant Therapy..........................................................................................35
Rescue Medications and Supportive Care ...................................................37
6.5.1
6.6
Dose Modification ................................................................................................37
6.7
Intervention After the End of the Study............................................................37
6.8
Clinical Supplies Disclosure................................................................................37
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL............................................................................................................37
7.1
Discontinuation of Study Intervention...............................................................37
7.2
Participant Withdrawal From the Study...........................................................38
7.3
Lost to Follow-up .................................................................................................39
8
STUDY ASSESSMENTS AND PROCEDURES ........................................................39
8.1
Administrative and General Procedures ...........................................................40
Informed Consent.........................................................................................40
8.1.1
8.1.1.1
General Informed Consent.................................................................40
8.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research.............................................................................................41
Inclusion/Exclusion Criteria ........................................................................41
8.1.2
Participant Identification Card.....................................................................41
8.1.3
Medical History ...........................................................................................41
8.1.4
Prior and Concomitant Medications Review ...............................................41
8.1.5
8.1.5.1
Prior Medications...............................................................................41
8.1.5.2
Concomitant Medications ..................................................................42
Assignment of Screening Number...............................................................42
8.1.6
Assignment of Treatment/Randomization Number .....................................42
8.1.7
Study Intervention Administration ..............................................................42
8.1.8
 
 
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8.1.8.1
Timing of Dose Administration.........................................................42
Discontinuation and Withdrawal .................................................................43
8.1.9
8.1.9.1
Withdrawal From Future Biomedical Research ................................43
Participant Blinding/Unblinding..................................................................43
8.1.10
Calibration of Equipment.............................................................................44
8.1.11
8.2
Efficacy Assessments ...........................................................................................44
Patient-reported Outcomes (PRO) ...............................................................44
8.2.1
8.2.1.1
Leicester Cough Questionnaire (LCQ) ..............................................44
8.2.1.2
Cough Severity Diary (CSD).............................................................45
8.2.1.3
EuroQoL 5 Version Five Dimensions Questionnaire (EQ5D-5L) ....45
8.2.1.4
Patient Global Impression of Change (PGIC) ...................................45
8.3
Safety Assessments...............................................................................................45
Chest Radiography/Computed Tomography Thorax Scan ..........................45
8.3.1
Physical Examinations.................................................................................46
8.3.2
Vital Signs and Weight and Height Measurements .....................................46
8.3.3
Electrocardiograms ......................................................................................46
8.3.4
Spirometry....................................................................................................46
8.3.5
Clinical Safety Laboratory Assessments .....................................................47
8.3.6
Renal and Urological Safety Procedures .....................................................47
8.3.7
8.4
Adverse Events (AEs), Serious Adverse Events (SAEs), and Other 
Reportable Safety Events ....................................................................................48
Time Period and Frequency for Collecting AE, SAE, and Other 
8.4.1
Reportable Safety Event Information ..........................................................48
Method of Detecting AEs, SAEs, and Other Reportable Safety Events......50
8.4.2
Follow-up of AE, SAE, and Other Reportable Safety Event Information...50
8.4.3
Regulatory Reporting Requirements for SAE .............................................51
8.4.4
Pregnancy and Exposure During Breastfeeding ..........................................51
8.4.5
Disease-related Events and/or Disease-related Outcomes Not Qualifying 
8.4.6
as AEs or SAEs............................................................................................51
Events of Clinical Interest (ECIs) ................................................................51
8.4.7
8.5
Treatment of Overdose........................................................................................52
8.6
Pharmacokinetics.................................................................................................52
8.7
Pharmacodynamics..............................................................................................52
8.8
Biomarkers ...........................................................................................................52
Planned Genetic Analysis Sample Collection..............................................53
8.8.1
8.9
Future Biomedical Research Sample Collection...............................................53
8.10
Visit Requirements...............................................................................................53
Pre-screening................................................................................................53
8.10.1
 
 
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Screening......................................................................................................53
8.10.2
Baseline........................................................................................................53
8.10.3
Treatment Period..........................................................................................54
8.10.4
Discontinued Participants Continuing to be Monitored in the Study ..........54
8.10.5
Follow-up Period .........................................................................................54
8.10.6
9
STATISTICAL ANALYSIS PLAN .............................................................................54
9.1
Statistical Analysis Plan Summary.....................................................................55
9.2
Responsibility for Analyses/In-house Blinding .................................................55
9.3
Hypotheses/Estimation ........................................................................................56
9.4
Analysis Endpoints...............................................................................................56
Efficacy Endpoints.......................................................................................56
9.4.1
Safety Endpoints ..........................................................................................56
9.4.2
9.5
Analysis Populations............................................................................................56
Efficacy Analysis Population.......................................................................56
9.5.1
Safety Analysis Population..........................................................................57
9.5.2
9.6
Statistical Methods...............................................................................................57
Statistical Methods for Efficacy Analyses ...................................................57
9.6.1
Statistical Methods for Safety Analyses ......................................................57
9.6.2
Summaries of Baseline Characteristics, Demographics, and Other 
9.6.3
Analyses.......................................................................................................58
9.7
Interim Analyses ..................................................................................................58
9.8
Multiplicity ...........................................................................................................58
9.9
Sample Size and Power Calculations .................................................................58
9.10
Subgroup Analyses...............................................................................................59
9.11
Compliance (Medication Adherence).................................................................59
9.12
Extent of Exposure...............................................................................................59
10
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS .....................................................................................................60
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations ........60
Code of Conduct for Clinical Trials.............................................................60
10.1.1
Financial Disclosure.....................................................................................62
10.1.2
Data Protection.............................................................................................62
10.1.3
10.1.3.1
Confidentiality of Data ......................................................................63
10.1.3.2
Confidentiality of Participant Records...............................................63
10.1.3.3
Confidentiality of IRB/IEC Information............................................63
Publication Policy........................................................................................63
10.1.4
Compliance with Study Registration and Results Posting Requirements ...64
10.1.5
Compliance with Law, Audit, and Debarmen .............................................64
10.1.6
 
 
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Data Quality Assurance ...............................................................................65
10.1.7
Source Documents .......................................................................................65
10.1.8
Study and Site Closure.................................................................................66
10.1.9
10.2
Appendix 2: Clinical Laboratory Tests..............................................................67
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting...............................................................68
Definition of AE ..........................................................................................68
10.3.1
Definition of SAE ........................................................................................69
10.3.2
Additional Events Reported.........................................................................70
10.3.3
Recording AE and SAE ...............................................................................70
10.3.4
Reporting of AE, SAE, and Other Reportable Safety Events to the 
10.3.5
Sponsor ........................................................................................................74
10.4
Appendix 4: Medical Device Incidents: Definition and Procedures for 
Recording, Evaluating, Follow-up, and Reporting...........................................76
10.5
Appendix 5: Contraceptive Guidance and Pregnancy Testing........................77
Definitions....................................................................................................77
10.5.1
Contraception Requirements........................................................................77
10.5.2
Pregnancy Testing........................................................................................78
10.5.3
10.6
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research............................................................................................79
10.7
Appendix 7: Country-specific Requirements ....................................................84
10.8
Appendix 8: Abbreviations .................................................................................85
11
REFERENCES...............................................................................................................87
 
 
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LIST OF TABLES
Table 1
Study Interventions ....................................................................................33
Table 2
Example of Concomitant Treatments Permitted in the Study ...................37
Table 3
Reporting Time Periods and Time Frames for Adverse Events and 
Other Reportable Safety Events.................................................................49
Table 4
Protocol-required Safety Laboratory Assessments....................................67
Table 5
Contraceptive Methods ..............................................................................78
 
 
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LIST OF FIGURES
Figure 1
Study Design..............................................................................................16
 
 
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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A Phase 3, Randomized, Double-blind Clinical Study to Evaluate the Long-
term Safety and Efficacy of MK-7264 in Japanese Adult Participants with Refractory or 
Unexplained Chronic Cough
Short Title: MK-7264 Phase 3 long-term study in Japanese adult participants with refractory
or unexplained chronic cough
Acronym: Not Applicable
Hypotheses, Objectives, and Endpoints:
There are no hypothesis for this study.
In this study, the objectives and endpoints below will be evaluated by treatment group and 
combined in Japanese adult participants with refractory or unexplained chronic cough.
Primary Objectives
Primary Endpoints
- To evaluate the safety and tolerability of 
MK-7264 through 52 weeks
- Adverse event (AE)
- Study treatment discontinuations due to AE
Secondary Objectives
Secondary Endpoints
- To evaluate the efficacy of MK-7264 in 
improving cough specific quality of life with 
change from baseline at Week 12 and 
through 52 weeks
- Leicester Cough Questionnaire (LCQ) 
 
 
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Overall Design:
Study Phase
Phase 3
Primary Purpose
Treatment
Indication
Treatment of refractory or unexplained chronic cough
Population
Japanese adult participants at least 20 years of age with 
refractory or unexplained chronic cough
Study Type
Interventional
Intervention Model
Parallel
This is a multi-site study.
Type of Control
No Treatment Control
Study Blinding
Double-blind
Masking
Participant, Investigator
Estimated Duration of Study
The Sponsor estimates that the study will require 
approximately 23 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 160 participants will be randomized and 84 participants will complete the 
study to evaluate the 1-year safety as described in Section 9.9.
 
 
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Intervention Groups and Duration:
Intervention 
Groups
Intervention 
Group Name
Drug
Dose 
Strength
Dose 
Frequency
Route 
of 
Admin.
Treatment 
Period
Use
MK-7264 45 mg
MK-7264 
45 mg
45 mg
1 tablet
BID
Oral
52 weeks
Experimental
Placebo 
matched to 
MK-7264 
15 mg
0 mg
1 tablet
BID
Oral
52 weeks
Placebo
MK-7264 15 mg
MK-7264 
15 mg
15 mg
1 tablet
BID
Oral
52 weeks
Experimental
Placebo 
matched to 
MK-7264 
45 mg
0 mg
1 tablet
BID
Oral
52 weeks
Placebo
Total 
Number
2
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 2 weeks, each participant 
will be receiving assigned intervention for approximately 52 weeks.  After 
the end of treatment period, each participant will be followed for 2 weeks.
Study Governance Committees:
Steering Committee
No
Executive Oversight Committee
No
Data Monitoring Committee
No
Clinical Adjudication Committee
No
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.
 
 
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1.2
Schema
The study design is depicted in Figure 1.
Abbreviations: SC=screening; FU=follow up; TC=telephone contact
Figure 1
Study Design
 
 
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1.3
Schedule of Activities (SoA)
Study Period
Screening
Base
line/
Rand
omiz
ation
Treatment Period
Follow
-up
Disc.
Notes
Visit Number
V1
V2
V3
V4
V5
TC*
V6
TC*
V7
TC*
V8
TC
*These TC can be 
conducted as site visits
Scheduled Day
Day-14 to 
Day -7
Day
1
Day
28
Day
56
Day
84
Day
126
Day
168
Day
217
Day
266
Day
315
Day
365
Day
378
Schedule Window 
(Recommended)
NA
NA
±4
dys
±4
dys
±4
dys
±7
dys
±7
dys
±14
dys
±14
dys
±14
dys
±14
dys
+7
dys 
Scheduled Week
Wk-2 to 
Wk-1
Wk
1
Wk
4
Wk
8
Wk
12
Wk
18
Wk
24
Wk
31
Wk
38
Wk
45
Wk
52
Wk
54
Administrative Procedure
Written Informed 
Consent
X
See Section 4.1.
Written Informed 
Consent for Future 
Biomedical Research
X
Inclusion/Exclusion 
Criteria
X
X
Participant 
Identification Card
X
Demographics, 
Medical & 
Medication History
X
X
Prior/Concomitant 
Medication Review
X
X
X
X
X
X
X
X
X
X
X
X
X
Intervention 
Randomization
X
MK-7264
Administration
<=
=
=
=
=
=
=
=
=
=>
See Section 8.1.8.
Study Treatment 
Accountability
X
X
X
X
X
X
X
X
X
X
X
At TC, general treatment 
compliance will be
checked.
 
 
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Study Period
Screening
Base
line/
Rand
omiz
ation
Treatment Period
Follow
-up
Disc.
Notes
Visit Number
V1
V2
V3
V4
V5
TC*
V6
TC*
V7
TC*
V8
TC
*These TC can be 
conducted as site visits
Scheduled Day
Day-14 to 
Day -7
Day
1
Day
28
Day
56
Day
84
Day
126
Day
168
Day
217
Day
266
Day
315
Day
365
Day
378
Schedule Window 
(Recommended)
NA
NA
±4
dys
±4
dys
±4
dys
±7
dys
±7
dys
±14
dys
±14
dys
±14
dys
±14
dys
+7
dys 
Scheduled Week
Wk-2 to 
Wk-1
Wk
1
Wk
4
Wk
8
Wk
12
Wk
18
Wk
24
Wk
31
Wk
38
Wk
45
Wk
52
Wk
54
Contact Participant 
Enrollment Center
X
X
X
X
X
X
X
X
X
Efficacy Procedures
LCQ
X
X
X
X
X
X
X
X
CSD
Daily
X
X
X
X
X
X
See Section 8.2.1.2.
EQ5D-5L
X
X
X
X
X
PGIC
X
X
X
X
Safety Procedure
Chest radiograph or 
CT Thorax
X
See Section 8.3.1.
Spirometry
X
See Section 8.3.5.
Physical examination 
X
X
X
X
See Section 8.3.2.
Vital Signs
X
X
X
X
X
X
X
X
X
Height
X
Weight
X
X
X
X
X
X
12-lead ECG
X
Hematology &
Chemistry
X
X
X
X
X
Urinalysis
(w/Microscopy)
X
X
X
X
X
Dipstick for 
hematuriaperformed for 
ALL paticipants at the 
site. Samples are also 
collected and sent to 
central laboratory for 
ALL participants.
 
 
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Study Period
Screening
Base
line/
Rand
omiz
ation
Treatment Period
Follow
-up
Disc.
Notes
Visit Number
V1
V2
V3
V4
V5
TC*
V6
TC*
V7
TC*
V8
TC
*These TC can be 
conducted as site visits
Scheduled Day
Day-14 to 
Day -7
Day
1
Day
28
Day
56
Day
84
Day
126
Day
168
Day
217
Day
266
Day
315
Day
365
Day
378
Schedule Window 
(Recommended)
NA
NA
±4
dys
±4
dys
±4
dys
±7
dys
±7
dys
±14
dys
±14
dys
±14
dys
±14
dys
+7
dys 
Scheduled Week
Wk-2 to 
Wk-1
Wk
1
Wk
4
Wk
8
Wk
12
Wk
18
Wk
24
Wk
31
Wk
38
Wk
45
Wk
52
Wk
54
Specialized Urine 
Collection for 
Crystal Assay
X
X
X
X
Urine Pregnancy 
Test (WOCBP only)
X
See Appendix 5 for 
instructions on when 
pregnancy testing should 
be performed after Visit 
1.
Serum β-Human 
Chorionic 
Gonadotropin
X
Only if urine pregnancy 
test is positive
Adverse Event 
Monitoring
X
X
X
X
X
X
X
X
X
X
X
X
X
See Table 3 for further 
details
Biomarkers
Blood for Genetic 
Analysis
X
Collected from 
randomized participants 
only; See Section 8.8.1 
and 8.9
Abbreviations: CSD = Cough Severity Diary; CT = computed tomography; Disc. = discontinuation; dys = days; ECG = electrocardiogram; EQ5D-5L = EuroQoL 
5 Version Five Dimensions Questionnaire; LCQ = Leicester Cough Questionnaire; NA = not applicable; PGIC = Patient Global Impression of Change; TC = 
telephone contact; V = visit; Wk =Week
 
 
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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] [Irwin, R. 
S., et al 2006] [Morice, A. H., et al 2006] [The committee for The Japanese Respiratory 
Society guidelines 2006] [Kardos, P., et al 2010]. In these clinical guidelines, including 
Japan, cough is categorized based upon the duration of the cough; within each category 
(acute, subacute, and chronic) are likely diagnostic possibilities [Irwin, R. S., et al 2006].
Acute cough is present for less than 3 weeks and most often due to acute viral upper 
respiratory tract infection (URTI). A cough that has been present longer than 3 weeks is 
either sub-acute (3 to 8 weeks) or chronic (> 8 weeks).
It is reported in Japan that the prevalence of the chronic cough may affect up to
approximately 2% of the adult population and the most common underlying condition is 
asthma/cough-variant asthma followed by sinobronchial syndrome, atopic cough, 
gastroesophageal reflux disease (GERD) and postinfections[Fujimura, M. 2012]. Most of the 
patients with cough could be effectively managed by optimizing therapy for the underlying 
condition. However, a minority of patients with a potential 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 Japan 
Ministry of Health, Labour and Welfare, the United States Food and Drug Administration or
European Medicines Agency for the treatment of chronic cough. Given the prolonged nature,
significant morbidity, and the lack of effective treatment, refractory or unexplained 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. ATP is released by
 
 
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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 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]. ATP and P2X3-containing receptors have been shown to be involved in 
airways sensitization and their involvement provides a rationale for P2X3 antagonism in the 
treatment of cough.
Cough Hypersensitivity Syndrome
Recently, the term cough hypersensitivity syndrome has been proposed to describe a group of
patients with chronic cough and similar clinical characteristics [Chung, K. F. 2014]. These
similar clinical characteristics include irritation in the throat or upper chest, cough triggered
by 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. The data from Protocol 012 support the role 
of P2X3 antagonism in the treatment of patients with refractory or unexplained chronic
cough.
2.1
Study Rationale
The purpose of this study is to evaluate the long-term safety of MK-7264, an orally available 
P2X3 antagonist, in adult Japanese participants, at least 20 years of age, who have either 
refractory or unexplained chronic cough.
Current therapies for 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 for MK-7264 in non-Japanese adult participants with refractory and 
unexplained chronic cough (refer to the Investigator’s Brochure [IB]). The purpose of this 
study is to evaluate the long-term safety of MK-7264 with regulatory required number of 
Japanese refractory or unexplained chronic cough patients.
2.2
Background
Refer to the IB for detailed nonclinical and clinical background information on MK-7264.
 
 
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Pharmaceutical and Therapeutic Background
2.2.1
MK-7264, a P2X3 receptor antagonist, has been evaluated in clinical studies for the
treatment of chronic cough, interstitial cystitis/bladder pain syndrome, osteoarthritis pain,
and asthma. MK-7264 has also been evaluated in an extensive nonclinical program.
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 tablet, respectively, in 
appearance. The placebo tablets contain no MK-7264, but contain the same inactive 
excipients as those included in the active tablets.
Clinical Studies in Chronic Cough Patients
2.2.2
Two phase 3 studies (Protocol 027 and Protocol 030) are ongoing to evaluate the efficacy 
and safety of MK-7264 in adult participants with refractory or unexplained chronic cough. 
As for Japanese adult participants with refractory or unexplained chronic cough, a phase 2 
study (Protocol 033) was conducted to evaluate the safety and efficacy. This study has been 
completed and the Clinical Study Report is not finalized.
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 adverse events (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 gustatorysensory 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 the IB and the lack of 
significant safety findings in completed and ongoing nonclinical and clinical studies, the 
benefit risk balance of MK-7264 is assessed as positive.
Additional details regarding specific benefits and risks for participants participating in this 
clinical study may be found in the accompanying IB and ICF documents.
 
 
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3
HYPOTHESIS, OBJECTIVES, AND ENDPOINTS
There are no hypothesis for this study.
In this study, the objectives and endpoints below will be evaluated by treatment group and 
combined in Japanese adult participants with refractory or unexplained chronic cough.
Objectives
Endpoints
Primary
•
To evaluate the safety and tolerability of 
MK-7264 through 52 weeks
•
Adverse event (AE)
•
Study treatment discontinuations due to 
AE
Secondary
•
To evaluate the efficacy of MK-7264 in 
improving cough specific quality of life 
with change from baseline at Week 12 
and through 52 weeks
•
Leicester Cough Questionnaire (LCQ) 
Exploratory
•
To evaluate the efficacy of MK-7264 in 
improving self-rated cough severity with 
change from baseline at Week 12 and 
through 52 weeks
•
Cough Severity Diary (CSD) 
•
To evaluate the impact of MK-7264 on 
generic health-related quality of life and 
global rating of change through 52 weeks
•
EuroQoL 5 Version Five Dimensions 
Questionnaire (EQ5D-5L)
•
Patient Global Impression of Change 
(PGIC)
•
To explore the relationship between 
genetic variation and response to the 
treatment(s) administered, and 
mechanisms of disease. Variation across 
the human genome may be analyzed for 
association with clinical data collected in 
this study.
•
Germline genetic variation
 
 
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4
STUDY DESIGN
4.1
Overall Design
This is a randomized, no treatment controlled, parallel-group, multi-site, double-blinded 
study of MK-7264 in Japanese adult participants with refractory or unexplained chronic 
cough.
Approximately 160 participants who meet entry criteria will enter the study. The study 
duration for each participant is as follows:

Screening Period: a minimum of 7 days and up to 14 days. For those who need to 
washout therapy, the washout starts after obtaining the informed consent and the
screening period starts from the completion of washout.

Baseline/Randomization: Day 1

Treatment period: 52 weeks

Follow-up period: 14 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.
At study entry, participants will be randomized in 1:1 ratio to 1 of 2 treatment groups: 
MK-7264 45 mg twice daily (BID) or MK-7264 15 mg BID. Participants should remain on 
their assigned treatment throughout the study period. 
A safety follow-up telephone contact will be conducted at a minimum of 14 days (with an 
allowed variance of up to +7 days) after last dose of study intervention. Please refer to details 
in Section 8.10.6.
There will be one planned interim analysis when all the randomized participants have 
completed Week 24, or discontinued prior to Week 24. The initial database lock (to support 
the interim analysis) and all safety and efficacy analyses will be performed on the data up to 
Week 24.  The sponsor will be unblinded at this point in order to analyze and report the data
as the result will be used for the regulatory filing of MK-7264  in Japan. The study team 
responsible for the ongoing monitoring of the study will remain blinded to the treatment-
level results of this interim analysis (safety and efficacy). The final database lock will be 
conducted when all participants have completed or discontinued prior to the completion of 
study.
 
 
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4.2
Scientific Rationale for Study Design
Rationale for Endpoints
4.2.1
4.2.1.1
Safety Endpoints
The safety data for MK-7264 to date has been described in detail in the IB.
To evaluate the safety and tolerability profile of MK-7264 in Japanese adults, the safety and 
tolerability endpoints will be assessed by clinical evaluation of adverse events and 
inspection of other study parameters including vital signs, physical examination, and 
standard laboratory safety tests at time points specified in the SoA. Adverse events are 
graded and recorded according to Section 8.4 and Appendix 3.
4.2.1.2
Efficacy Endpoints
An assessment of cough from the participant’s perspective is important for evaluating the 
response to therapy. Patient-reported outcomes (PROs) associated with cough can be
measured in terms of cough-specific quality of life, cough frequency, intensity, disruption
due to cough, cough severity and global rating of change in chronic cough. The following
cough related measures will be included in this study as secondary and exploratory 
endpoints:
Secondary endpoint:
Leicester Cough Questionnaire (LCQ)
Exploratory endpoints:
Cough Severity Diary (CSD) and Patient Global Impression of Change (PGIC)
As validated PRO measures of cough-specific health-related quality of life (HRQoL) and 
cough severity, data obtained from the LCQ, and CSD will provide important information 
relevant to the efficacy of MK-7264 in participants with refractory or unexplained chronic 
cough.
In regards to the LCQ, a Japanese translated version of the LCQ has been validated for the 
use in Japanese chronic cough patients [Kanemitsu, Y., et al 2016]. There is experience in
using the Japanese translated version of the CSD in the MK-7264 development program. The 
CSD will be linguistically validated.
The impact of chronic cough on HRQoL as assessed by the LCQ is included as the secondary 
endpoint. The LCQ is a 19-item cough-specific HRQoL questionnaire which contains three 
domains (physical, psychological and social), calculated as a mean score for each domain 
ranging from 1 to 7 and total score ranging from 3 to 21. Each item on the LCQ assesses 
symptoms or the impact of symptoms on HRQoL over the past two weeks using a 7-point 
Likert scale ranging from 1 to 7. Higher scores indicate better HRQoL. Data obtained from 
 
 
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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.
The minimally important change of LCQ was defined based on the study with 52 chronic 
cough patients [Raj, A. A., et al 2009]. Improvement of ≥1.3 points was found to be 
predictive of patient-reported improvement on their cough-related symptoms, feelings as 
consequence of their cough, work or social life, and overall quality of life as rated on the 
Global Rating of Change Questionnaires.
The CSD is a 7-item, disease-specific PRO measure completed daily in the evening, with a
recall period of “today.” The measure evaluates frequency of cough (3 items), intensity of
cough (2 items) and disruption (2 items); each item is rated on an 11-point scale ranging from
0 to 10 with higher scores indicating greater severity. A CSD total score and 3 domain scores
(frequency, intensity, disruption) can be calculated.
The PGIC is a single-item question asking the participant to rate the change in their chronic 
cough compared to the start of the study with response options ranging from “very much 
improved” to “very much worse”
In addition to the above cough related PROs,  EuroQoL 5 Version Five Dimensions 
Questionnaire (EQ5D-5L) will be included in this study as exploratory endpoints to evaluate 
generic HRQoL:
Exploratory endpoints: EuroQoL 5 Version Five Dimensions Questionnaire (EQ5D-5L)
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 vertical VAS where the endpoints are labeled “best imaginable health state” and 
“worst imaginable health state”. This information can be used as a quantative measure of 
health outcomes as judged by the individual participant. 
4.2.1.3
Planned Exploratory Biomarker Research
4.2.1.3.1
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.
 
 
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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.
4.2.1.4
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.
Rationale for the Use of Comparator/Placebo
4.2.2
No comparator or placebo arm is included in this study. This study will be conducted as 
double dummy study and as appearance of MK-7264 45 mg and 15 mg tablets are different, 
matching placebos are used to maintain blinding.
4.3
Justification for Dose
Doses for This Study
4.3.1
The dose for this study will be either MK-7264 45 mg BID or MK-7264 15 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 two different doses to study in the Phase 3 program.
 
 
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Maximum Dose/Exposure for This Study
4.3.2
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 52 weeks.
Rationale for Dose Interval and Study Design
4.3.3
In this study, MK-7264 will be orally administered as MK-7264 45 mg BID or 15 mg BID 
based on the safety and pharmacokinetic efficacy results observed to date (refer to the IB).
Based on pharmacokinetic studies, MK-7264 is rapidly absorbed with a median time to reach
maximum plasma concentration (Tmax) of 1.0 to 2.0 hours. In addition, the half-life of 
MK-7264 is approximately 7 to 10 hours and consistent with a BID dosing schedule.
The duration of treatment is up to 1 year in order to provide a more robust assessment of the 
long-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).
Clinical Criteria for Early Study Termination
4.4.1
There are no prespecified criteria for terminating the study early.
5
STUDY POPULATION
Male/Female participants with chronic cough ≥ 4 months and a diagnosis of refractory or 
unexplained chronic cough at least 20 years of age will be enrolled in this study. 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 related to cough (eg, 
gastroesophageal reflux disease [GERD], asthma, or upper airway cough syndrome), the 
participant has received appropriate diagnostic workup and therapy according to the Japanese
Respiratory Society (JRS) guidelines, and the participant continues to cough despite being on 
therapy. Also in this study, unexplained chronic cough is defined as participants who have
had a clinical evaluation of their cough per JRS guidelines and this evaluation has not
suggested a co-morbid condition that may be related to cough. 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
 
 
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5.1
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
Type of Participant and Disease Characteristics
1. Chest radiograph or computed tomography scan of the thorax (within 5 years of Visit 1 
and after the onset of chronic cough) not demonstrating any abnormality considered to be 
significantly contributing to the chronic cough or any other clinically significant lung 
disease in the opinion of the principal investigator or the sub-investigator.
2. Have cough for ≥ 4 months at signing informed consent and a diagnosis of refractory or 
unexplained chronic cough as specified in Section 5.
3. The participant has persistent cough despite of treatment in accordance with the latest 
guideline of cough from the Japanese Respiratory Society and is burden to the participant 
and need further treatment in the opinion of the principal investigator or the sub-
investigator.
Demographics
4. Participant is Japanese Male or Female from 20 years of age inclusive, at the time of 
signing the informed consent.
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 
signing informed consent to 14 days after the last dose of study intervention.
Informed Consent
6. The participant is able to provide written informed consent for the study on their own 
behalf. The participant may also provide consent for Future Biomedical Research.
However the participant may participate in the main study without participating in Future 
Biomedical Research.
 
 
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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 completion of the patient 
report outcomes [PROs]) to the satisfaction of the investigator/qualified designee prior to 
randomization (see Section 8.1.2).
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 Visit 1.
3. Forced expiratory volume in 1 second (FEV1)/ forced vital capacity (FVC) ratio <60% 
(spirometry performed within the past year and after the onset of chronic cough 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).
4. History of upper or lower respiratory tract infection or recent clinically significant change 
in pulmonary status within 4 weeks of Visit 1.
5. 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.
6. Individuals who are currently taking an angiotensin converting enzyme inhibitor or have 
taken an angiotensin converting enzyme inhibitor within 3 months of signing informed 
consent.
7. 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 Visit 1 with unstable renal function 
(defined as a ≥50% increase of serum creatinine compared to a value obtained at least 
6 months prior to Visit 1).
8. 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.
9. Is, at the time of signing informed consent, a user of recreational or illicit drugs or has
had a recent history (within the last year) of drug or alcohol abuse or dependence in the 
opinion of the principal investigator or the sub-investigator.
10. Systolic blood pressure >160 mm Hg or a diastolic blood pressure >90 mm Hg at Visit 1.
 
 
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11. History of anaphylaxis or cutaneous adverse drug reaction (with or without systemic 
symptoms) to sulfonamide antibiotics or other sulfonamide-containing drugs.
12. 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)
13. Has donated or lost ≥1 unit of blood (approximately 300 mL) within 8 weeks prior to the 
first dose of MK-7264.
14. A WOCBP who has a positive urine and serum pregnancy test at Visit 1. If the urine test 
is positive or cannot be confirmed as negative, a serum pregnancy test is required.
Prior/Concomitant Therapy
15. Requiring treatment with a therapy that does not adhere to the guidance parameters
specified in Section 6.5.
Prior/Concurrent Clinical Study Experience
16. Has previously received MK-7264 (excluding participants who received MK-7264 and 
completed the treatment in Protocol 033).
17. Is currently participating in or has participated in an interventional clinical study with an 
investigational compound or device within 30 days of participating in this current study.
Diagnostic Assessments
18. Significantly abnormal laboratory tests at Visit 1 (see Section 8.3.6), including:
a.
alkaline phosphatase (ALP), 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 g/dL, white blood cell count (WBC) <2500 /µl, neutrophil count 
<1500 /µl, platelet count <10 × 104 /µl.
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 
19. Has history or current evidence of any condition, therapy, laboratory abnormality or other 
circumstance that may increase the risk associated with study participation or
investigational product administration or may interfere with the interpretation of study 
results and, in the judgment of the investigator or Sponsor, would make the participant 
inappropriate for entry into this study.
 
 
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20. 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.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
Meals and Dietary Restrictions
5.3.1
No restrictions are required.
Caffeine, Alcohol, and Tobacco Restrictions
5.3.2
Use of any tobacco products will not be allowed during the course of the study. For the 
purposes of the study, smoking is intended to include cigars, e-cigarettes, cigarettes, vapes, 
etc.
Based on known metabolism of MK-7264, there are no effects of alcohol and caffeine 
associated with the study intervention and therefore no related restrictions are required.
Activity Restrictions
5.3.3
No restrictions are required.
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. 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
A participant who discontinues from study intervention or withdraws from the study will not 
be replaced.
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 [study intervention(s) provided by the Sponsor] will be packaged to support 
enrollment .  Clinical supplies will be affixed with a clinical label in accordance with 
regulatory requirements.
 
 
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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 
Administration
Regimen/
Treatment 
Period/
Vaccination 
Regimen
Use
IMP/
NIMP
Sourcing
MK-
7264 
45 mg 
BID
Experi
mental
MK-7264 
45 mg
Drug
Tablet
45 mg
1 tablet 
BID
Oral
52 weeks
Experi
mental
IMP
Sponsor
MK-
7264 
15 mg 
BID
Experi
mental
MK-7264 
15 mg
Drug
Tablet
15 mg
1 tablet 
BID
Oral
52 weeks
Experi
mental
IMP
Sponsor
MK-
7264 
45 mg 
BID
Experi
mental
Placebo 
matched to 
MK-7264 
15 mg
Drug
Tablet
0 mg
1 tablet 
BID
Oral
52 weeks
Placebo
IMP
Sponsor
MK-
7264 
15 mg 
BID
Experi
mental
Placebo 
matched to 
MK-7264 
45 mg
Drug
Tablet
0 mg
1 tablet 
BID
Oral
52 weeks
Placebo
IMP
Sponsor
 
 
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All placebos were created by the Sponsor to match the active product.
All supplies indicated in Table 1 will be provided per the “Sourcing” row depending upon 
local country operational requirements. Every attempt should be made to source these 
supplies from a single lot/batch number where possible (eg, not applicable in the case where 
multiple lots or batches may be required due to the length of the study, etc.).
Refer to Section 8.1.8 for details regarding administration of the study intervention.
Medical Devices
6.1.1
No medical device is used in this study.
6.2
Preparation/Handling/Storage/Accountability
Dose Preparation
6.2.1
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.
Handling, Storage, and Accountability
6.2.2
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 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.
 
 
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6.3
Measures to Minimize Bias: Randomization and Blinding
Intervention Assignment
6.3.1
Participants will be assigned randomly according to a computer-generated allocation 
schedule.
Stratification
6.3.2
No stratification will be used in this study.
Blinding
6.3.3
In this study double-blinding technique with in-house blinding will be used. MK-7264 45 mg 
and MK-7264 15 mg will be packaged identically relative to their matching placebos so that 
blind is maintained. 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.
The study will continue as double-blind only after Week 24 acknowledging that the sponsor 
will be unblinded at that point in order to analyze and report the data.  The study team 
responsible for the ongoing monitoring of the study will remain blinded to the treatment-
level results of this interim analysis  (safety and efficacy).
See Section 8.1.10 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.
Interruptions from the protocol specified intervention plan for compliance <80% between 
visits 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 otherwise stated 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 
 
 
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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 within 1 year prior to Visit 1 will also be recorded. 
The investigator(s) will record any AE on the AEs CRF for which a concomitant therapy was 
administered.
Listed below are specific restrictions for prior/concomitant therapy during the course of the
study:
1. Opioids (including codeine) for the treatment of cough are not allowed from 1 week prior 
to Visit 1 through Visit 2. Participants should not initiate therapy with opioids (including 
codeine) for the treatment of cough from Visit 2 through completion of the treatment 
period.
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 Visit 1 and in the opinion of the investigator, is likely to remain on the stable treatment 
regimen through completion of the treatment period.
2. Pregabalin, gabapentin, or amitriptyline for the treatment of cough is not allowed from 2 
weeks prior to Visit 1 through Visit 2. Participants should not initiate therapy with 
pregabalin, gabapentin, or amitriptyline for the treatment of cough from Visit 2 through 
completion of the treatment period.
Pregabalin, gabapentin, or amitriptyline for indications other than chronic cough are
permitted provided the participant is receiving a stable treatment regimen for at least 2 
weeks prior to Visit 1 and in the opinion of the investigator, is likely to remain on the
stable treatment regimen through completion of the treatment period.
3. Dextromethorphan, guaifenesin, benzonatate and any other over the counter or antitussive 
prescription for the treatment of cough are not allowed from 2 weeks prior to Visit 1 
through Visit 2. Participants should not initiate therapy with any over the counter or 
prescription treatments for cough from Visit 2 through completion of the treatment 
period.
4. Treatments for conditions associated with chronic cough such as GERD, asthma, 
sinobronchial syndrome (SBS), or atopic cough, are permitted provided that participants
are receiving a stable treatment regimen for at least 2 weeks prior to Visit 1 and in the
opinion of the investigator, are likely to remain on the stable treatment regimen through 
completion of the treatment period. Sponsor should be consulted if the treatment were to 
be modified. Possible treatments are provided in Table 2. Note, this list is not meant to be 
comprehensive. Sponsor needs to be consulted for further information.
 
 
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Table 2
Example of Concomitant Treatments Permitted in the Study
Condition
Treatment
GERD
Anti-reflux therapy (proton pump or H2 blockers), and/or pro-
kinetic agents
Asthma
Bronchodilators, inhaled corticosteroids, and/or other anti-
inflammatory agents
SBS
14-membered ring macrolides (e.g. erythromycin)
Atopic cough
Antihistamine
5. Angiotensin converting enzyme inhibitors are not allowed from 3 months prior to signing 
informed consent through completion of the treatment period.
Rescue Medications and Supportive Care
6.5.1
The concomitant therapy defined in Section 6.5 will be allowed for up to 3 weeks for 
treatment of acute cough.
6.6
Dose Modification
Dose modification is not 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 allocation/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 
8.1.10). The Sponsor will not provide random code/disclosure envelopes or lists with the 
clinical supplies.
See Section 8.1.10 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-
 
 
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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 Section 1.3 and Section
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 8.1.9.
A participant must be discontinued from study intervention but continue to be monitored in 
the study for any of the following reasons:
•
The participant requests to discontinue study intervention.
•
The participant’s treatment assignment has been unblinded by the investigator, MSD 
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 (including recommendation to discontinue 
participant from study intervention as part of monitoring for crystalluria/urolithiasis, see 
Section 8.3.7).
•
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, see Section 1.3 and Section 8.10.5 for those procedures to be completed at each 
specified visit.
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 withdraws consent from the 
study.
 
 
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If a participant withdraws from the study, they will no longer receive study treatment or be 
followed at scheduled protocol visits.
Specific details regarding procedures to be performed at the time of withdrawal from the 
study,as well as specific details regarding withdrawal from future biomedical research, are 
outlined in Section 8.1.9. 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.
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 Study File Binder (or equivalent).
•
All study-related medical (or dental) decisions must be made by an investigator who is a 
qualified physician (or dentist when appropriate).
•
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
 
 
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•
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.
The standard amount of blood collected from each participant over the duration of the study 
will be approximately 50 mL (Appendix 2).
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with 
the samples.
8.1
Administrative and General Procedures
Informed Consent
8.1.1
The investigator must obtain documented consent from each potential participant prior to 
participating in a clinical study or future biomedical research .If there are changes to the 
participant’s status during the study (eg, health or age of majority requirements), the 
investigator or qualified designee must ensure the appropriate consent is in place.
8.1.1.1
General Informed Consent
Consent must be documented by the participant’s dated signature on a consent form along 
with the dated signature of the person conducting the consent discussion.
A copy of the signed and dated consent form should be given to the participant before 
participation in the study.
The initial ICF, any subsequent revised written ICF, and any written information provided to 
the participant must receive the Institutional Review Board/Independent Ethics Committee’s 
(IRB/IEC’s) approval/favorable opinion in advance of use. The participant should be 
informed in a timely manner if new information becomes available that may be relevant to 
the participant’s willingness to continue participation in the study. The communication of 
this information will be provided and documented via a revised consent form or addendum to 
the original consent form that captures the participant’s dated signature.
Specifics about a study and the study population will be added to the consent form template 
at the protocol level.
The informed consent will adhere to IRB/IEC requirements, applicable laws and regulations, 
and Sponsor requirements.
 
 
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8.1.1.2
Consent and Collection of Specimens for Future Biomedical Research
The investigator 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.
Inclusion/Exclusion Criteria
8.1.2
All inclusion and exclusion criteria will be reviewed by the investigator to ensure that the 
participant qualifies for the study. This includes assessing the participant’s CSD before 
randomization at Visit 2 to confirm that the participant has an ability to complete the PROs 
during the treatment period.
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 Visit 1 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 Visit 1), documentation of stable 
serum creatinine must be retained as source documentation at the study site.
Participant Identification Card
8.1.3
All participants will be given a participant identification card identifying them as participants 
in a research study. The card will contain study site contact information (including direct 
telephone numbers) to be 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.
Medical History
8.1.4
A medical history will be obtained by the investigator or qualified designee.
Prior and Concomitant Medications Review
8.1.5
8.1.5.1
Prior Medications
The investigator or qualified designee will review prior medication use and record prior 
medication taken by the participant (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 in the eCRF concomitant medication, if 
any, taken by the participant during the study.
Assignment of Screening Number
8.1.6
All consented participants will be given a unique screening number that will be used to 
identify the participant for all procedures that occur prior to randomization.Each participant 
will be assigned only 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 8.10.2.
Assignment of Treatment/Randomization Number
8.1.7
All eligible participants will be randomly allocated and will receive a 
treatment/randomization number. The treatment/randomization number identifies the 
participant for all procedures occurring after treatment allocation/randomization. Once a 
treatment/randomization number is assigned to a participant, it can never be re-assigned to 
another participant.
A single participant cannot be assigned more than 1 treatment/randomization number.
Study Intervention Administration
8.1.8
Since MK-7264 45 mg and 15 mg will differ in appearance and have corresponding matching 
placebos, participants will receive two study intervention bottles for the treatment period (ie, 
either MK-7265 45 mg and placebo matched to MK-7264 15 mg OR MK-7264 15 mg and 
placebo matched to MK-7264 45 mg). Participant should be instructed to take one tablet 
from each bottle BID. 
Participants will be provided with enough study intervention to last between study site visits. 
Prescription and distribution of study interventions are allowed at unscheduled visits as well 
as scheduled visits.
The first dose of study intervention will be administered at the study site at Visit 2 after 
completing baseline assessments. 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. The last dose will be on the day before Visit 8.
8.1.8.1
Timing of Dose Administration
Study intervention will be administered orally BID, approximately 12 hours apart for 
apporoximately 52 weeks during the treatment period.
 
 
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Discontinuation and Withdrawal
8.1.9
Participants who discontinue study intervention prior to completion of the treatment period
should be encouraged to continue to be followed for all remaining study visits.
When a participant withdraws from participation in the study, all applicable activities 
scheduled for the discontinuation visit should be performed (at the time of withdrawal). Any 
AEs that are present at the time of withdrawal should be followed in accordance with the 
safety requirements outlined in Section 8.4 .
8.1.9.1
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). 
Subsequently, the participant's consent for future biomedical research will be withdrawn. A 
letter will be sent from the Sponsor to the investigator confirming the withdrawal. It is the 
responsibility of the investigator to inform the participant of completion of withdrawal. Any 
analyses in progress at the time of request for withdrawal or already performed prior to the 
request being received by the Sponsor will continue to be used as part of the overall research 
study data and results. No new analyses would be generated after the request is received.
In the event that the medical records for the main study are no longer available (eg, if the 
investigator is no longer required by regulatory authorities to retain the main study records) 
or the specimens have been completely anonymized, there will no longer be a link between 
the participant’s personal information and their specimens. In this situation, the request for 
specimen withdrawal cannot be processed. 
Participant Blinding/Unblinding
8.1.10
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.
For emergency situations where the investigator or medically qualified designee needs to 
identify the drug 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 treatment assignment, the investigator or medically qualified 
designee 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.
 
 
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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/medically 
qualified designee and/or nonstudy treating physician must be discontinued from study 
intervention, but should continue to be monitored in the study.
Calibration of Equipment
8.1.11
The investigator or qualified designee has the responsibility to ensure that any device or 
instrument used for a clinical evaluation/test during a clinical study that provides information 
about inclusion/exclusion criteria and/or safety or efficacy parameters shall be suitably 
calibrated and/or maintained to ensure that the data obtained is reliable and/or reproducible. 
Documentation of equipment calibration must be retained as source documentation at the 
study site.
8.2
Efficacy Assessments
Compliance with the efficacy 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.
Patient-reported Outcomes (PRO)
8.2.1
Each participant will be properly trained on CSD at Visit 1 and instructed on the PRO 
measurements at each visit. Participants will be contacted and reminded to complete the CSD 
as trained (eg, at telephone contacts).
Participants who discontinue study intervention early will continue to be monitored in the 
study and should be encourage to continue to complete the PROs measures as outlined in the 
SoA.
8.2.1.1
Leicester Cough Questionnaire (LCQ)
Participants will be asked to complete the 19-item LCQ to assess the impact of their cough 
severity on physical, social and psychological functioning.
Participants will be complete the LCQ at study site visits outlined in the SoA
 
 
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8.2.1.2
Cough Severity Diary (CSD)
Participants will be asked to record their cough frequency, intensity and disruption due to 
cough using the 7-item CSD. Participants will rate each item using an 11-point scale ranging 
from 0 to 10 with higher scores indicating greater severity.
Participants will complete the CSD, daily every evening beginning in the evening on the day 
of  Visit 1 to the day before Visit 2 (for a minimum of 7 days between Visit 1 and prior to  
Visit 2). For Visit 3, 4, 5, 6, 7, and 8, the CSD will be completed every evening beginning 
1 week prior to the visits. Participant should be contacted (eg, by telephone)  around 1 week 
prior to those visits to remind them to complete the CSD during these weeks.
8.2.1.3
EuroQoL 5 Version Five Dimensions Questionnaire (EQ5D-5L)
The EQ5D-5L is a standardized instrument for measuring generic health status used for 
estimating preference weights for that health status. The participant will be asked to indicate 
their health state using a 5-level rating scale. The participant will also be asked to complete 
the EQ VAS to record the participant’s self-rated health on a vertical VAS.
Participants will complete the EQ5D-5L at the study site visits outlined in the SoA.
8.2.1.4
Patient Global Impression of Change (PGIC)
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”. 
Participants will complete the PGIC at the study site visits outlined in the SoA.
8.3
Safety Assessments
Details regarding specific safety procedures/assessments to be performed in this study are 
provided below. The total amount of blood volumes drawn can be found in Section 8.
Planned time points for all safety assessments are provided in the SoA.
Chest Radiography/Computed Tomography Thorax Scan
8.3.1
A chest radiograph or computer tomography scan of the thorax should be performed locally 
for participants, at Screening, if this has not been done within the last 5 years and after the 
onset of chronic cough. The chest radiograph or computer tomography scan of the thorax 
should not demonstrate any abnormality considered to be significantly contributing to the 
chronic cough or any other clinically significant lung disease in the opinion of the 
investigator (see inclusion criterion 1, Section 5.1).
 
 
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Physical Examinations
8.3.2
A complete physical examination will include assessments of the following general
appearance; skin and lymphatic; eyes, ears, nose, throat; cardiovascular system; respiratory
system; abdomen/gastrointestinal system; urological system; musculoskeletal and
neurological systems. Other body systems may be examined.
A brief directed physical examination may be performed as outlined in the SoA except for 
Visit 1. A physical exam (complete or directed) can be performed at any unscheduled visit if 
deemed necessary by the investigator.
Clinically significant changes identified after randomization will be recorded as AEs in the 
eCRF.
Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
Vital Signs and Weight and Height Measurements
8.3.3
Vital sign measurements, including systolic blood pressure (mm Hg), diastolic blood
pressure (mm Hg), heart rate (beats per minute), respiratory rate (breaths per minute), and 
body temperature (in centigrade) will be collected as outlined in the SoA. All blood pressure 
measurements should be performed on the same arm at the same positon, preferably by the
same person. All body temperature should be measured by the same method. 
Height (cm) and weight (kg) will also be collected as per the SoA
Any clinically significant abnormalities in vital signs and changes in weight identified after 
randomization will be recorded as AEs in the eCRF.
Electrocardiograms
8.3.4
A 12-lead electrocardiogram (ECG) will be obtained at Visit 1 using local standard 
procedures.
Spirometry
8.3.5
A spirometry assessment will be performed locally at Visit 1 using a calibrated spirometer. 
Assessments will include FEV1, FVC, and FEV1/FVC ratio.
Spirometry performed within the past year of Visit 1 and after the onset of chronic cough 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).
 
 
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Clinical Safety Laboratory Assessments
8.3.6
•
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 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 14 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.
Renal and Urological Safety Procedures
8.3.7
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 through urinalysis 
(performed at the central laboratory). Dipstick and urinalyses (including microscopy
performed at the central laboratory) will be collected as outlined in the SoA. 
If during screening, a participant has crystalluria and/or unexplained hematuria (defined as 
participants without a history of recent menses, urinary tract infection, or recent 
procedure/instrumentation that would explain the hematuria), the investigator should:

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.
 
 
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
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, the participant has confirmed, unexplained hematuria and/or urinary 
crystals, an urine sample collected via a specialized filter will be shipped to Sponsor or 
designee and assessed for the presence of MK-7264 urinary crystals via Raman 
spectroscopy. Raman spectroscopy is sensitive to the chemical structure of the molecule and 
MK-7264 has unique chemical structure compared to common urinary crystals. See vendor’s 
site manual for further procedural details.
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 analysis performed until resolution of MK-7264 urinary crystals. 
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 or surrogate).
The investigator, who is a qualified physician, is responsible for detecting, assessing, 
documenting, and reporting events that meet the definition of an AE or SAE, as well as other 
reportable safety events. Investigators remain responsible for following up AE, SAEs, and 
other reportable safety events for outcome according to Section 8.4.3.
Time Period and Frequency for Collecting AE, SAE, and Other Reportable 
8.4.1
Safety Event Information
All AEs, SAEs, and other reportable safety events that occur after the consent form is signed 
but before treatment allocation/randomization must be reported by the investigator if the 
participant is receiving placebo run-in or other run-in treatment, if the event 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 phone call, all AEs, SAEs and other reportable safety events must be 
reported by the investigator; however, for those participants who discontinue from the 
study intervention but continue to be monitored, only the AEs and other reportable safety 
events that are shown in Table 3 need to be reported. This specific approach for reporting 
 
 
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starts from completion of the safety follow-up phone call/visit following cessation of 
intervention until the last study-related off-intervention phone 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.
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 all*
Previously reported –
Follow to 
completion/termination; 
report outcome
Within 24 
hours of 
learning of 
event
 
 
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Type of Event
Reporting Time 
Period:
Consent to 
Randomization/ 
Allocation
Reporting Time 
Period:
Randomization/ 
Allocation 
through Protocol-
Specified 
Follow-up Period
Reporting Time Period:
After the Protocol 
Specified Follow-up 
Period
Timeframe 
to Report 
Event and 
Follow-up 
Information 
to 
SPONSOR:
Event of Clinical 
Interest (require 
regulatory reporting)
Report if:
- due to 
intervention
- causes 
exclusion
Report*
- Potential DILI
- Require 
regulatory 
reporting
Not required
Within 24 
hours of 
learning of 
event
Event of Clinical 
Interest (Do not 
require regulatory 
reporting)
Report if:
- due to 
intervention
- causes 
exclusion
Report*
- non-DILI ECIs 
and those not 
requiring 
regulatory 
reporting
Not required
Within 5 
calendar 
days of 
learning of 
event
Cancer
Report if:
- due to 
intervention
- causes 
exclusion
Report all
Not required
Within 5 
calendar 
days of 
learning of 
event
Overdose
Report if:
- receiving 
placebo run-in or 
other run-in 
medication 
Report all*
Not required
Within 5 
calendar 
days of 
learning of 
event
* Participants who discontinue 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/lactation exposure need to be followed 
for completion/termination; report outcome.
Method of Detecting AEs, SAEs, and Other Reportable Safety Events
8.4.2
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.
Follow-up of AE, SAE, and Other Reportable Safety Event Information
8.4.3
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All AE, SAE, and other reportable safety events 
including pregnancy and exposure during breastfeeding, 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.
 
 
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Regulatory Reporting Requirements for SAE
8.4.4
Prompt notification (within 24 hours) by the investigator to the Sponsor of SAE is essential 
so that legal obligations and ethical responsibilities towards the safety of participants and the 
safety of a study 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.
Pregnancy and Exposure During Breastfeeding
8.4.5
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 
serious events (Important Medical Events). If the pregnancy continues to term, the outcome 
(health of infant) must also be reported.
Disease-related Events and/or Disease-related Outcomes Not Qualifying as 
8.4.6
AEs or SAEs
There are no disease-related events and/or disease-related outcomes not qualifying as AEs or 
SAEs.
Events of Clinical Interest (ECIs)
8.4.7
Selected nonserious and SAEs are also known as ECIs and must be reported to the Sponsor.
 
 
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Events of clinical interest for this study include:
1.
An elevated AST or ALT lab value that is greater than or equal to 3X the upper limit 
of normal and an elevated total bilirubin lab value that is greater than or equal to 2X 
the upper limit of normal and, at the same time, an alkaline phosphatase lab value that 
is less than 2X the upper limit of normal, as determined by way of protocol-specified 
laboratory testing or unscheduled laboratory testing.*
*Note: These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may require 
an additional evaluation for an underlying etiology. The study site guidance for 
assessment and follow-up of these criteria can be found in the Investigator 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. 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.
8.6
Pharmacokinetics
PK parameters will not be evaluated in this 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 participants as 
specified in the SoA:

Blood for Genetic Analysis
 
 
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Planned Genetic Analysis Sample Collection
8.8.1
The planned genetic analysis sample should be drawn for planned analysis of the association 
between genetic variants in DNA and drug response. This sample will not be collected at the 
site if there is either a local law or regulation prohibiting collection, or if the IRB/IEC does 
not approve the collection of the sample for these purposes. If the sample is collected, 
leftover extracted DNA will be stored for future biomedical research if the participant signs 
the future biomedical research consent. If the planned genetic analysis is not approved, but 
future biomedical research is approved and consent is given, this sample will be collected for 
the purpose of future biomedical research.
Sample collection, storage, and shipment instructions for planned genetic analysis samples 
will be provided in the operations/laboratory manual.
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.
Pre-screening
8.10.1
Participants who require washout of any therapy (see Section 6.5) should start washout after 
the written informed consent is obtained. The procedures scheduled at Visit 1, for 
participants who require washout, should be started as soon as the washout completes.
Screening period, for these participants, starts from the completion of the washout of 
required therapy.
Screening
8.10.2
Approximately 2 weeks prior to treatment randomization, participants will be evaluated to 
determine that they fulfill the entry requirements as set forth in Section 5. If any participant 
fails to meet the study entry criteria, screening procedures may be repeated once based on 
investigator judgement after initial screening, and after consultation with the Sponsor.
Baseline
8.10.3
Visit 2 must be scheduled between 7 days and 14 days after Visit 1. The first dose is 
administered at the study site.
 
 
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Treatment Period
8.10.4
Participants will be required to be seen in the clinic at Visit 3, 4, 5, 6, 7 and 8 and they are to 
be reminded to bring their CSD with them to the site for these visits. Participants will be
contacted by telephone between Visit 5, 6, 7, and 8 respectively. These telephone contact can 
be conducted as site visits.
Discontinued Participants Continuing to be Monitored in the Study
8.10.5
If a participant is discontinued from the study intervention early, the Discontinuation Visit 
assessments are to be performed as soon as possible.
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. The follow-up information, limited to AEs, concomitant 
medication use, and patient report outcomes (site visits only) will be collected as outlined in 
the SoA. 
Concomitant therapies specifically prohibited (see Section 6.5) while the participant 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 Visit 8 date.
Additionally, the ICF will explain the importance of continued data collection from 
participants, including the use of continued contact by telephone.
Follow-up Period
8.10.6
All participants will be required to complete the safety follow-up telephone contact 
approximately 14 days (+7 days) after the last dose of study intervention to determine if any 
AEs have occurred since discontinuing study intervention.
9
STATISTICAL ANALYSIS PLAN
This section outlines the statistical analysis strategy and procedures for the study.  Changes 
to analyses made after the protocol has been finalized, but prior to unblinding, will be 
documented in a supplemental SAP (sSAP) and referenced in the Clinical Study Report 
(CSR) for the study.  Post hoc exploratory analyses will be clearly identified in the CSR.  
 
 
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9.1
Statistical Analysis Plan Summary
Key elements of the statistical analysis plan are summarized below; the comprehensive plan 
is provided in Sections 9.2-9.12.
Study Design Overview
Phase 3 study, Randomized, Double-blind Clinical Study to 
Evaluate the Long-term Safety and Efficacy of MK-7264 in 
Japanese Adult Participants with Refractory or Unexplained 
Chronic Cough
Treatment Assignment
Participants will be randomized in a 1:1 ratio to either MK-7264 
45 mg BID or MK-7264 15 mg BID.
Analysis Populations
Efficacy: Full Analysis Set (FAS) population.  
Safety: All Participants as Treated (APaT) population.
Primary Endpoint

Adverse events (AEs)

Study treatment discontinuations due to AE
Statistical Methods for 
Key Efficacy Analyses
Change from baseline in LCQ total score at Week 12 and 
through Week 52 will be analyzed using the longitudinal 
analysis of covariance (ANCOVA) model. The model will 
include terms for treatment, visit, the interactions of treatment 
by visit, and baseline value as covariates. The change from 
baseline to each visit and 95% CIs will be estimated from this 
model.
Statistical Methods for 
Key Safety Analyses
AEs will be summarized by the number and percentage of
the participants who experienced respective events. Change 
from baseline in laboratory tests, vital signs at respective
timepoints will be summarized by descriptive statistics.
Interim Analyses
The planned interim analysis (safety and efficacy) will be 
performed based on the data up to Week 24 when all the 
randomized participants have completed Week 24 or 
discontinued prior to Week 24.
Multiplicity
No multiplicity adjustment is planned in this trial.
Sample Size and Power A total of 160 participants will be enrolled. Assuming a 
discontinuation rate of approximately 47% at Week 52, 84
participants are expected to complete 52 weeks of treatment.
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 will be conducted as a double-blind study under in-house blinding procedures.  
Double blinding technique with in-house blinding will be used until all the randomized 
participants have completed Week 24 or discontinued prior to Week 24 after which a double 
blinding only technique will be used.  The official, final database will not be unblinded until 
 
 
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medical/scientific review has been performed, protocol deviations have been identified, and 
data have been declared final and complete.
The Clinical Biostatistics department will generate the randomized allocation schedule(s) for 
study treatment assignment.
9.3
Hypotheses/Estimation
There are no hypotheses for this study.
9.4
Analysis Endpoints
Efficacy Endpoints
9.4.1
•
Leicester Cough Questionnaire (LCQ) total score
•
Mean weekly Cough Severity Diary (CSD) total score
•
EuroQoL 5 Version Five Dimension Questionnaire (EQ5D-5L)
•
Patient Global Impression Change (PGIC)
Safety Endpoints
9.4.2
•
Adverse event (AE)
•
Study treatment discontinuations due to AE
•
Laboratory test
•
Vital sign
•
Taste related AE
•
Oral paraesthesia/hypoethesia
9.5
Analysis Populations
Efficacy Analysis Population
9.5.1
The FAS population will serve as the primary population for the analysis of efficacy data in 
this study. The FAS population consists of all randomized participants who have taken at 
least one dose of study medication and provided at least one baseline and one post-baseline 
endpoint observations during the treatment period. 
 
 
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Participants will be included in the treatment group to which they are randomized for the 
analysis of efficacy data using the FAS populations.
Safety Analysis Population
9.5.2
The APaT population will be used for the analysis of safety data in this study. The APaT 
population consists of all randomized participants who received at least one dose of study 
treatment. Participants will be included in the treatment group corresponding to the study 
treatment they actually received for the analysis of safety data using the APaT population. 
Discontinued participants before Week 52 will be included in APaT population. For most 
participants this will be the treatment group to which they are randomized. Participants who 
take incorrect study treatment for the entire treatment period will be included in the treatment 
group corresponding to the study treatment actually received.
At least one laboratory or vital sign measurement obtained subsequent to at least one dose of 
study treatment is required for inclusion in the analysis of each specific parameter. To assess 
change from baseline, a baseline measurement is also required.
9.6
Statistical Methods
The results will be provided by treatment group and total (combined treatment group). There 
is no plan to do between treatment group comparisons.
Statistical Methods for Efficacy Analyses
9.6.1
The analysis of efficacy endpoints will be based on the FAS population.
The continuous endpoints will be analyzed using the longitudinal analysis of covariance 
(ANCOVA) model. In this model, response variable will be change from baseline. The 
model will include terms for treatment, visit, and the interactions of treatment by visit and 
baseline value as covariates. Visit is treated as a categorical variable so that no restriction is 
imposed on the trajectory of the means over time. This model uses the maximum likelihood 
principle to estimate the parameters and account for missing data in an implicit fashion. The 
change from baseline to each visit and 95% CIs will be estimated from this model. Baseline 
variable is defined as the last non-missing value prior to the treatment.
Statistical Methods for Safety Analyses
9.6.2
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
AEs, study treatment discontinuations due to AE, laboratory tests, vital signs measurements.
All safety analyses will be based on APaT population. 
AEs and other safety events will be summarized using the number and percentage of the
participants who experienced respective events.
 
 
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Taste-related AEs (including dysgeusia, ageusia, and hypogeusia, as well as other related 
terms) and oral paraesthesia/hypoesthesia are considered as AEs of interest.
Continuous measures such as changes from baseline in laboratory, vital signs parameters will 
be summarized using descriptive statistics.
Summary statistics for baseline, on treatment, and change from baseline values will be 
provided in table format.
Summaries of Baseline Characteristics, Demographics, and Other Analyses
9.6.3
Demographic and Baseline Characteristics
The number and percentage of participants screened, randomized, the primary reasons for 
screening failure, and the primary reason for discontinuation will be displayed. 
Demographic variables (including age, gender, weight, and height), baseline characteristics, 
primary and comorbid conditions, and prior and concomitant therapies will be summarized 
either by descriptive statistics or categorical tables.
9.7
Interim Analyses
All safety and efficacy analyses will be performed based on the data up to Week 24 when all 
the randomized participants have completed Week 24 or discontinued prior to Week 24.
Regardless of the result of the interim analysis (safety and efficacy), the study will continue 
as planned. Double blinding only to treatment assignment will be maintained at all 
investigational sites after all participants have completed Week 24.  The results of interim 
analyses (safety and efficacy) will not be shared with the investigators prior to the 
completion of the study.  The study will continue as double-blind only after Week 24 
acknowledging that the sponsor will be unblinded at that point in order to analyze and report 
the data.  The study team responsible for the ongoing monitoring of the study will remain 
blinded to the treatment-level results of this interim analysis  (safety and efficacy).
9.8
Multiplicity
No multiplicity adjustment is planned in this trial.
9.9
Sample Size and Power Calculations
A total of 160 participants will be enrolled. Assuming a discontinuation rate of 
approximately 47%, 84 participants are expected to complete 52 weeks of treatment.  The 
discontinuation rate was estimated from previous study (Protocol 012), which was 12 weeks 
study.
The probability of observing at least one AE in this study depends on the number of 
participants treated and underlying incidence with an AE in the study population. If the 
underlying incidence of an AE is 2%, probability of observing at least one AE is 82% among 
 
 
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84 participants and 57% among 42 participants. If no participants had a specific AE, then 
upper bound of the 95% CI of the underlying incidence rate would be 4.3% for 84 
participants and 8.4% for 42 participants. For LCQ total score, assuming a 3.7 change from 
baseline and a SD of 3.9 at Week 12 based on Protocol 012, a 95% confidence interval of 
change from baseline in LCQ total score would be (2.9, 4.5) for 84 participants and  (2.5, 
4.9) for 42 participants.
9.10
Subgroup Analyses
No subgroup analysis is planned in this study.
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 medication as instructed in Section 8 – Study Assessments and Procedures. When a 
participant takes less than or more than the required medication on a day, that day is not 
considered an On-Therapy day.
For participants who are followed for the entire study period, the “Number of Days Should 
be on Therapy” is the total number of days from the first scheduled treatment day to the last 
scheduled treatment day. For participants who discontinue from the study permanently, the 
“Number of Days Should Be on Therapy” is the total number of days from the first scheduled 
treatment day to the last dose day.
Summary statistics will be provided on percent compliance for the APaT population.
9.12
Extent of Exposure
The duration of treatment for each participant will be evaluated by calculating the number of 
days on therapy.  Exposure to study medication will be summarized using descriptive 
statistics (mean, SD, median, minimum, and maximum) for the APaT population.
 
 
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10
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
Code of Conduct for Clinical Trials
10.1.1
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 
are investigated. When necessary, the clinical site will be closed, the responsible regulatory authorities and 
ethics review committees notified.
 
 
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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.
Financial Disclosure
10.1.2
Financial Disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54). It is the 
Sponsor's responsibility to determine, based on these regulations, whether a request for 
Financial Disclosure information is required. It is the investigator's/subinvestigator's 
responsibility to comply with any such request.
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 
21 CFR Part 54, to provide his/her financial interests in and/or arrangements with the 
Sponsor to allow for the submission of complete and accurate certification and disclosure 
statements. The investigator/subinvestigator(s) further agree to provide this information on a 
Certification/Disclosure Form, commonly known as a financial disclosure form, provided by 
the Sponsor. The investigator/subinvestigator(s) also consent to the transmission of this 
information to the Sponsor in the United States for these purposes. This may involve the 
transmission of information to countries that do not have laws protecting personal data.
Data Protection
10.1.3
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.
Publication Policy
10.1.4
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.
 
 
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Compliance with Study Registration and Results Posting Requirements
10.1.5
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.
By signing this protocol, the investigator acknowledges that the statutory obligations under 
FDAAA, the EMA clinical trials directive or other locally mandated registries are that of the 
Sponsor and agrees not to submit any information about this study or its results to those 
registries. 
Compliance with Law, Audit, and Debarmen
10.1.6
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.
 
 
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Data Quality Assurance
10.1.7
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the Sponsor or designee electronically (eg, laboratory data). The investigator 
or qualified designee is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF.
Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.
Study documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the study site upon request for inspection, 
copying, review, and audit at reasonable times by representatives of the Sponsor or any 
regulatory authorities. The investigator agrees to promptly take any reasonable steps that are 
requested by the Sponsor or 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.
Source Documents
10.1.8
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.
 
 
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Study and Site Closure
10.1.9
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 4 will be performed by the central laboratory or at the study 
site.
•
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.
Table 4
Protocol-required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet Count 
RBC Indices:
MCV
MCH
MCHC
%Reticulocytes
WBC count with 
Differential:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
RBC Count
Hemoglobin
Hematocrit
Chemistry
Electrolytes
Sodium
Potassium
Chloride
Bicarbonate
Calcium
Phosphorous
Liver function tests
Aspartate Aminotransferase
(AST)/ Serum Glutamic-Oxaloacetic Transaminase (SGOT)
Alanine Aminotransferase
(ALT)/ Serum Glutamic-Pyruvic Transaminase (SGPT)
Alkaline phosphatase
Total bilirubin (and direct bilirubin, if total bilirubin is elevated 
above the upper limit of normal)
Renal function tests
Blood Urea Nitrogen
Creatinine 
eGFR calculation
eGFR will be calculated with each serum creatinine measurement 
(using the Japanese Equation for Estimating GFR [Japanese 
Society of Nephrology])
Other
Glucose (nonfasting)
Albumin
Total Protein
Routine 
Urinalysis
At site: Hematuria by dipstick
Central lab: Specific gravity, pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, 
nitrite, leukocyte esterase, Microscopic examination (crystals and blood cell will be 
characterized)
Other Screening 
Tests
Serum or urine β human chorionic gonadotropin (β hCG) pregnancy test (as needed for 
WOCBP)
Urine pregnancy test will be performed at sites inWOCBP. Refer to SoA.
Investigators 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
Definition of AE
10.3.1
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, or are considered clinically significant in the 
medical and scientific judgment of the investigator.
•
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.
•
New conditions detected or diagnosed after study 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 8.4.7 for protocol-specific exceptions.
Definition of SAE
10.3.2
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.
 
 
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•
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (eg, sprained ankle) 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.
Additional Events Reported
10.3.3
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
Recording AE and SAE
10.3.4
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.
 
 
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•
It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to the Sponsor in lieu of completion of the AE CRF page.
•
There may be instances when copies of medical records for certain cases are requested by 
the Sponsor. In this case, all participant identifiers, with the exception of the participant 
number, will be blinded on the copies of the medical records before submission to the 
Sponsor.
•
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.
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.
 
 
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•
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 
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 
 
 
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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?
•
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.
 
 
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Follow-up of AE and SAE
•
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Sponsor to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals.
•
New or updated information will be recorded in the CRF.
•
The investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information.
Reporting of AE, SAE, and Other Reportable Safety Events to the Sponsor
10.3.5
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).
 
 
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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
This appendix is not applicable for this study.
 
 
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10.5
Appendix 5: Contraceptive Guidance and Pregnancy Testing
Definitions
10.5.1
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.
Contraception Requirements
10.5.2
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 
1 of the contraception methods described in Table 5 consistently and correctly during the 
protocol-defined time frame in Section 5.1.
Table 5
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 contraception
○
Oral
●
Progestogen only hormonal contraception
○
Oral
Highly Effective Methods That Have Low User Dependency
Failure rate of <1% per year when used consistently and correctly.
●
Intrauterine hormone-releasing system (IUS)
●
Intrauterine device (IUD)
●
Bilateral tubal occlusion
●
Vasectomized partner
A vasectomized partner is a highly effective contraception method provided that the partner is the sole 
male sexual partner of the WOCBP and the absence of sperm has been confirmed. If not, an additional 
highly effective method of contraception should be used.
●
Sexual abstinence
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study 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:
a
Typical use failure rates are higher than perfect-use failure rates (ie, when used consistently and correctly).
Pregnancy Testing
10.5.3
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 Visit1 whenever an 
expected menstrual cycle is missed or when pregnancy is otherwise suspected.
 
 
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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. 
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.
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
 
 
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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 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.
 
 
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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 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 
 
 
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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.
12. Questions
Any questions related to the future biomedical research should be emailed directly to 
clinical.specimen.management@merck.com.
 
 
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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
This appendix is not applicable to this study.
 
 
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10.8
Appendix 8: Abbreviations
Abbreviation
Expanded Term
AE
adverse event 
ALP
alkaline phosphatase
ALT (SGPT)
alanine aminotransferase (serum glutamic pyruvic transaminase)
APaT
all participants as treated
AST (SGOT)
aspartate aminotransferase (serum glutamic oxaloacetic transaminase) 
ATP
adenosine triphosphate
BID
twice daily
β-hCG
beta-human chorionic gonadotropin
CFR
Code of Federal Regulations
CI
confidence interval
CONSORT
Consolidated Standards of Reporting Trials
CRF
Case Report Form 
CSD
Cough Severity Diary
CT
computed tomography
DILI
drug-induced liver injury
DNA
deoxyribonucleic acid 
ECG
electrocardiogram 
ECI
event of clinical interest
EQ5D-5L
EuroQoL 5 Version Five Dimensions Questionnaire
eCRF
electronic Case Report Form
EDC
electronic data collection 
eGFR
estimated glomerular filtration rate
EMA
European Medicines Agency
FAS
full analysis set
FDAAA
Food and Drug Administration Amendments Act
FEV1
forced expiratory volume in 1 second
FSH
follicle stimulating hormone 
FVC
forced vital capacity
GCP
Good Clinical Practice 
GERD
gastroesophageal reflux disease
HIV
human immunodeficiency virus
HRQoL
health-related quality of life
HRT
hormone replacement therapy
IB
Investigator’s Brochure 
ICF
Informed Consent Form 
ICH
International Conference on Harmonization
IEC
Independent Ethics Committee
IMP
investigational medical product
IRB
Institutional Review Board 
IUD
intrauterine device
IUS
intrauterine hormone-releasing system
JRS
the Japanese Respiratory Society
LCQ
Leicester Cough Questionnaire
MCH
mean corpuscular hemoglobin
MCV
mean corpuscular volume 
NA
not applicable
NIMP
non investigational medical product
PGIC
Patient Global Impression of Change
PRO
patient reported outcome
 
 
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Abbreviation
Expanded Term
RBC
red blood cell (count)
RNA
ribonucleic acid
SAE
serious adverse event 
SD
standard deviation
SLAB
supplemental laboratory tests
SoA
schedule of activities
sSAP
supplemental Statistical Analysis Plan
SUSAR
suspected unexpected serious adverse reaction
TC
telephone contact
V
visit
WBC
white blood cell (count)
WOCBP
women of child bearing potential
 
 
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11
REFERENCES
[Barclay, J., et al 
2002]
Barclay J, Patel S, Dorn G, Wotherspoon G, 
Moffatt S, Eunson L, et al. Functional 
downregulation of P2X3 receptor subunit in 
rat sensory neurons reveals a significant role 
in chronic neuropathic and inflammatory pain. 
J Neurosci. 2002 Sep 15;22(18):8139-47.
04JQYJ
[Chung, K. F. 2014]
Chung KF. Approach to chronic cough: the 
neuropathic basis for cough hypersensitivity 
syndrome. J Thorac Dis. 2014 Oct;6(Suppl 
7):S699-707.
04R3SD
[Cockayne, D. A., et al 
2000]
Cockayne DA, Hamilton SG, Zhu QM, Dunn 
PM, Zhong Y, Novakovic S, et al. Urinary 
bladder hyporeflexia and reduced pain-related 
behaviour in P2X3-deficient mice. Nature. 
2000 Oct 26;407(6807):1011-5.
04K6LW
[Fujimura, M. 2012]
Fujimura M. Frequency of persistent cough 
and trends in seeking medical care and 
treatment - results of an internet survey. 
Allergol Int. 2012;61(4):573-81.
04W32Z
[Gibson, P., et al 
2016]
Gibson P, Wang G, McGarvey L, Vertigan 
AE, Altman KW, Birring SS. Treatment of 
Unexplained Chronic Cough: CHEST 
Guideline and Expert Panel Report. Chest. 
2016 Jan;149(1):27-44.
04MMZ9
[Irwin, R. S., et al 
2006]
Irwin RS, Baumann MH, Bolser DC, Boulet 
LP, Braman SS, Brightling CE, et al. 
Diagnosis and management of cough 
executive summary: ACCP evidence-based 
clinical practice guidelines. Chest. 2006 
Jan;129(1 Suppl):1S-23S.
04KW7B
[Kanemitsu, Y., et al 
2016]
Kanemitsu Y, Niimi A, Matsumoto H, Iwata 
T, Ito I, Oguma T, et al. Gastroesophageal 
dysmotility is associated with the impairment 
of cough-specific quality of life in patients 
with cough variant asthma. Allergol Int. 2016 
Jul;65(3):320-6.
04SV2L
 
 
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[Kardos, P., et al 
2010]
Kardos P, Berck H, Fuchs KH, Gillissen A, 
Klimek L, Morr H, et al. Guidelines of the 
German Respiratory Society for diagnosis and 
treatment of adults suffering from acute or 
chronic cough. Pneumologie. 2010 
Nov;64(11):701-11.
04KQP6
[Khakh, B. S. 2006]
Khakh BS, North RA. P2X receptors as cell-
surface ATP sensors in health and disease. 
Nature. 2006 Aug 3;442(7102):527-32.
04JRKF
[Morice, A. H., et al 
2004]
Morice AH, Fontana GA, Sovijarvi AR, 
Pistolesi M, Chung KF, Widdicombe J, et al. 
The diagnosis and management of chronic 
cough. Eur Respir J. 2004 Sep;24(3):481-92.
04KQPD
[Morice, A. H., et al 
2006]
Morice AH, McGarvey L, Pavord I, on behalf 
of the British Thoracic Society Cough 
Guideline Group. Recommendations for the 
management of cough in adults. Thorax 
2006;61(Suppl 1):i1-i24.
03QMXM
[North, R. A. 2004]
North RA. P2X3 receptors and peripheral pain 
mechanisms. J Physiol. 2004 Jan 15;554(Pt 
2):301-8.
04JRR8
[Raj, A. A., et al 2009]
Raj AA, Pavord DI, Birring SS. Clinical 
cough IV: what is the minimal important 
difference for the Leicester Cough 
Questionnaire? Handb Exp Pharmacol. 
2009;187:311-20.
04W0Q7
[Souslova, V., et al 
2000]
Souslova V, Cesare P, Ding Y, Akopian AN, 
Stanfa L, Suzuki R, et al. Warm-coding 
deficits and aberrant inflammatory pain in 
mice lacking P2X3 receptors. Nature. 2000 
Oct 26;407(6807):1015-7.
04K76C
[The committee for 
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The committee for The Japanese Respiratory 
Society guidelines for management of cough. 
Concept and use of guidelines. Respirology. 
2006:11(Suppl 4);S135-S136
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Supplemental Statistical Analysis Plan (sSAP)
 
 
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TABLE OF CONTENETS
TABLE OF CONTENETS ..................................................................................................2
LIST OF TABLES...............................................................................................................3
1.0 INTRODUCTION .........................................................................................................4
2.0 SUMMARY OF CHANGES.........................................................................................4
3.0 ANALYTICAL AND METHODOLOGICAL DETAILS............................................4
3.1 STATISTICAL ANALYSIS PLAN SUMMARY .........................................4
3.2 RESPONSIBILITY FOR ANALYSES / IN-HOUSE 
BLINDING.....................................................................................................5
3.3 HYPOTHESES / ESTIMATION ...................................................................5
3.4 ANALYSIS ENDPOINTS .............................................................................6
3.4.1
Efficacy Endpoints..............................................................................6
3.4.2
Safety Endpoints.................................................................................6
3.5 ANALYSIS POPULATIONS ........................................................................6
3.5.1
Efficacy Analysis Population..............................................................6
3.5.2
Safety Analysis Populations ...............................................................6
3.6 STATISTICAL METHODS...........................................................................7
3.6.1
Statistical Methods for Efficacy Analyses..........................................7
3.6.2
Statistical Methods for Safety Analyses.............................................9
3.6.3
Summaries of Baseline Characteristics, Demographics, 
and Other Analyses.................................................................................10
3.7 INTERIM ANALYSES................................................................................10
3.8 MULTIPLICITY ..........................................................................................10
3.9 SAMPLE SIZE AND POWER CALCULATIONS.....................................10
3.10
SUBGROUP ANALYSES AND EFFECT OF BASELINE
FACTORS ....................................................................................................11
3.11
COMPLIANCE (MEDICATION ADHERENCE) ................................11
3.12
EXTENT OF EXPOSURE.....................................................................11
 
 
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LIST OF TABLES
Table 1 Analysis Strategy for Efficacy Endpoints.................................................................... 9
 
 
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1.0 INTRODUCTION
This supplemental SAP (sSAP) is a companion document to the protocol. In addition to the 
information presented in the protocol SAP which provides the principal features of analyses 
for this trial, this supplemental SAP provides additional sensitivity statistical analysis details, 
data derivations and documents modifications or additions to the analysis plan that are not 
“principal” in nature and result from information that was not available at the time of 
protocol finalization.
2.0 SUMMARY OF CHANGES
[14-Apr-2020 Amendment 2]
Sections 3.1 and 3.7
The scope of the interim analysis of safety data was expanded to include all available data up 
to the cutoff date for the interim database lock.
[13-Feb-2020 Amendment 1]
Section 3.6.1
The covariance structure for the longitudinal analysis of covariance was changed from 
Toeplitz to unstructured.
Analysis of EQ VAS was added.
Section 3.11
It was clarified that the “Number of Days Should Be on Therapy” is the total number of days 
from the first scheduled treatment day to the last dose day for those participants who 
discontinued study medication
permanently, instead of for those participants who 
discontinued the study permanently.
Appendix
The relative day ranges for body weight was modified to include the additional timepoints 
(Visits 3 and 6) included in the protocol amendment (038-01).
3.0 ANALYTICAL AND METHODOLOGICAL DETAILS
3.1
Statistical Analysis Plan Summary
Key elements of the statistical analysis plan are summarized below; the comprehensive plan
is provided in Sections 3.2-3.12.
 
 
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Study Design Overview
Phase 3 study, Randomized, Double-blind Clinical Study to Evaluate 
the Long-term Safety and Efficacy of MK-7264 in Japanese Adult 
Participants with Refractory or Unexplained Chronic Cough
Treatment Assignment
Participants will be randomized in a 1:1 ratio to either MK-7264 
45 mg BID or MK-7264 15 mg BID.
Analysis Populations
Efficacy: Full Analysis Set (FAS) population.  
Safety: All Participants as Treated (APaT) population.
Primary Endpoint

Adverse events (AEs)

Study treatment discontinuations due to AE
Statistical Methods for 
Key Efficacy Analyses
Change from baseline in LCQ total score at Week 12 and through 
Week 52 will be analyzed using the longitudinal analysis of 
covariance (ANCOVA) model. The model will include terms for 
treatment, visit, the interactions of treatment by visit, and baseline 
value as covariates. The change from baseline to each visit and 95% 
CIs will be estimated from this model.
Statistical Methods for 
Key Safety Analyses
AEs will be summarized by the number and percentage of the 
participants who experienced respective events. Change from baseline 
in laboratory tests, vital signs at respective timepoints will be 
summarized by descriptive statistics.
Interim Analyses
The planned interim efficacy analysis will be performed based on the 
data up to Week 24 when all the randomized participants have 
completed Week 24 or discontinued prior to Week 24. Safety analysis 
will include all available data up to the cutoff date for the interim 
database lock.
Multiplicity
No multiplicity adjustment is planned in this trial.
Sample Size and Power 
A total of 160 participants will be enrolled. Assuming a 
discontinuation rate of approximately 47% at Week 52, 84 participants 
are expected to complete 52 weeks of treatment.
3.2
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 will be conducted as a double-blind study under in-house blinding procedures.  
Double blinding technique with in-house blinding will be used until all the randomized 
participants have completed Week 24 or discontinued prior to Week 24 after which a double
blinding only technique will be used.  The official, final database will not be unblinded until 
medical/scientific review has been performed, protocol deviations have been identified, and 
data have been declared final and complete.
The Clinical Biostatistics department will generate the randomized allocation schedule(s) for 
study treatment assignment.
3.3
Hypotheses / Estimation
There are no hypotheses for this study.
 
 
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3.4
Analysis Endpoints
3.4.1
Efficacy Endpoints

Leicester Cough Questionnaire (LCQ) total score

Mean weekly Cough Severity Diary (CSD) total score

EuroQoL 5 Version Five Dimension Questionnaire (EQ5D-5L)

Patient Global Impression Change (PGIC)
3.4.2
Safety Endpoints

Adverse event (AE)

Study treatment discontinuations due to AE

Laboratory test

Vital sign

Taste related AE

Oral paraesthesia/hypoethesia
3.5
Analysis Populations
3.5.1
Efficacy Analysis Population
The FAS population will serve as the primary population for the analysis of efficacy data in 
this study. The FAS population consists of all randomized participants who have taken at 
least one dose of study medication and provided at least one baseline and one post-baseline 
endpoint observations during the treatment period. 
Participants will be included in the treatment group to which they are randomized for the 
analysis of efficacy data using the FAS populations.
3.5.2
Safety Analysis Populations
The APaT population will be used for the analysis of safety data in this study. The APaT 
population consists of all randomized participants who received at least one dose of study 
treatment. Participants will be included in the treatment group corresponding to the study 
treatment they actually received for the analysis of safety data using the APaT population. 
Discontinued participants before Week 52 will be included in APaT population. For most 
participants this will be the treatment group to which they are randomized. Participants who 
take incorrect study treatment for the entire treatment period will be included in the treatment 
group corresponding to the study treatment actually received.
 
 
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If a participant is found to have taken one or more incorrect doses of study medication from 
that to which he/she was randomized, then the participant will be counted in the higher dose 
arm he/she actually received; that is, if a participant was originally randomized to MK-7264 
15 mg but during the course of the study has taken 1 or more doses of MK-7264 45 mg, then 
the participant will be included in the MK-7264 45 mg treatment arm in the safety analysis.
At least one laboratory or vital sign measurement obtained subsequent to at least one dose of 
study treatment is required for inclusion in the analysis of each specific parameter. To assess 
change from baseline, a baseline measurement is also required.
3.6
Statistical Methods
The results will be provided by treatment group and total (combined treatment group). There 
is no plan to do between treatment group comparisons.
3.6.1
Statistical Methods for Efficacy Analyses
The analysis of efficacy endpoints will be based on the FAS population. Unless specified
otherwise, analyses will include all follow-up efficacy data collected for those participants
who discontinued treatment.
The continuous endpoints will be analyzed using the longitudinal analysis of covariance 
(ANCOVA) model. In this model, response variable will be change from baseline. The 
model will include terms for treatment, visit, and the interaction of treatment by visit and 
baseline value as a covariate. Visit is treated as a categorical variable so that no restriction is 
imposed on the trajectory of the means over time. An unstructured covariance matrix will be 
used to model correlations among repeated measures. If the unstructured covariance structure 
fails to converge with the default algorithm, then the AR(1) structure can be used to provide 
initial values of the covariance parameters. This model uses the maximum likelihood 
principle to estimate the parameters and account for missing data in an implicit fashion. The 
change from baseline to each visit and 95% CIs will be estimated from this model. Baseline 
variable is defined as the last non-missing value prior to the treatment.
Categorical endpoints will be analyzed by calculating the percentage of participants in each 
response category at each timepoint. For some endpoints (change from baseline in LCQ total 
score, change from baseline in mean weekly CSD total score), percentage of participants 
meeting certain threshold values will also be provided. Only observed data will be included 
in the analysis.
Considerations for the analysis specific to the respective endpoints are provided below.
LCQ total score
Change from baseline in the LCQ total score will be analyzed using the longitudinal 
ANCOVA model above
to estimate within-treatment change from baseline and 
corresponding 95% CI at each time point. Percentage of participants who had an increase in 
the total score of ≥1.3 points from baseline at each time point will also be summarized.
 
 
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The Physical domain score will be considered as missing if there are 2 or more items are
missing. If there is only 1 item is missing, the Physical domain score will be based on the
actual non-missing items. Psychological domain score will be derived in a similar fashion. 
The Social domain score will be considered as missing if any item is missing. The LCQ total 
score will be considered as missing if any of the 3 domain scores is missing.
Mean weekly CSD total score
Change from baseline in the mean weekly CSD total score will be analyzed using the 
longitudinal ANCOVA model above to estimate within-treatment change from baseline and 
corresponding 95% CI at each time point. Percentage of participants who had a reduction in 
the total score of ≥1.3 and ≥2.7 points from baseline at each time point, respectively, will 
also be summarized.
The mean weekly total score will be considered missing if there are less than 4 non-missing 
days during the week prior to each visit. If there are less than 7 but at least 4 non-missing
days during the week prior to a visit, the mean weekly total score will be based on the actual 
non-missing days of the week prior to the visit. Mean weekly subscales will be derived in a 
similar fashion.
EQ5D-5L
Change from baseline in the EQ5D-5L index utility score will be analyzed using the 
longitudinal ANCOVA model above to estimate within-treatment change from baseline and 
corresponding 95% CI at each time point. If a participant has a missing response to any of the 
five individual questions at a particular timepoint, then the entire response for that participant 
at that timepoint will be considered missing.
EQ VAS
Change from baseline in EQ VAS will also be analyzed using the longitudinal ANCOVA 
model above to estimate within-treatment change from baseline and corresponding 95% CI at 
each time point.
PGIC
Percentage of participants with each response to the PGIC questionnaire will be summarized
at each timepoint. Percentage of participants with improvements (either "very much 
improved" or "much improved" on the PGIC scale) will also be summarized at each time 
point.
 
 
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Table 1 summarizes the analysis strategy for efficacy endpoints.
Table 1
Analysis Strategy for Efficacy Endpoints
Endpoint / Variable
(Description / Timepoint)
Statistical Method
Analysis 
Population
Missing data approach
Secondary objective
Change from baseline in LCQ total score
Longitudinal ANCOVA†
FAS
Model-based
% of participants who had an increase in the total 
score of ≥1.3 points from baseline
Descriptive statistics
FAS
Data as observed
Exploratory objective #1
Change from baseline in mean weekly CSD score
Longitudinal ANCOVA†
FAS
Model-based
% of participants who had a decrease in the total 
score of ≥1.3 and ≥2.7 points from baseline
Descriptive statistics
FAS
Data as observed
Exploratory objective #2
Change from baseline in the EQ5D-5L index 
utility score
Longitudinal ANCOVA†
FAS
Model-based
Change from baseline in EQ VAS
Longitudinal ANCOVA†
FAS
Model-based
% of participants with each response to the PGIC 
questionnaire
Descriptive statistics
FAS
Data as observed
% of participants with improvements in the PGIC 
questionnaire
Descriptive statistics
FAS
Data as observed
† Longitudinal analysis of covariance model with terms for treatment, visit and the interaction of treatment by visit, and 
baseline value as a covariate
LCQ = Leicester Cough Questionnaire, CSD = Cough Severity Diary, EQ5D-5L = EuroQoL 5 Version Five Dimensions
Questionnaire, PGIC = Patient Global Impression of Change, ANCOVA = analysis of covariance, FAS = Full Analysis Set.
3.6.2
Statistical Methods for Safety Analyses
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
AEs, study treatment discontinuations due to AE, laboratory tests, vital signs measurements.
All safety analyses will be based on the APaT population. 
AEs and other safety events will be summarized using the number and percentage of the
participants who experienced respective events. The AEs observed up to 14 days after the 
last dose will be included in the analysis.
Taste-related AEs (including dysgeusia, ageusia, and hypogeusia, as well as other related 
terms) and oral paraesthesia/hypoesthesia are considered as AEs of interest.
Continuous measures such as changes from baseline in laboratory, vital signs parameters will 
be summarized using descriptive statistics.
Summary statistics for baseline, on treatment, and change from baseline values will be 
provided in table format.
 
 
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3.6.3
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, weight, and height), baseline characteristics, 
primary and comorbid conditions, and prior and concomitant therapies will be summarized 
either by descriptive statistics or categorical tables.
3.7
Interim Analyses
All efficacy analyses will be performed based on the data up to Week 24 when all the 
randomized participants have completed Week 24 or discontinued prior to Week 24. Safety 
analysis will include all available data up to the cutoff date for the interim database lock. 
Regardless of the result of the interim analysis (safety and efficacy), the study will continue 
as planned. Double blinding only to treatment assignment will be maintained at all 
investigational sites after all participants have completed Week 24.  The results of interim 
analyses (safety and efficacy) will not be shared with the investigators prior to the 
completion of the study.  The study will continue as double-blind only after Week 24 
acknowledging that the sponsor will be unblinded at that point in order to analyze and report 
the data.  The study team responsible for the ongoing monitoring of the study will remain 
blinded to the treatment-level results of this interim analysis (safety and efficacy).
3.8
Multiplicity
No multiplicity adjustment is planned in this trial.
3.9
Sample Size and Power Calculations
A total of 160 participants will be enrolled. Assuming a discontinuation rate of 
approximately 47%, 84 participants are expected to complete 52 weeks of treatment.  The 
discontinuation rate was estimated from previous study (Protocol 012), which was a 12 week 
study.
The probability of observing at least one AE in this study depends on the number of 
participants treated and the underlying incidence with an AE in the study population. If the 
underlying incidence of an AE is 2%, the probability of observing at least one AE is 82% 
among 84 participants and 57% among 42 participants. If no participants had a specific AE, 
then the upper bound of the 95% CI of the underlying incidence rate would be 4.3% for 84 
participants and 8.4% for 42 participants. For LCQ total score, assuming a 3.7 change from 
baseline and a SD of 3.9 at Week 12 based on Protocol 012, a 95% confidence interval of 
change from baseline in LCQ total score would be (2.9, 4.5) for 84 participants and  (2.5, 
4.9) for 42 participants.
 
 
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3.10
Subgroup Analyses and Effect of Baseline Factors
No subgroup analysis is planned in this study.
3.11
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 medication as instructed in Section 8 of the Protocol – Study Assessments and 
Procedures. When a participant takes less than or more than the required medication on a 
day, that day is not considered an On-Therapy day.
For participants who are followed for the entire study period, the “Number of Days Should 
Be on Therapy” is the total number of days from the first scheduled treatment day to the last 
scheduled treatment day. For participants who discontinue from the study medication 
permanently, the “Number of Days Should Be on Therapy” is the total number of days from 
the first scheduled treatment day to the last dose day.
Summary statistics will be provided on percent compliance for the APaT population.
3.12
Extent of Exposure
The duration of treatment for each participant will be evaluated by calculating the number of 
days on therapy.  Exposure to study medication will be summarized using descriptive 
statistics (mean, SD, median, minimum, and maximum) for the APaT population.
Appendix: Relative day ranges
Since it is not always possible for all study participants to come in for their clinic visits on 
the exact day specified in the protocol schedule, the following relative day ranges will be 
defined for each time point.
Scheduled day
LCQ, CSD, vital signs
EQ5D-5L, PGIC,
laboratory parameters
Body weight
Baseline
1
Day ≤1
Day ≤1
Day ≤1
Week 4
28
2≤Day ≤41
--
2≤Day ≤55
Week 8
56
42≤Day ≤69
--
--
Week 12
84
70≤Day ≤125
2≤Day ≤125
56≤Day ≤125
Week 24
168
126≤Day ≤216
126≤Day ≤266
126≤Day ≤266
Week 38
266
217≤Day ≤315
--
--
Week 52
365
316≤Day
267≤Day
267≤Day
For the analysis of safety parameters, Day at post-baseline timepoints must be ≤14 days following the last dose.
The analysis week for CSD will be defined based on the day of study visit by subjects. Seven (7) days to 1 day before the 
study visit will be used as the measurements for the analysis week to which the study visit day belongs.
 
 
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If a subject has data on multiple days within a day range, the measurement closest to the 
scheduled day within the day range will be used in the analysis. If there are observations 
before and after the scheduled day that are equally apart from the scheduled day, then the 
observation after the scheduled day will be used for analysis. If two or more measurements 
are obtained on the same day, the average will be used as the observation for the day.
Baseline variable is defined as the last non-missing value prior to treatment. Typically this is 
the measurement taken at Visit 1 or Visit 2, depending on the endpoint.
 
 
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