Conditions: Chronic Cough
Keywords: Cough Urinary Incontinence, Stress Respiration disorders Respiratory tract diseases Signs and symptoms, respiratory Signs and symptoms
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 376
Healthy volunteers: no

Brief summary:
The purpose of this study is to evaluate the efficacy and safety of gefapixant, in improving symptoms of cough-induced stress urinary incontinence (SUI) in adult female participants with refractory or unexplained chronic cough. The primary hypothesis is that gefapixant is superior to placebo in reducing the frequency of cough-induced SUI episodes over 12 weeks.

Detailed description:

Arms:
arm 1: Participants will receive gefapixant at a dose of 45 mg administered as an oral tablet twice daily for 12 weeks. arm 2: Participants will receive placebo matching gefapixant, administered as an oral tablet twice daily for 12 weeks.

Interventions: intervention 1: Gefapixant intervention 2: Placebo
Intervention descriptions: intervention 1: Administered twice daily as an oral tablet of 45 mg intervention 2: Administered twice daily as a placebo oral tablet matching gefapixant

Protocol document:
Prot_SAP_000.pdf: 
Official Protocol Title: 
NCT number: 
NCT04193176 
Document Date: 
23-Nov-2020
A Phase 3b Randomized Double-blind, Placebo Controlled, 
Multicenter Study to Evaluate the Efficacy and Safety of 
Gefapixant in Women with Chronic Cough and Stress Urinary 
Incontinence


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Title Page
THIS PROTOCOL AMENDMENT AND ALL OF THE INFORMATION RELATING 
TO IT ARE CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK 
SHARP & DOHME CORP., A SUBSIDIARY OF MERCK & CO., INC., NJ, U.S.A. 
(MSD).
Protocol Title: A Phase 3b Randomized Double-blind, Placebo Controlled, Multicenter 
Study to Evaluate the Efficacy and Safety of Gefapixant in Women with Chronic Cough and 
Stress Urinary Incontinence
Protocol Number: 042-03
Compound Number: MK-7264
Sponsor Name:
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
(hereafter referred to as the Sponsor or MSD)
Legal Registered Address:
One Merck Drive
P.O. Box 100
Whitehouse Station, New Jersey, 08889-0100, U.S.A.
Regulatory Agency Identifying Number(s):
IND
EudraCT
123007
2019-002321-29
Approval Date: 23 November 2020
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Sponsor Signatory
Typed Name:
Title:
Date
Protocol-specific Sponsor contact information can be found in the Investigator Study
File Binder (or equivalent).
Investigator Signatory
I agree to conduct this clinical study in accordance with the design outlined in this protocol 
and to abide by all provisions of this protocol.
Typed Name:
Title:
Date
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DOCUMENT HISTORY
Document
Date of Issue
Overall Rationale
Protocol Amendment 03
23-NOV-2020
Removal of procedures/assessments for specialized urine crystal 
analysis added in Protocol Amendment 02 and other clarifications.
Protocol Amendment 02
19-FEB-2020
Addition of procedures/assessments required for specialized urine 
crystal analysis.
Protocol Amendment 01
19-SEP-2019
Corrections to Exclusion Criteria and other clarifications
Original Protocol
10-SEP-2019
Not applicable
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PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment: 03
Overall Rationale for the Amendments:
Removal of procedures/assessments for specialized urine crystal analysis.
Summary of Changes Table:
Section # and Name
Description of Change 
Brief Rationale 
Section 1.3 – Schedule of 
Activities (SoA)
Added note to PGIC:
Completed at clinic visit.
To clarify that PGIC is completed at clinic visit..
Section 1.3 – Schedule of 
Activities (SoA)
Deleted text:
Urine Collection and Preparation for 
Specialized Urine Crystal Analysis
Urine sample collected (at Visit 
6/Discontinuation) is immediately 
prepared per central laboratory manual 
and stored at site; if central laboratory 
urinalysis is positive for crystals and/or 
unexplained hematuria, sample is to be 
shipped to Sponsor or designee for 
Specialized Urine Crystal Analysis.
See Section 8.3.9.
Urine collection for specialized urine crystal analysis is
removed from the list of assessments performed during 
the study.
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Section # and Name
Description of Change 
Brief Rationale 
Section 1.3 – Schedule of 
Activities (SoA)
Added footnote “d” for Pharmacokinetic 
Blood Collection:
A pharmacokinetic blood sample should be 
collected within approximately 96 hours of 
the final dose of study medication. If the 
discontinuation or final visit is scheduled 
to occur greater than 96 hours following 
the final dose of study medication, please 
contact the Sponsor for guidance.
To clarify the timing for pharmacokinetic samples. 
Section 5.2 – Exclusion 
Criteria
Updated text (new text in bold, 
strikethrough deleted text):
29. Requires pharmacologic treatments for
urinary incontinence, that may impact 
bladder function, which are not allowed 
from 2 weeks prior to the Placebo 
Run-in/Visit 2 through the completion of 
the study. These therapies include, but are 
not limited to the following:
To clarify that the excluded medications listed in 
exclusion 29 may impact bladder function and are 
therefore excluded for all indications (unless otherwise 
noted).
Section 5.2 – Exclusion 
Criteria
Added note to number 34:
Note: Participants with a known history or 
current evidence of SARS-CoV-2 
(COVID-19) infection are ineligible to 
enroll in the study.
To clarify that participants with a known history or 
current evidence of SARS-CoV-2 (COVID-19)
infection are ineligible to enroll in the study.
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Section # and Name
Description of Change 
Brief Rationale 
Section 7.1 –
Discontinuation of Study 
Intervention
Updated text (deleted strikethrough text):

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 8.3.9).
To remove the recommendation for participants to be 
discontinued from the study intervention if gefapixant 
crystalluria is detected.
Section 8.1.11 – Participant 
Blinding/Unblinding
Deleted text:
In the instance of identifying gefapixant 
crystals in the urine (see Section 8.3.9 for 
further details), the participant will be 
discontinued from the study intervention 
(see Section 7.1 for further details). If a 
participant has confirmed gefapixant 
crystals, it will be known that the 
participant was receiving gefapixant. In 
this circumstance, formal non emergency 
unblinding should not be performed.
To remove that participants should be discontinued 
from the study intervention if gefapixant crystalluria is
detected.
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Section # and Name
Description of Change 
Brief Rationale 
Section 8.2.1 Patient-
reported Outcomes
Updated text (new text in bold font, 
deleted text with strikethrough):
the e-Diary will allow the participant, 
based on recall, to complete these missed 
measures at any time in the next 24 hours
day (also see vendor’s site manual for 
further details)
To clarify when missed measures can be completed.
Section 8.3.9 – Renal and 
Urological Safety 
Assessments
Updated text (new text in bold font, 
deleted text with strikethrough):
8.3.9.2 Visit 6/Discontinuation
At Visit 6 or Discontinuation Visit, a urine 
sample will be collected from all
participants, as outlined in the SoA. All
urine samples will be collected and 
prepared as detailed in the central 
laboratory manual:

Part of the collected sample will be 
shipped to the central laboratory for 
urinalysis (that includes, but is not 
limited to, testing for blood and 
urinary crystals). 

The second part of the collected 
sample will be immediately prepared 
using a specialized filter for gefapixant 
urinary crystal analysis. The filtered 
sample will be stored at the study site 
until the urinalysis results from the 
central laboratory are received.
To remove procedures/assessments for specialized 
urine crystal analysis.
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Section # and Name
Description of Change 
Brief Rationale 
On receipt of the urinalysis results from 
the central laboratory, If results indicate a 
participant has unexplained hematuria 
and/or urinary crystals are identified and 
deemed to be clinically significant by the 
investigator, the participant should be 
considered for further evaluation. the 
filtered sample stored at the site will be 
immediately shipped to the Sponsor or 
designee and assessed for the presence of 
gefapixant urinary crystals via Raman 
spectroscopy. Raman spectroscopy is 
sensitive to the chemical structure of the 
molecule and gefapixant has a unique 
chemical structure compared with common 
urinary crystals. If there is an explanation 
for hematuria (for example, recent menses, 
urinary tract infection, or a recent 
procedure/instrumentation that would 
explain the hematuria) the sample will not 
be sent to the Sponsor or designee. See 
central laboratory manual for further 
procedural details.
If a participant has confirmed gefapixant 
urinary crystals, the Sponsor will inform 
the investigator and recommend follow up
with the participant at approximately 2
week intervals; additional specialized 
urine crystal analyses should be performed 
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Section # and Name
Description of Change 
Brief Rationale 
until resolution of the gefapixant urinary 
crystals. Once a participant has confirmed 
gefapixant crystals, it will be known that 
the participant was receiving gefapixant 
(formal unblinding should not be 
performed [see Section 8.1.11]).
If an investigator deems it necessary to 
perform an unscheduled urinalysis at any 
time during the study (after 
randomization), the same procedures for 
collection/preparation of the urine sample 
and evaluation of hematuria (as explained 
or unexplained) described for Visit 6 or 
Discontinuation Visit should be performed.
The sample will be analyzed for the 
presence of gefapixant urinary crystals as 
appropriate. 
8.6.1 Blood Collection for 
Plasma Gefapixant
Added text:
A pharmacokinetic blood sample should be 
collected within approximately 96 hours of 
the final dose of study medication. If the 
discontinuation or final visit is scheduled 
to occur greater than 96 hours following 
the final dose of study medication, please 
contact the Sponsor for guidance.
To clarify the timing for pharmacokinetic samples.
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Section # and Name
Description of Change 
Brief Rationale 
8.10.4 Discontinued 
Participants Continuing to be 
Monitored in the Study
Updated text (new text in bold font):
If a participant is discontinued from the 
study intervention early:

the Discontinuation Visit should be 
performed as soon as possible;
If feasible, participants should be 
instructed to complete the 
Incontinence Diary and other 
PROs during the 7 days prior to 
the Discontinuation Visit.
Procedures, including e-Diary 
assessments, should be performed 
as outlined for the 
Discontinuation Visit in the SoA 
(Section 1.3).
Note: If a participant discontinues 
at a regularly scheduled study 
visit, the procedures outlined for 
the Discontinuation Visit in the 
SoA should be followed in place of 
the procedures for the regularly 
scheduled study visit. 
To clarify the procedures that should be performed if a 
participant discontinues.
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Section # and Name
Description of Change 
Brief Rationale 
8.10.4 Discontinued 
Participants Continuing to be 
Monitored in the Study
Updated text (new text in bold font):

Study site visits should continue to 
be performed at timepoints that 
correspond to each remaining 
study visit. These visits will allow 
collection of follow-up information, 
limited to:
-
AEs;
-
Concomitant medication 
use; and 
-
e-Diary assessments, as 
outlined in the SoA (Section 
1.3);
Note: If the participant discontinues 
study intervention at a regularly 
scheduled study visit but remains in the 
study, the Discontinuation Visit should be 
performed, and the regularly scheduled 
study visits should resume thereafter. For 
example: If a participant discontinues 
study intervention at the time of Visit 4, 
procedures for the Discontinuation Visit 
should be performed at that time. The 
next expected study visit would be Visit 5, 
followed by Visit 6.
To clarify the procedures that should be performed if a 
participant discontinues study intervention but remains 
in the study.
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Section # and Name
Description of Change 
Brief Rationale 
Section 9.1 Statistical 
Analysis Plan Summary
Updated text (new text in bold font):
Study Design Overview
A Phase 3b, Randomized, Placebo 
Controlled, Multicenter Study to Evaluate 
the Efficacy and Safety of Gefapixant in 
Women with Chronic Cough and Stress 
Urinary Incontinence (P042)
To clarify that the study evaluates efficacy and safety.
Section 9.1 Statistical 
Analysis Plan Summary
Updated text (new text in bold font, 
deleted text with strikethrough):
Interim Analyses
Timing: To be performed when 
approximately 40% of participants 
(approximately the first 152 enrolled
randomized participants) have either 
completed the study or discontinued the 
study intervention early.
Revised enrolled participants to randomized 
participants.
Section 9.6.1 Statistical 
Methods for Efficacy 
Analyses
Updated text (strikethrough deleted text):
The model will use all available data from 
post-Baseline on treatment visits at Weeks 
4, 8, and 12.
To clarify that all post-baseline data (on or off 
treatment) will be used in the primary analysis. 
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Section # and Name
Description of Change 
Brief Rationale 
Section 9.7.1 Interim 
Efficacy Analysis
Updated text (new text in bold font, 
deleted text with strikethrough):
A single planned IA will be conducted 
when approximately 40% of target 
participants (approximately the first 152 
enrolled randomized participants) have 
either completed the study (approximately 
129 enrolled randomized participants) or 
discontinued study intervention early.
Revised enrolled participants to randomized 
participants.
Section 9.7.2 Interim Safety 
Analysis
Updated text (new text in bold font, 
deleted text with strikethrough):
Interim safety will also be assessed at the 
time of the pre-specified IA for interim 
efficacy or futility, ie, when approximately 
40% of target participants (approximately 
the first 152 enrolled randomized
participants) have either completed the 
study or discontinued the study 
intervention early.
Revised enrolled participants to randomized 
participants.
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Section # and Name
Description of Change 
Brief Rationale 
Section 10.2 Appendix 2: 
Clinical Laboratory Tests
Added standard template text:

Pregnancy testing:
-
Pregnancy testing 
requirements for study 
inclusion are described in 
Section 5.1.
-
Additional serum or urine 
pregnancy tests may be 
performed, as determined 
necessary by the 
investigator or required by 
local regulation, to establish 
the absence of pregnancy at 
any time during the 
subject’s participation in 
the study.
To add optional template text that was previously 
deleted.
Throughout the document
Editorial and formatting changes.
Consistency.
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Table of Contents
DOCUMENT HISTORY ........................................................................................................3
PROTOCOL AMENDMENT SUMMARY OF CHANGES...............................................4
1
PROTOCOL SUMMARY ............................................................................................23
1.1
Synopsis.................................................................................................................23
1.2
Schema ..................................................................................................................26
1.3
Schedule of Activities (SoA)................................................................................27
2
INTRODUCTION..........................................................................................................31
2.1
Study Rationale....................................................................................................33
2.2
Background ..........................................................................................................33
2.2.1
Pharmaceutical and Therapeutic Background .............................................33
2.2.2
Preclinical and Clinical Studies ...................................................................34
2.2.3
Ongoing Clinical Studies.............................................................................34
2.3
Benefit/Risk Assessment......................................................................................34
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS................................................35
4
STUDY DESIGN............................................................................................................37
4.1
Overall Design......................................................................................................37
4.2
Scientific Rationale for Study Design.................................................................38
4.2.1
Rationale for Endpoints ...............................................................................38
4.2.1.1
Efficacy Endpoints.............................................................................38
4.2.1.2
Safety Endpoints................................................................................40
4.2.1.3
Pharmacokinetic Endpoints ...............................................................40
4.2.1.4
Pharmacodynamic Endpoints.............................................................40
4.2.1.5
Planned Exploratory Biomarker Research.........................................40
4.2.1.5.1
Planned Genetic Analysis ........................................................40
4.2.1.6
Future Biomedical Research..............................................................40
4.2.2
Rationale for the Use of Comparator/Placebo .............................................41
4.3
Justification for Dose...........................................................................................41
4.4
Beginning and End of Study Definition .............................................................41
4.4.1
Clinical Criteria for Early Study Termination .............................................42
5
STUDY POPULATION ................................................................................................42
5.1
Inclusion Criteria.................................................................................................42
5.2
Exclusion Criteria................................................................................................45
5.3
Lifestyle Considerations......................................................................................48
5.3.1
Meals and Dietary Restrictions....................................................................48
5.3.2
Caffeine, Alcohol, and Tobacco Restrictions ..............................................49
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5.3.3
Activity Restrictions ....................................................................................49
5.4
Screen Failures.....................................................................................................49
5.5
Participant Replacement Strategy......................................................................50
6
STUDY INTERVENTION............................................................................................50
6.1
Study Intervention(s) Administered...................................................................50
6.1.1
Medical Devices...........................................................................................52
6.2
Preparation/Handling/Storage/Accountability .................................................52
6.2.1
Dose Preparation..........................................................................................52
6.2.2
Handling, Storage, and Accountability........................................................52
6.3
Measures to Minimize Bias: Randomization and Blinding..............................53
6.3.1
Intervention Assignment..............................................................................53
6.3.2
Stratification.................................................................................................53
6.3.3
Blinding........................................................................................................53
6.4
Study Intervention Compliance..........................................................................53
6.5
Concomitant Therapy..........................................................................................54
6.5.1
Rescue Medications and Supportive Care ...................................................55
6.6
Dose Modification ................................................................................................55
6.7
Intervention After the End of the Study............................................................56
6.8
Clinical Supplies Disclosure................................................................................56
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL............................................................................................................56
7.1
Discontinuation of Study Intervention...............................................................56
7.2
Participant Withdrawal From the Study...........................................................57
7.3
Lost to Follow-up .................................................................................................57
8
STUDY ASSESSMENTS AND PROCEDURES........................................................58
8.1
Administrative and General Procedures ...........................................................58
8.1.1
Informed Consent.........................................................................................58
8.1.1.1
General Informed Consent.................................................................59
8.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research.............................................................................................59
8.1.2
Inclusion/Exclusion Criteria ........................................................................59
8.1.3
Participant Identification Card.....................................................................60
8.1.4
Medical History ...........................................................................................60
8.1.5
Medical Epidemiological and Social Aspects of Aging (MESA) 
Questionnaire...............................................................................................60
8.1.6
Prior and Concomitant Medications Review...............................................61
8.1.6.1
Prior Medications...............................................................................61
8.1.6.2
Concomitant Medications..................................................................61
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8.1.7
Assignment of Screening Number...............................................................61
8.1.8
Assignment of Treatment/Randomization Number.....................................61
8.1.9
Study Intervention Administration ..............................................................61
8.1.9.1
Timing of Dose Administration.........................................................62
8.1.10
Discontinuation and Withdrawal .................................................................62
8.1.10.1
Withdrawal From Future Biomedical Research ................................62
8.1.11
Participant Blinding/Unblinding..................................................................63
8.1.12
Calibration of Equipment.............................................................................63
8.2
Efficacy Assessments ...........................................................................................64
8.2.1
Patient-reported Outcomes...........................................................................64
8.2.1.1
Incontinence Diary.............................................................................65
8.2.1.2
Cough Severity Diary ........................................................................66
8.2.1.3
Cough Severity Visual Analog Scale.................................................66
8.2.1.4
Incontinence Quality of Life Questionnaire ......................................66
8.2.1.5
Patient Global Impression of Change Questionnaire.........................66
8.2.1.6
Work Productivity and Activity Impairment Questionnaire..............66
8.3
Safety Assessments...............................................................................................66
8.3.1
Chest Radiography/Computed Tomography Thorax Scan..........................67
8.3.2
Physical Examinations.................................................................................67
8.3.3
Pelvic Examination......................................................................................67
8.3.4
Cough Stress Test ........................................................................................68
8.3.5
Vital Signs....................................................................................................68
8.3.6
Electrocardiograms ......................................................................................68
8.3.7
Spirometry....................................................................................................68
8.3.8
Clinical Safety Laboratory Assessments .....................................................69
8.3.9
Renal and Urological Safety Assessments...................................................69
8.3.9.1
Screening............................................................................................70
8.3.9.2
Visit 6/Discontinuation......................................................................70
8.4
Adverse Events (AEs), Serious Adverse Events (SAEs), and Other 
Reportable Safety Events ....................................................................................70
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ..........................................................71
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events......73
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information...73
8.4.4
Regulatory Reporting Requirements for SAE .............................................73
8.4.5
Pregnancy and Exposure During Breastfeeding ..........................................73
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying 
as AEs or SAEs............................................................................................74
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8.4.7
Events of Clinical Interest (ECIs)................................................................74
8.5
Treatment of Overdose........................................................................................74
8.6
Pharmacokinetics.................................................................................................75
8.6.1
Blood Collection for Plasma Gefapixant .....................................................75
8.7
Pharmacodynamics..............................................................................................75
8.8
Biomarkers ...........................................................................................................75
8.8.1
Planned Genetic Analysis Sample Collection..............................................75
8.9
Future Biomedical Research Sample Collection...............................................76
8.10
Visit Requirements...............................................................................................76
8.10.1
Screening......................................................................................................76
8.10.2
Single-blind Placebo Run-in Period.............................................................76
8.10.3
Double-blind Treatment Period ...................................................................77
8.10.4
Discontinued Participants Continuing to be Monitored in the Study ..........77
8.10.5
Poststudy......................................................................................................78
9
STATISTICAL ANALYSIS PLAN .............................................................................79
9.1
Statistical Analysis Plan Summary.....................................................................79
9.2
Responsibility for Analyses/In-house Blinding .................................................81
9.3
Hypotheses/Estimation ........................................................................................81
9.4
Analysis Endpoints...............................................................................................81
9.4.1
Efficacy Endpoints.......................................................................................81
9.4.1.1
Primary Efficacy Endpoint ................................................................81
9.4.1.2
Secondary Efficacy Endpoints...........................................................82
9.4.1.3
Exploratory Efficacy Endpoints.........................................................82
9.4.2
Safety Endpoints..........................................................................................82
9.5
Analysis Populations............................................................................................83
9.5.1
Efficacy Analysis Populations.....................................................................83
9.5.2
Safety Analysis Populations ........................................................................83
9.6
Statistical Methods...............................................................................................83
9.6.1
Statistical Methods for Efficacy Analyses...................................................83
9.6.2
Statistical Methods for Safety Analyses ......................................................84
9.6.3
Summaries of Baseline Characteristics, Demographics, and Other 
Analyses.......................................................................................................86
9.6.3.1
Demographic and Baseline Characteristics .......................................86
9.7
Interim Analyses ..................................................................................................87
9.7.1
Interim Efficacy Analysis ............................................................................87
9.7.2
Interim Safety Analysis................................................................................88
9.8
Multiplicity ...........................................................................................................88
9.9
Sample Size and Power Calculations .................................................................88
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9.10
Subgroup Analyses...............................................................................................89
9.11
Compliance (Medication Adherence).................................................................90
9.12
Extent of Exposure...............................................................................................90
10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS.....................................................................................................91
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations........91
10.1.1
Code of Conduct for Clinical Trials.............................................................91
10.1.2
Financial Disclosure.....................................................................................93
10.1.3
Data Protection.............................................................................................93
10.1.3.1
Confidentiality of Data ......................................................................94
10.1.3.2
Confidentiality of Participant Records...............................................94
10.1.3.3
Confidentiality of IRB/IEC Information............................................94
10.1.4
Committees Structure...................................................................................94
10.1.4.1
Scientific Advisory Committee (SAC)..............................................94
10.1.4.2
Executive Oversight Committee........................................................95
10.1.4.3
External Data Monitoring Committee ...............................................95
10.1.5
Publication Policy........................................................................................95
10.1.6
Compliance with Study Registration and Results Posting Requirements ...95
10.1.7
Compliance with Law, Audit, and Debarment ............................................96
10.1.8
Data Quality Assurance ...............................................................................96
10.1.9
Source Documents .......................................................................................97
10.1.10
Study and Site Closure.................................................................................98
10.2
Appendix 2: Clinical Laboratory Tests..............................................................99
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting.............................................................101
10.3.1
Definition of AE ........................................................................................101
10.3.2
Definition of SAE ......................................................................................102
10.3.3
Additional Events Reported.......................................................................103
10.3.4
Recording AE and SAE .............................................................................103
10.3.5
Reporting of AEs, SAEs, and Other Reportable Safety Events to the 
Sponsor ......................................................................................................107
10.4
Appendix 4: Device Events, Adverse Device Events, and Medical Device 
Incidents: Definitions, Collection, and Documentation..................................108
10.5
Appendix 5: Contraceptive Guidance..............................................................109
10.5.1
Definitions..................................................................................................109
10.5.2
Contraception Requirements......................................................................110
10.5.3
Pregnancy Testing......................................................................................111
10.6
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research..........................................................................................112
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10.7
Appendix 7: Country-specific Requirements..................................................117
10.7.1
Argentina....................................................................................................117
10.8
Appendix 8: Abbreviations ...............................................................................118
11
REFERENCES.............................................................................................................120
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LIST OF TABLES
Table 1
Study Interventions....................................................................................51
Table 2
Examples of Concomitant Treatment Permitted in the Study ...................55
Table 3
Reporting Time Periods and Time Frames for Adverse Events and 
Other Reportable Safety Events.................................................................72
Table 4
Analysis Strategy for Safety Parameters....................................................86
Table 5
Protocol-required Safety Laboratory Assessments....................................99
Table 6
Contraceptive Methods ............................................................................110
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LIST OF FIGURES
Figure 1
Study Design..............................................................................................26
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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A Phase 3b Randomized Double-blind, Placebo Controlled, Multicenter 
Study to Evaluate the Efficacy and Safety of Gefapixant in Women with Chronic Cough and 
Stress Urinary Incontinence
Short Title: Efficacy of Gefapixant in Women with Chronic Cough and Stress Urinary 
Incontinence
Acronym: Not applicable
Hypotheses, Objectives, and Endpoints:
Hypotheses are aligned with objectives in the Objectives and Endpoints table.
In this study, the objectives/hypotheses and endpoints below will be evaluated in adult 
female participants with refractory or unexplained chronic cough and stress urinary 
incontinence as follows:
Primary Objectives
Primary Endpoints
- Objective: To evaluate the efficacy of 
gefapixant in reducing the frequency of 
cough-induced stress urinary incontinence 
episodes compared to placebo as determined 
by a participant Incontinence Diary, 
measured as percentage change from 
baseline in episodes of cough-induced stress 
urinary incontinence at Week 12 
Hypothesis (H1): Gefapixant is superior to 
placebo in reducing the frequency of cough-
induced stress urinary incontinence episodes 
over 12 weeks
- Episodes of cough-induced stress 
urinary incontinence
Secondary Objectives
Secondary Endpoints
- Objective: To evaluate the safety and 
tolerability of gefapixant compared to 
placebo in percent of participants with 
adverse events 
- Adverse events 
- Study intervention discontinuations due 
to an adverse event
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Overall Design:
Study Phase
Phase 3
Primary Purpose
Treatment
Indication
Chronic cough
Population
Women with refractory or unexplained chronic cough 
and stress urinary incontinence
Study Type
Interventional
Intervention Model
Parallel
This is a multi-site study.
Type of Control
Placebo
Study Blinding
Double-blind with in-house blinding
Masking
Participant or Subject
Investigator
Estimated Duration of Study
The Sponsor estimates that the study will require 
approximately 17 months from the time the first 
participant (or their legally acceptable representative) 
provides documented informed consent until the last 
participant’s last study-related contact.
Number of Participants:
Approximately 380 participants will be randomized, with 190 participants in each 
intervention group.
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Intervention Groups and Duration:
Intervention 
Groups
Intervention 
Group Name
Drug
Dose 
Strength
Dose 
Frequency
Route of 
Adminis-
tration
Regimen/ 
Treatment 
Period
Use
Gefapixant
Gefapixant
45 mg
BID
Oral
12 weeks
Experi-
mental
Placebo
Placebo
0 mg
BID
Oral
12 weeks
Experi-
mental
Abbreviations: BID = twice daily
Total Number
2 intervention groups
Duration of 
Participation
Each participant will participate in the study for approximately 22 weeks
from the time the participant provides documented informed consent
through the final contact. After a Screening period of up to 6 weeks and a 
Placebo Run-in period of 2 weeks, each participant will be receiving 
assigned intervention for approximately 12 weeks. Each participant will 
have a safety, follow-up telephone call approximately 14 days (with an 
allowed variance of up to +7 days) after discontinuation, or withdrawal of 
the study intervention.
Study Governance Committees:
Steering Committee
No
Executive Oversight Committee
Yes
Data Monitoring Committee
Yes
Clinical Adjudication Committee
No
Scientific Advisory Committee
Yes
Study governance considerations are outlined in Appendix 1.
Study Accepts Healthy Volunteers: No
A list of abbreviations used in this document can be found in Appendix 8.
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1.2
Schema
The study design is depicted in Figure 1.
Figure 1
Study Design
BID = twice daily; e-Diary = electronic diary.
The Screening period may be up to 6 weeks, which includes time for receipt of Screening laboratory results and 
washout (if required). Refer to Section 6.5 and Section 8.10.1 for further details on washout procedure.
Following the Screening period and a 2-week, single-blind, Placebo Run-in period, participants will be 
randomized under double-blind conditions in a 1:1 ratio to gefapixant 45 mg BID or placebo. Participants will 
remain on their assigned intervention at Randomization throughout the study. 
Telephone contact will be made on Day 7 (+3 days) to review any adverse events, concomitant medications, 
study drug administration compliance, and e-Diary completion.
A safety follow-up telephone call will be conducted a minimum of 14 days (with an allowed variance of up to 
+7 days) after Visit 6 or after the last dose of study intervention (for participants who discontinue from 
intervention early).
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1.3
Schedule of Activities (SoA)
Study Period
Screening
Placebo 
Run-in
Baseline/
Randomization
Intervention
Follow-
up 
Discc
Notes
Visit 
1
2
3
TC
4
5
6
TC 
Scheduled Day
Day -56 
to 
Day -15
Day -14 
to 
Day -1
Day 1
Day 7
Day 28
Day 56
Day 84
Day 98
Scheduling Window 
(Recommended)
NA
±4 days
NA
+3 
days
±4 days
±4 days
±4 days
+7 days
Scheduled Week
Wk -8 to 
Wk -3
Wk -2 to 
Day -1
-
Wk 1
Wk 4
Wk 8
Wk 12
Wk 14
Administrative Procedures
Informed Consent
X
Informed Consent for FBR
X
FBR is optional for the 
participant.
Participant Identification Card
X
X
Update with allocation 
number once 
randomized.
Inclusion/Exclusion Criteria
X
X
X
Demographics, Medication 
History 
X
MESA Questionnaire
X
Prior/Concomitant Medications
X
X
X
X
X
X
X
X
X
Randomization
X
Study Intervention Distribution 
X
X
X
X
Study Intervention Accountability
X
X
X
X
X
Contact IRT System
X
X
X
X
X
X
X
Efficacy Procedures
Activate ePROs
X
X
X
X
X
X
X
See ePRO Vendor 
Manual
Issue/instruct on use of e-Diary
X
Review e-Diary compliance and 
instructions for use, as 
appropriate
X
X
X
X
X
X
Disc: Only when 
participant discontinues 
from study intervention 
(not discontinues from 
study)
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Study Period
Screening
Placebo 
Run-in
Baseline/
Randomization
Intervention
Follow-
up 
Discc
Notes
Visit 
1
2
3
TC
4
5
6
TC 
Scheduled Day
Day -56 
to 
Day -15
Day -14 
to 
Day -1
Day 1
Day 7
Day 28
Day 56
Day 84
Day 98
Scheduling Window 
(Recommended)
NA
±4 days
NA
+3 
days
±4 days
±4 days
±4 days
+7 days
Scheduled Week
Wk -8 to 
Wk -3
Wk -2 to 
Day -1
-
Wk 1
Wk 4
Wk 8
Wk 12
Wk 14
Deactivate/collect e-Diary
X
X
Disc: Only when 
participant discontinues 
from study (not just 
discontinues study 
intervention)
Incontinence Diary
Complete episodic diary (throughout the day) for the 7 days prior to Visits 
2, 3, 4, 5, and 6.
Remind participant to 
complete prior to the 
7-day collection period.
I-QoL
X
X
X
X
X
X
Complete at clinic visit
before all other 
procedures. 
Visit 3: before the first 
dose of study 
intervention.
CSD
Complete daily (in the evening)
Remind participant of 
need to complete daily.
Cough Severity VAS
Complete at Visit 1 clinic visit and daily (in the evening)
Visits 2, 3, 4, 5 & 6:
Remind participant of 
need to complete daily.
PGIC 
X
X
Complete at clinic visit.
WPAI
X
X
X
Complete at clinic visit. 
Visit 3: before first dose 
of study intervention.
Safety Procedures
Chest Radiograph or CT Thorax
X
Not required if done in 
past 5 years and after 
onset of chronic cough.
Vital Signs
X
X
X
X
X
X
X
Height
X
Weight
X
X
X
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Study Period
Screening
Placebo 
Run-in
Baseline/
Randomization
Intervention
Follow-
up 
Discc
Notes
Visit 
1
2
3
TC
4
5
6
TC 
Scheduled Day
Day -56 
to 
Day -15
Day -14 
to 
Day -1
Day 1
Day 7
Day 28
Day 56
Day 84
Day 98
Scheduling Window 
(Recommended)
NA
±4 days
NA
+3 
days
±4 days
±4 days
±4 days
+7 days
Scheduled Week
Wk -8 to 
Wk -3
Wk -2 to 
Day -1
-
Wk 1
Wk 4
Wk 8
Wk 12
Wk 14
Physical Examination
X
X
X
Screening/Visit 1: Full 
examination.
Visit 6 and Disc: 
Directed examination.
Cough Stress Test
X
Performed by medically 
qualified personnel (eg, 
physician, nurse 
practitioner).
Pelvic Examination
X
Performed by medically 
qualified personnel (eg, 
physician, nurse 
practitioner) who 
routinely performs 
procedure.
12-lead ECG
X
Spirometry
X
Not required if done 
within past 1 year and 
during a clinically stable 
period.
Hematology & Chemistry
X
X
X
Urinalysis (w/ Microscopy)
X
X
X
Urine Pregnancy Test
X
Performed locally at 
study site. 
Serum Pregnancy Test
X
Only if urine pregnancy 
test is positive.
Adverse Event Monitoring
X
X
X
X
X
X
X
Xa
X
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Study Period
Screening
Placebo 
Run-in
Baseline/
Randomization
Intervention
Follow-
up 
Discc
Notes
Visit 
1
2
3
TC
4
5
6
TC 
Scheduled Day
Day -56 
to 
Day -15
Day -14 
to 
Day -1
Day 1
Day 7
Day 28
Day 56
Day 84
Day 98
Scheduling Window 
(Recommended)
NA
±4 days
NA
+3 
days
±4 days
±4 days
±4 days
+7 days
Scheduled Week
Wk -8 to 
Wk -3
Wk -2 to 
Day -1
-
Wk 1
Wk 4
Wk 8
Wk 12
Wk 14
Pharmacokinetics/Biomarkers
Pharmacokinetic Blood 
Collectiond
X
X
Only one sample will be 
collected, either at Visit 6
or Disc Visit, whichever 
is the first visit following 
the last dose of study 
intervention.
Blood for Genetic Analysisb
X
CSD = Cough Severity Diary; CT = computed tomography; Disc = discontinuation; ECG = electrocardiogram; e-Diary = electronic diary; ePRO = electronic patient-reported 
outcome; FBR = future biomedical research; IRT = interactive response technology; I-QoL = Incontinence Quality of Life Instrument; MESA = Medical Epidemiological and 
Social Aspects of Aging; NA = not applicable; PGIC = Patient Global Impression of Change; TC = telephone call; VAS = Visual Analog Scale; Wk = week; WPAI = Work 
Productivity and Activity Impairment.
a. A safety follow-up telephone call will be conducted a minimum of 14 days (with an allowed variance of up to +7 days) after the last dose of study intervention (for 
participants who complete the study, discontinue from the study intervention early, or discontinue from the study).
b. This 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 a site if there is 
either a local law or regulation prohibiting collection, or if the Institutional Review Board / Independent Ethics Committee 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 (or their legally acceptable representative) 
provides documented informed consent for future biomedical research. If the planned genetic analyses are not approved, but future biomedical research is approved and 
consent is given, this sample will be collected for the purpose of future biomedical research.
c. For participants who discontinue from study intervention early, study visits/assessments should continue to be performed at timepoints that correspond to each remaining 
study visit, but procedures will be limited to collection of adverse events, concomitant medications, and e-Diary assessments.
d. A pharmacokinetic blood sample should be collected within approximately 96 hours of the final dose of study medication. If the discontinuation or final visit is scheduled to 
occur greater than 96 hours following the final dose of study medication, please contact the Sponsor for guidance.
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2
INTRODUCTION
Chronic cough, defined as cough lasting >8 weeks, is a common complaint worldwide and 
one of the most frequent concerns prompting patients to seek a physician consultation. The 
overall global prevalence of chronic cough is approximately 10% [Song, W. J., et al 2015]. 
For approximately two-thirds of these patients, a potential co-morbid condition can be 
identified, and the cough effectively managed by optimizing therapy for the condition. 
Patients who have been diagnosed with conditions that are suspected to cause chronic cough 
(ie, asthma, GERD, UACS, or non eosinophilic bronchitis [Irwin, R. S., et al 2018]) but 
whose cough does not resolve with the appropriate treatment of those conditions are 
considered to have refractory chronic cough [McCrory, D. C., et al 2013]. Patients with 
chronic cough in whom an underlying etiology cannot be identified despite a thorough 
diagnostic work-up are considered to have unexplained chronic cough [McCrory, D. C., et al 
2013].
Chronic cough, particularly when refractory or unexplained, is associated with physical, 
psychological, and social morbidity, and a substantial quality of life decrement [French, C. 
L., et al 1998] [Young, E. C. 2010] [Chamberlain, S. A., et al 2015] [Dicpinigaitis, P. V., et 
al 2006] [Kuzniar, T. J., et al 2007] [French, C. L., et al 2017] [Everett, C. F., et al 2007].
Syncope, urinary incontinence, headache, and sleep deprivation are among the most severe
physical symptoms associated with chronic cough [Irwin, R. S. 2006]. Psychosocial 
symptoms including depression, embarrassment, and avoidance of activities are also common 
[Irwin, R. S. 2006]. Successful treatment of refractory or unexplained chronic cough confers 
benefits beyond a reduction in cough to an improvement in associated physical symptoms 
and overall quality of life. 
Professional guidelines describe systematic approaches to the evaluation and management of 
chronic cough. These guidelines are based largely on consensus opinion and observational 
data from the medical literature. There are currently no treatments approved by the US FDA 
or EMA for the treatment of chronic cough [Smith, J. A. 2016]. Given the prolonged nature, 
significant morbidity, and lack of effective treatment, unexplained or refractory chronic 
cough is a major unmet medical need.
Mechanism of Cough
Each cough occurs through the stimulation of a complex reflex arc. Cough is initiated 
following activation of airway sensory nerves in the upper and lower respiratory tract. 
Airway sensory nerves are tailored to detect changes in the physical and chemical 
environment, and if required, elicit protective reflex events such as cough. These reflexes are 
normally protective; however, in disease, airway reflexes can become hyperresponsive, 
leading to an increase in symptoms and a pathologic cough. 
P2X3 receptors are ligand-gated ion channels that respond to ATP and are almost exclusively 
localized on C-fiber sensory neurons, which innervate the upper and lower airways and are 
the main nerve fibers responsible for cough. Adenosine triphosphate is released by damaged, 
stressed, and inflamed tissues. The action of ATP at sensory neurons in the periphery and 
spinal cord contributes to neural excitability and may cause hyperresponsiveness through 
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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 RNA knock-down and pharmacological antagonists [Barclay, J., et al 2002] 
[Cockayne, D. A., et al 2000] [Souslova, V., et al 2000]. Adenosine triphosphate and P2X3-
containing receptors have been shown to be involved in airways sensitization, and their 
involvement provides a rationale for P2X3 antagonism in the treatment of cough.
Stress Urinary Incontinence and Chronic Cough
Stress urinary incontinence, defined as the involuntary loss of urine in association with 
increased intra-abdominal pressure from coughing, sneezing or physical exertion, is the most 
common type of urinary incontinence in women, with an overall prevalence ranging from 
29% to 75% depending on age [Wood, L. N. 2014]. Stress incontinence can be further
classified as “pure” or “predominant” SUI, depending on whether there are any co-existing
symptoms of urinary urgency [Welk, B. 2017]. Although the exact prevalence of stress 
incontinence in women with chronic cough has not been well established, limited data 
suggest that a significant subset of chronic cough patients also experience SUI [Shariat, S. F., 
et al 2009] [Hrisanfow, E. 2012]. In one specialty cough center in the US, approximately 
65% of women who presented with chronic cough, when specifically questioned, reported 
SUI exclusively with a cough episode [Dicpinigaitis, P. 2019]. Furthermore, SUI is likely 
underreported in women with chronic cough, who may be reluctant to disclose symptoms of 
incontinence unless specifically asked.
Stress urinary incontinence is an important and socially debilitating complication of chronic 
cough in women, with a significant impact on quality of life. Patients with refractory or 
unexplained chronic cough who experience the onset or worsening of SUI carry a 
particularly significant health and quality-of-life burden related to both cough and 
incontinence symptoms. Treatment for pure stress or stress predominant urinary incontinence 
consists of pelvic ﬂoor muscle training and behavioral interventions; if these fail, continence 
surgery is often recommended. There is currently no globally approved pharmacological 
agent for treating SUI. 
Mechanistically, episodes of stress incontinence occur with activities that increase 
intra-abdominal and bladder pressure beyond urethral resistance. Ineffective urethral 
resistance may be related to loss of connective tissue and/or pelvic muscular strength due to 
chronic pressure (ie, high-impact activity, chronic cough, or obesity) or trauma due to 
childbirth, particularly vaginal deliveries [Lukacz, E. S., et al 2017]. 
Patients with refractory or unexplained chronic cough are exposed to repetitive daily 
increases in intra-abdominal pressure, which may predispose them to episodic cough-induced
SUI. In addition, over time chronic cough may weaken pelvic floor musculature, contributing 
to overall episodes of SUI. Thus, symptoms of SUI may improve with successful treatment 
of refractory or unexplained chronic cough [Irwin, R. S. 2006].
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2.1
Study Rationale
The purpose of this study is to evaluate the efficacy and safety of gefapixant, an oral P2X3 
antagonist, in improving symptoms of cough-induced SUI in adult female participants with
refractory or unexplained chronic cough.
Previous Phase 2 studies have demonstrated dose-related efficacy and an acceptable safety 
and tolerability profile for gefapixant in participants with refractory or unexplained chronic 
cough. Gefapixant, at a dose of 50 mg BID for 12 weeks, demonstrated a significant 
reduction in the objective measure of awake cough frequency compared to placebo (see 
gefapixant IB). By improving symptoms of cough, and thereby reducing the associated 
repetitive increases in intra-abdominal pressure, treatment with gefapixant may also improve 
symptoms of stress incontinence in women with unexplained or refractory chronic cough and 
SUI. 
In order to be eligible for the study, participants are required to have experienced 
≥14 cough-induced SUI episodes in 1 week (average of 2 episodes/day). The choice of a 
14-episode threshold was based on prior clinical trial experience and is considered a 
reasonable number of episodes to evaluate eligibility. A mean baseline of 23 stress 
incontinence episodes per week was observed in a duloxetine study with the same threshold
[Cardozo, L., et al 2004]. Further, in participants with any type of incontinence, they may 
average 3 to 5 episodes per day.
This Phase 3b study will evaluate the efficacy and safety of gefapixant in reducing the 
frequency of cough-induced stress incontinence episodes in female participants with 
refractory or unexplained chronic cough and SUI. 
2.2
Background
Refer to the IB for detailed background information on gefapixant.
2.2.1
Pharmaceutical and Therapeutic Background
Gefapixant, 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, and is currently being evaluated in endometriosis-related pain and obstructive 
sleep apnea. Based on data generated from clinical studies to date, the gefapixant
development program is primarily focused on cough. Gefapixant has also been evaluated in 
an extensive nonclinical program. 
Gefapixant is an oral intervention provided as a film-coated tablet. The gefapixant tablets 
provided for this study contain gefapixant 45 mg. The placebo tablets provided in this study 
are indistinguishable from the gefapixant tablets in appearance. The placebo tablets contain 
no gefapixant but contain the same inactive excipients as those included in the active tablets.
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2.2.2
Preclinical and Clinical Studies
Refer to the IB for detailed information on preclinical and clinical studies.
2.2.3
Ongoing Clinical Studies
Gefapixant Chronic Cough Program
The current gefapixant cough development plan consists of three 12-month Phase 3 studies
(Protocols 027, 030 and 038), still ongoing, in participants with refractory or unexplained 
chronic cough. Protocols 027 and 030 are being conducted in approximately 720 and 
1290 participants, respectively, in the US, Europe and other regions. In both studies, 
participants are randomized in a 1:1:1 ratio to either gefapixant 45 mg BID, gefapixant 15 mg 
BID, or placebo. Protocol 038 is being conducted in approximately 160 participants in Japan; 
participants are randomized in a 1:1 ratio to either gefapixant 45 mg BID or gefapixant
15 mg BID.
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.
Gefapixant has been evaluated in an extensive nonclinical program. To date, there is little 
evidence from nonclinical studies that gefapixant has any direct cellular or direct target organ 
toxicity. 
The efficacy and safety of gefapixant has been evaluated in multiple completed clinical 
studies for cough. In those studies, participants with chronic cough who took gefapixant 
showed a reduction in cough frequency while awake and improvement in PROs (see 
gefapixant IB for further details).
In the completed and ongoing clinical studies, no major safety concerns have been noted. 
Taste-related adverse experiences (eg, dysgeusia [distortion in taste], hypogeusia [diminished 
taste], ageusia [loss of taste]) were the most frequently reported AEs in clinical studies with 
doses up to 1800 mg BID for 14 days. The percentage of participants receiving doses ≤50 mg 
BID reported less taste-related AEs than those receiving doses >50 mg BID. Some 
participants also described oral paresthesias (tingling sensation in the mouth and/or throat). 
In many instances, participants reported oral paresthesia or hypoesthesia (numbness) 
concurrent with taste disturbances. 
There is a rationale for taste disturbance with P2X2/3 antagonism because of the putative 
participation of ATP, acting via this receptor, in transducing taste signals from taste bud cells 
to sensory neurons. Attenuation of taste acuity is considered a tolerability concern as opposed 
to a safety concern, and is fully reversible after discontinuation of study intervention, and 
amenable to monitoring in clinical studies.
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Overall, based on growing clinical evidence supporting the efficacy of gefapixant in 
participants with refractory or unexplained chronic cough and the lack of significant safety 
findings in completed and ongoing nonclinical and clinical studies, the benefit risk balance of 
gefapixant is assessed as positive.
The risks and side effects related to this study are expected to be manageable and consistent 
with those observed thus far across the gefapixant program. 
Additional details regarding specific benefits and risks for participants participating in this 
clinical study may be found in the accompanying IB and informed consent documents.
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS
Hypotheses are aligned with objectives in the Objectives and Endpoints table.
Objectives
Endpoints
Primary
•
Objective: To evaluate the efficacy of 
gefapixant in reducing the frequency of 
cough-induced stress urinary 
incontinence episodes compared to 
placebo as determined by a participant 
Incontinence Diary, measured as 
percentage change from baseline in 
episodes of cough-induced stress urinary 
incontinence at Week 12
Hypothesis (H1): Gefapixant is superior 
to placebo in reducing the frequency of 
cough-induced stress urinary 
incontinence episodes over 12 weeks
•
Episodes of cough-induced stress 
urinary incontinence
Secondary
•
Objective: To evaluate the safety and 
tolerability of gefapixant compared to 
placebo in percent of participants with 
adverse events 
•
Adverse events
•
Study intervention discontinuations 
due to an adverse event
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Objectives
Endpoints
Tertiary/Exploratory
•
Objective: To evaluate the efficacy of 
gefapixant in improving incontinence 
specific quality of life, measured as 
change from baseline in the Incontinence 
Quality of Life score at Week 12 
•
Incontinence Quality of Life score
•
Objective: To evaluate the efficacy of 
gefapixant in improving self-rated cough 
severity, measured as change from 
baseline in the Cough Severity Diary total 
score and the Cough Severity Visual 
Analog Scale score at Week 12
•
Cough Severity Diary total score 
•
Cough Severity Visual Analog Scale 
score
•
Objective: To evaluate the efficacy of 
gefapixant in reducing the frequency of 
overall incontinence episodes compared 
to placebo as determined by a participant 
Incontinence Diary, measured as change 
from baseline in overall incontinence 
episodes at Week 12
•
Overall incontinence episodes 
•
Objective: To evaluate the impact of 
gefapixant on work productivity 
(measured as change from baseline in the 
Work Productivity and Activity 
Impairment score) and global rating of 
change (measured by the proportion of 
participants with improvement in Patient 
Global Impression of Change) at 
Week 12
•
Work Productivity and Activity 
Impairment score
•
Patient Global Impression of Change 
•
Objective: To explore the relationship 
between genetic variation and response to 
the treatment(s) administered, and 
mechanisms of disease. Variation across 
the human genome may be analyzed for 
association with clinical data collected in 
this study.
•
Germline genetic variation
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4
STUDY DESIGN
4.1
Overall Design
This is a randomized, double-blind, placebo-controlled, multi-site study of gefapixant in 
female participants with refractory or unexplained chronic cough and SUI. Approximately 
380 participants who meet entry criteria will be randomized in a ratio of 1:1 to 1 of 2 study 
intervention groups: placebo or gefapixant (45 mg BID). The duration of intervention for 
each participant is as follows:

Screening Period: up to approximately 42 days (see Section 8.10.1)

Single-blind, Placebo Run-in period: approximately 14 days (see Section 8.10.2)

Double-blind, Study intervention period, including Randomization (12-week 
treatment period): approximately 84 days (see Section 8.10.3)

Follow-up Period: approximately 14 days (see Section 8.10.5)
Individual participation is expected to be approximately 22 weeks from Screening through 
the Follow-up period.
The study will include 6 study visits and 2 scheduled telephone calls: Visit 1 (Screening from 
Week -8), Visit 2 (Placebo Run-in from Week -2 to Day -1), Visit 3 
(Baseline/Randomization Day 1), Telephone Call (Day 7), Visit 4 (Week 4), Visit 5 
(Week 8), Visit 6 (Week 12), and Telephone Safety Follow-up (Week 14). In addition, 
reminder telephone calls will be made prior to Incontinence Diary completion.
Specific procedures to be performed during the study, as well as their prescribed times and 
associated visit windows, are outlined in the SoA in Section 1.3. Details of each procedure 
are provided in Section 8.
This study will be using an external DMC to monitor safety and efficacy. There will be one 
planned IA when approximately 40% of the total randomized participants have either 
completed the study or discontinued study intervention early (all available follow-up data 
will be included in the analysis).
Results of the IA will be reviewed by the DMC, which will make recommendations to the 
EOC of the Sponsor to continue or stop the study according to the statistical analysis plan 
described in Section 9. The study may be stopped according to the results of the IA, either for 
futility or for efficacy (strong benefit).
Final database lock will occur after all participants have completed or discontinued the study 
intervention early; and a full analysis will be conducted. Details on the analysis and blinding 
are provided in Section 9.2.
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4.2
Scientific Rationale for Study Design
A 2-week, single-blind, Placebo Run-in period is included in the study design due to the high 
placebo response observed in urinary incontinence studies. A high placebo response is 
generally observed early in these studies and decreases over time; thus, the Placebo Run-in 
should allow sufficient time to exclude participants with an initial high placebo response. The 
inclusion of a 2-week, Placebo run-in period is consistent with published studies in SUI.    
A treatment period of 12 weeks in duration was chosen for this study based on prior studies 
of gefapixant in chronic cough which have shown meaningful efficacy in cough reduction
over 12 weeks. In addition, a 12-week treatment period is consistent with most published 
studies in SUI. Based on these existing data, 12 weeks is a reasonable and sufficient duration 
of time in which to observe a meaningful reduction in cough symptoms, as well as in SUI 
episodes.
4.2.1
Rationale for Endpoints
4.2.1.1
Efficacy Endpoints
Primary Endpoint:
The primary study endpoint is cough-induced SUI episodes. The goal of this study is to 
demonstrate that gefapixant is effective in improving cough-induced SUI in women with 
refractory or unexplained chronic cough, as evidenced by the percent change (reduction) 
from baseline in episodes of cough-induced SUI at Week 12 relative to placebo.
The cough-induced SUI episodes will be assessed using an event-driven Incontinence Diary.
The use of diaries to record episodes of SUI is supported by multiple published studies, 
including Phase 3 clinical studies evaluating the use of duloxetine in SUI [Blaivas, Jerry G., 
et al 1997] [Dmochowski, R. R., et al 2003] [Millard, R. J., et al 2004]. In this study, 
episodes of incontinence will be recorded in electronic diaries for a week before each 
baseline and treatment visit as outlined in the SoA (Section 1.3). For each incontinence 
episode, the participant will record the main cause of the episode: coughing, another stress 
reason, or other cause.
Exploratory Endpoints:
Recommendations for evaluating treatment outcomes in urinary incontinence include the 
assessment of health-related quality of life [Blaivas, Jerry G., et al 1997] [Lose, Gunnar, et al 
2001]. Therefore, an exploratory objective of the study will be to evaluate the efficacy of 
gefapixant in improving SUI-related quality of life in women with refractory or unexplained 
chronic cough, as assessed by the I-QoL. Another exploratory objective of the study will be 
to evaluate the impact of gefapixant on cough severity, as assessed by the CSD and Cough 
Severity VAS. The study will also evaluate the impact of gefapixant on overall incontinence 
episodes, global rating of change using the PGIC questionnaire and impact on work 
productivity using the WPAI.
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
Incontinence Quality of Life Questionnaire: The I-QoL is a validated disease-specific
questionnaire to evaluate the impact of urinary incontinence on activities and emotions in 
women [Patrick, D. L., et al 1999]. The I-QoL consists of 22 questions, each rated using a 
5-point response scale ranging from “extremely” to “not at all”. Item responses are 
summed across the 22 items and transformed to a 0 to 100 scale with lower scores 
reflecting better QoL. Three domain scores can also be calculated: avoidance and limiting 
behavior, psychosocial impacts, and social embarrassment.

Cough Severity Diary: The CSD is a validated, 7-item, disease-specific PRO measure 
with a recall period of “today.” The measure evaluates frequency of cough (3 items), 
intensity of cough (2 items), and disruption due to cough (2 items); each item is rated on 
an 11-point scale ranging from 0 to 10, with higher scores indicating greater severity. A 
CSD total score and 3 domain scores (frequency, intensity, disruption) can be calculated.
Domain scores are calculated as the average of the items within the domain and range 
from 1 to 7. The total score is the sum of the domain scores with a range of 3 to 21.

Cough Severity Visual Analog Scale: The Cough Severity VAS is a single-item 
question asking the participant to rate the severity of their cough “today” using a 100 mm 
VAS anchored with “No Cough” at 0 and “Extremely Severe Cough” at 100. Similar to 
the well-established use of VAS scores in chronic pain, the Cough Severity VAS measure 
provides a quick and easily-interpreted subjective assessment useful for clinicians to 
monitor improvement of their chronic cough patients following treatment.

Patient Global Impression of Change Questionnaire: The PGIC is a 2-part measure
asking the participant to rate the change in their urinary incontinence compared to the 
start of the study, with response options ranging from “very much better” to “much 
worse” (7-point scale). Based on the response to the initial question, the participant is 
asked a follow-up question to evaluate the meaningfulness of the improvement or 
worsening, with response options of “yes” or “no” indicating whether the improvement 
or worsening was important or not.

Work Productivity and Activity Impairment Questionnaire: The WPAI questionnaire 
yields 4 types of scores as follows: (1) absenteeism (work time missed); (2) presenteeism 
(impairment at work/reduced on-the-job effectiveness); (3) work productivity loss 
(overall work impairment/absenteeism plus presenteeism); and (4) activity impairment. 
The WPAI outcomes are expressed as impairment percentages, with higher numbers 
indicating greater impairment and less productivity, ie, worse outcomes [Reilly, M. C., et 
al 1993]. 
Participants will be asked to indicate if they are currently employed and to respond to the 
following questions referring to “the past 7 days”: work hours missed due to health 
problems, work hours missed for other reasons, hours actually worked, the degree to 
which their health has affected productivity while working, and the degree to which their 
health affected productivity in regular unpaid activities.
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4.2.1.2
Safety Endpoints
The safety data for gefapixant to date has been described in detail in the gefapixant IB. 
In support of the objective to evaluate the safety and tolerability profile of gefapixant, the 
safety and tolerability endpoints will be assessed by clinical evaluation of AEs and inspection 
of other study parameters including vital signs, physical examination, and standard 
laboratory safety tests at timepoints specified in the SoA (Section 1.3). Adverse events are 
graded and recorded according to Section 8.4 and Appendix 3.
4.2.1.3
Pharmacokinetic Endpoints
To determine exposure to gefapixant, a blood sample will be collected, as specified in the 
SoA (Section 1.3), to estimate the Ctrough. 
4.2.1.4
Pharmacodynamic Endpoints
No pharmacodynamic biomarkers that will require modeling are planned for this study.
4.2.1.5
Planned Exploratory Biomarker Research
4.2.1.5.1
Planned Genetic Analysis
Genetic variation may impact a participant’s response to therapy, susceptibility to, severity, 
and progression of disease. Variable response to therapy may be due to genetic determinants 
that impact drug absorption, distribution, metabolism, and excretion; mechanism of action of 
the drug; disease etiology; and/or molecular subtype of the disease being treated. Therefore, 
where local regulations and IRB/IEC allow, a sample will be collected for DNA analysis 
from consenting participants.
DNA samples may be used for research related to the study intervention(s), the disease under 
study, or 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, the analysis of genetic 
markers throughout the genome, or analysis of the entire genome. Analysis may be 
conducted if it is hypothesized that this may help further understand the clinical data.
The samples may be analyzed as part of a multi-study assessment of genetic factors involved 
in the response to understand study disease or related conditions.
4.2.1.6
Future Biomedical Research
The Sponsor will conduct future biomedical research on DNA specimens for which consent 
was provided during this clinical study.
Such research is for biomarker testing to address emergent questions not described elsewhere 
in the protocol (as part of the main study) and will only be conducted on specimens from 
appropriately consented participants. The objective of collecting/retaining specimens for 
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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 future biomedical research are presented in Appendix 6.
4.2.2
Rationale for the Use of Comparator/Placebo
A placebo is included in this study to maintain the study blinding, allowing for an unbiased 
assessment of efficacy and safety. Participants may discontinue the study intervention at any 
time. Given that there is no approved treatment for chronic cough, use of a placebo is 
justified.
4.3
Justification for Dose
In this study, gefapixant will be orally administered as gefapixant 45 mg BID based on the 
safety and efficacy results observed to date. Although the Phase 2 studies demonstrated 
efficacy of gefapixant at a dose of 50 mg BID, based on modeling and simulation work, a 
dosing regimen of 45 mg BID is proposed to provide maximum efficacy with a more 
acceptable tolerability profile than the 50 mg BID dose.
The known mechanism of action of gefapixant and related clinical study results support that 
the efficacy of gefapixant in decreasing cough, and the prevalence of the most common AE, 
dysgeusia, are both dose-related. Gefapixant 15 mg and 45 mg BID are being evaluated in 
the main Phase 3 program for chronic cough. The 45 mg BID dose is anticipated to provide
meaningful efficacy in the reduction of cough symptoms with a manageable incidence of 
dysgeusia.
Because the impact of gefapixant on SUI is hypothesized to be an indirect benefit of cough 
reduction, the 45 mg BID dose was selected for this study to provide maximal efficacy with 
respect to cough, and in turn, increase the potential to show a meaningful benefit in the 
reduction of cough-induced stress incontinence episodes.
Based on pharmacokinetic studies, gefapixant is rapidly absorbed with a median time to 
reach maximum plasma concentration of 1.0 to 2.0 hours. In addition, the half-life of 
gefapixant is approximately 7 to 10 hours and consistent with a BID dosing schedule.
4.4
Beginning and End of Study Definition
The overall study begins when the first participant (or their legally acceptable representative) 
provides documented informed consent. The overall study ends when the last participant 
completes the last study-related contact, withdraws consent, or is lost to follow-up (ie, the 
participant is unable to be contacted by the investigator).
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4.4.1
Clinical Criteria for Early Study Termination
Early study termination will be the result of the following specified criterion:
1. During the IA, based on the interim data:
a.
If the futility criteria are met, then the study may be stopped for futility and all 
participants would be discontinued from the study.
b. If the efficacy criteria are met, then the study may be stopped for efficacy and 
all participants would be discontinued from the study.
5
STUDY POPULATION
Female participants at least 18 years of age with refractory or unexplained chronic cough,
according to the current ACCP Guidelines and SUI, will be enrolled in this study.
The 2010 International Urogynecological Association/International Continence Society
definition of SUI, the “involuntary loss of urine on effort, physical exertion, or on sneezing 
or coughing”, will be used in this study. Gefapixant is expected to indirectly impact stress 
incontinence by reducing cough symptoms. Therefore, although participants may experience 
stress incontinence from multiple triggers, they must experience cough-induced stress 
incontinence in order to participate in the study. For the purposes of this study, incontinence 
will be defined as pure or predominant stress incontinence, and further classified as 
cough-induced, based on medical history (ie, the MESA Questionnaire) and the results of the 
incontinence diaries completed during the Screening period.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
5.1
Inclusion Criteria
A participant will be eligible for inclusion in the study if the participant:
Type of Participant and Disease Characteristics
Chronic Cough
1. Has a chest radiograph or computed tomography scan of the thorax (within 5 years of 
Screening/Visit 1 and after the onset of chronic cough) not demonstrating any 
abnormality considered to be significantly contributing to the chronic cough or any other 
clinically significant lung disease, in the opinion of the principal investigator or 
subinvestigator (Note: subinvestigator must be a physician). Note: If not available, can be 
performed at Screening/Visit 1.
2. Has a chronic cough (defined as duration of >8 weeks after onset of symptoms) for 
≥12 months.
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3. Has a diagnosis of refractory chronic cough or unexplained chronic cough. Note: For the 
purposes of this study:
a) A participant is defined as having refractory chronic cough when:
1. the participant has had a clinical evaluation that suggests a co-morbid condition 
that may be associated with chronic cough (eg, GERD, asthma, or UACS), AND
2. the participant has received appropriate diagnostic work-up and at least 2 months 
of therapy for the co-morbid condition, prior to Screening, according to the 
current ACCP guidelines, AND
3. the participant continues to cough despite being on therapy for the co-morbid 
condition.
b) A participant is defined as having unexplained chronic cough when:
1. the participant has had a clinical evaluation of their chronic cough per current 
ACCP guidelines, AND
2. the evaluation does not suggest a co-morbid condition that may be associated with 
chronic cough.
4. Has a score of ≥40 mm on the Cough Severity VAS at Screening/Visit 1 and Placebo 
Run-in/Visit 2.
Stress Urinary Incontinence
5. Has symptoms of SUI, defined as involuntary loss of urine on effort, physical exertion, or 
on sneezing or coughing, for ≥ 3 months.
6. Has pure or predominant SUI, based on the following criteria:
a) MESA Questionnaire Stress total score ≥7;
b) MESA Questionnaire Urge total score ≤12; AND
c) MESA Questionnaire SUI score ratio > urge incontinence score ratio.
7. Has a history of cough-induced SUI, based on the following criteria: 
a) Responds either “sometimes” or “often” to the question, “Does coughing gently 
cause you to lose urine?” on the MESA Questionnaire; OR
b) Responds either “sometimes” or “often” to the question, “Does coughing hard 
cause you to lose urine?” on the MESA Questionnaire.
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8. Has, on average, ≥ 2 cough-induced SUI episodes per day during each 7-day period prior 
to Placebo Run-in/Visit 2 and Randomization/Visit 3, as measured by the Incontinence 
Diary.
9. Has a positive cough stress test at Screening/Visit 1.
Demographics
10. Is female, 18 years of age or older, at the time of signing the informed consent.
11. Has a body mass index of ≤ 40 kg/m2.
Female Participants
Contraceptive use by women should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies.
12. A female participant is eligible to participate if she is not pregnant or breastfeeding, and 
at least one of the following conditions applies:
-
Is not a woman of childbearing potential (WOCBP)
OR
-
Is a WOCBP and using an acceptable contraceptive method, or be abstinent from 
heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long 
term and persistent basis), as described in Appendix 5 during the intervention period 
and for at least 2 weeks (14 days) after the last dose of study intervention. The 
investigator should evaluate the potential for contraceptive method failure (ie, 
noncompliance, recently initiated) in relationship to the first dose of study 
intervention.
Informed Consent
13. Provides documented informed consent/assent for the study (or legally acceptable 
representative). The participant may also provide consent for future biomedical research. 
However, the participant may participate in the study without participating in future 
biomedical research.
Study Participation
14. Demonstrates compliance with the Incontinence Diary completion requirements, as 
evidenced by fully completing the diary for at least 4 of the 7 days prior to Visit 2 
(Screening period) and at least 4 of the 7 days prior to Randomization/Visit 3 (Placebo 
Run-in period).
Note: the participant should be retrained on completion of the Incontinence Diary at 
Placebo Run-in/Visit 2 and Randomization/Visit 3, if completion of the diary is <7 days.
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15. Is willing and able to comply with all aspects of the protocol, including agreeing not to 
smoke during the study and demonstrating an ability to follow study procedures 
(including completion of the I-QoL, CSD, and Cough Severity VAS) to the satisfaction 
of the investigator/qualified designee prior to randomization.
5.2
Exclusion Criteria
The participant must be excluded from the study if the participant:
Medical Conditions
Chronic Cough
1. Is a current smoker.
2. Has given up smoking within 12 months of Screening/Visit 1.
3. Is a former smoker with a smoking history greater than 20 pack-years (eg, 1 pack 
[20 cigarettes] per day for 20 years).
4. Has a FEV1/ FVC ratio <60% (spirometry performed within the past year is acceptable if 
the investigator confirms that the spirometry was done during a period where the 
participant was clinically stable, eg, not during an upper respiratory infection).
5. Has a history of upper or lower respiratory tract infection or recent clinically significant 
change in pulmonary status within 4 weeks of Screening/Visit 1.
6. Has a 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.
Stress Urinary Incontinence
7. Has a history of surgery to treat SUI within 1 year of the Screening/Visit 1. 
8. Has a history of other specialized treatments for SUI, including intravesical balloon or 
urethral bulking agent therapy.
9. Has a pessary or other external incontinence device currently or within 1 month of the 
Screening/Visit 1.
10. Has a history of Grade 3 or higher pelvic organ prolapse previously documented (unless 
corrected by surgery at least 1 year prior to Screening) or diagnosed on screening 
examination.
11. Has a neurogenic bladder.
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12. Has unexplained hematuria (gross or microscopic) or has dysuria at Screening/Visit 1.
13. Has a history of adult nocturnal incontinence.
14. Has a history of continuous urine leakage within 1 month of the Screening/Visit 1.
15. Has a history of interstitial cystitis.
16. Has a history of clinically significant neurological disease (including stroke) or injury 
that could affect the lower urinary tract or its nerve supply.
17. Has active or recurrent urinary tract infection.
18. Has a history of having a permanent urinary catheter (at any time) or any urinary 
catheterization within 3 months of the Screening/ Visit 1.
General
19. Has an eGFR <30 mL/min/1.73 m2 at Screening/Visit 1 OR eGFR ≥30 mL/min/1.73 m2
and <50 mL/min/1.73 m2 at Screening/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 Screening/Visit 1).
20. 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.
21. Is, at the time of signing the 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.
22. Has a history of anaphylaxis or cutaneous adverse drug reaction (with or without 
systemic symptoms) to sulfonamide antibiotics or other sulfonamide-containing drugs.
23. Has a known allergy/sensitivity or contraindication to gefapixant or its excipients (Note:
refer to the IB for details regarding excipients for gefapixant).
24. Has donated or lost ≥1 unit of blood (approximately 300 mL) within 8 weeks prior to the 
first dose of gefapixant.
25. Is a WOCBP who has a positive urine pregnancy test at Screening/Visit 1. If the urine 
test is positive or cannot be confirmed as negative, a serum pregnancy test will be 
required.
Prior/Concomitant Therapy
Chronic Cough
26. Requires treatment with a therapy for chronic cough that does not adhere to the guidance 
parameters specified in Section 6.5.
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27. Is currently taking an angiotensin converting enzyme inhibitor or has taken an 
angiotensin converting enzyme inhibitor within 3 months of Screening/Visit 1.
Stress Urinary Incontinence
28. Requires the following pharmacologic therapies that may impact bladder function, which 
are not allowed from 2 weeks prior to Screening/Visit 1 through completion of the study: 
a) Alpha1-antagonists: eg, alfuzosin, doxazosin;
b) H1-receptor antagonists: eg, cyproheptadine, dimenhydrinate;
Note: Diuretics and calcium channel blockers are permitted, provided the participant 
is receiving a stable treatment regimen for at least 2 weeks prior to Placebo 
Run-in/Visit 2, and in the opinion of the investigator, is likely to remain on the stable 
treatment regimen through completion of the study.
29. Requires pharmacologic treatments that may impact bladder function, which are not 
allowed from 2 weeks prior to the Placebo Run-in/Visit 2 through the completion of the 
study. These therapies include, but are not limited to the following:
a) Serotonin–noradrenaline reuptake inhibitors: eg, duloxetine;
b) Anticholinergics: eg, oxybutynin, tolterodine, fesoterodine, propantheline, 
hyoscyamine, benztropine, trospium;
c) Smooth muscle relaxants: eg, flavoxate, dicyclomine, propiverine;
d) Tricyclic antidepressants: eg, imipramine, doxepin;
Note: Tricyclic antidepressants for indications other than urinary incontinence are 
permitted, provided the participant is receiving a stable treatment regimen for at 
least 2 weeks prior to the Placebo Run-in/Visit 2, and in the opinion of the 
investigator, is likely to remain on the stable treatment regimen through 
completion of the study.
e) Alpha-adrenergic agonists: eg, phenylpropanolamine, ephedrine, 
pseudoephedrine;
f)
Beta-3 agonists: eg, mirabegron;
g) Botulinum toxins, including BOTOX® (onabotulinumtoxin A), for the treatment 
of any bladder condition.
Note: Participants with a history of receiving regular or periodic botulinum toxin
treatments for conditions other than SUI (eg, migraine) may participate.
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30. Requires non-pharmacologic treatments (eg, behavioral modification, biofeedback, pelvic 
floor muscle training, posterior tibial nerve stimulation, sacral nerve stimulation) for 
incontinence which are not allowed from 1 month prior to Screening/Visit 1 through 
completion of the study.
Prior/Concurrent Clinical Study Experience
31. Has previously received gefapixant or other P2X3 antagonists.
32. Is concurrently 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
33. Has significantly abnormal laboratory tests at Screening/Visit 1 including:
a)
Alkaline phosphatase, ALT (SGPT), AST (SGOT) >200% of the upper limit of 
normal, or bilirubin >150% of the upper limit of normal.
b)
Hemoglobin <10 g/dL, WBC <2500 mm3 (<2.5 ×103/µL), neutrophil count 
<1500 mm3 (<1.5 ×103/µL), platelet count <100 ×103/mm3 (<100×103/uL).
For any of the above listed laboratory assessments, 1 repeat measurement will be allowed at 
the investigator’s discretion, before being considered a screen failure.
Other Exclusions
34. Has a history or current evidence of any condition, therapy, lab abnormality, or other 
circumstance that may increase the risk associated with study participation or study 
intervention administration or may interfere with the interpretation of study results, and 
in the judgment of the investigator or Sponsor, would make the participant inappropriate 
for entry into this study.
Note: Participants with a known history or current evidence of SARS-CoV-2 
(COVID-19) infection are ineligible to enroll in the study.
35. Is or has an immediate family member (eg, spouse, parent/legal guardian, sibling, or 
child) who is investigational site or Sponsor staff directly involved with this study.
5.3
Lifestyle Considerations
5.3.1
Meals and Dietary Restrictions
There are no meal or dietary restrictions.
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5.3.2
Caffeine, Alcohol, and Tobacco Restrictions
Participants will be advised that smoking (including cigarettes, cigars, vapes/e-cigarettes, etc) 
is not permitted during the course of the study, and alcohol consumption should not increase 
during the study.
5.3.3
Activity Restrictions
Participants will be advised to continue a consistent level of activity (including exercise) 
from Screening/Visit 1 until the end of the study, and not to begin a new exercise regimen or 
begin/change behavioral modifications or neuromodulation during the course of the study.
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.
Participants identified as screen failures prior to starting the Placebo Run-in period can be 
rescreened once for possible participation, with the following exceptions:

If the Cough Severity VAS inclusion criterion is not met at Screening/Visit 1, the 
participant is not permitted to be rescreened. 

If the Cough Severity VAS inclusion criterion is not met at Placebo Run-in/Visit 2, 
the participant may be rescreened only with Sponsor consultation.

If the MESA Questionnaire inclusion criterion is not met at Screening/Visit 1, the 
participant is not permitted to be rescreened.

If the SUI Diary inclusion criterion is not met at Placebo Run-in/Visit 2, the 
participant is not permitted to be rescreened.
Any participant who is rescreened will retain the original screening number assigned at 
Screening/Visit 1.
Note: while participants may screen fail any time up to the time of intervention allocation/ 
randomization (through the IRT system) at Randomization/Visit 3, participants that screen 
fail during the Placebo Run-in period (between Placebo Run-in/Visit 2 and Randomization/
Visit 3) will NOT be permitted to rescreen.
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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 of study interventions provided by the Sponsor will be packaged to support 
enrollment. Clinical supplies will be affixed with a clinical label in accordance with 
regulatory requirements.
6.1
Study Intervention(s) Administered
The study interventions to be used in this study are outlined in Table 1.
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Table 1
Study Interventions
Arm 
Name
Arm Type
Intervention 
Name
Type
Dose 
Formulation
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Administra-
tion
Regimen/
Treatment 
Period
Use
IMP/
NIMP
Sourcing
Gefapixant
Experimental
Gefapixant
Drug
Tablet
45 mg
1 tablet 
BID
Oral
12 weeks
Experimental
IMP
Central
Placebo
Placebo 
Comparator
Placebo 
matched to 
Gefapixant 
45 mg
Other
Tablet
0 mg
1 tablet 
BID
Oral
12 weeks
Placebo
IMP
Central
BID = twice daily. IMP = Investigational Medicinal Product, NIMP = Non-Investigational Medicinal Product.
Note: Definition of IMP and NIMP is based on guidance issued by the European Commission. Regional and/or Country differences of the definition of IMP/NIMP may exist. In 
these circumstances, local legislation is followed.
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All supplies indicated in Table 1 will be provided per the "Sourcing" column depending upon 
local country operational requirements.
Refer to Section 8.1.9 for details regarding administration of the study intervention.
All placebos were created by the Sponsor to match the active product.
6.1.1
Medical Devices
Not applicable.
6.2
Preparation/Handling/Storage/Accountability
6.2.1
Dose Preparation
There are no specific calculations or evaluations required to be performed in order to 
administer the proper dose to each participant. The rationale for selection of doses to be used 
in this study is provided in Section 4.3.
6.2.2
Handling, Storage, and Accountability
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received, and any discrepancies are 
reported and resolved before use of the study intervention.
Only participants enrolled in the study may receive study intervention, and only authorized 
site staff may supply or administer study intervention. All study interventions must be stored 
in a secure, environmentally controlled, and monitored (manual or automated) area in 
accordance with the labeled storage conditions with access limited to the investigator and 
authorized site staff.
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records).
For all study sites, the local country Sponsor personnel or designee will provide appropriate 
documentation that must be completed for drug accountability and return, or local discard 
and destruction if appropriate. Where local discard and destruction is appropriate, the 
investigator is responsible for ensuring that a local discard/destruction procedure is 
documented.
The study site is responsible for recording the lot number, manufacturer, and expiry date for 
any locally purchased product (if applicable) as per local guidelines unless otherwise 
instructed by the Sponsor.
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
6.3.1
Intervention Assignment
Intervention allocation/randomization will occur centrally using an interactive response 
technology (IRT) system. There are 2 study intervention arms. Participants will be assigned 
randomly in a 1:1 ratio to gefapixant 45 mg BID or placebo.
6.3.2
Stratification
Intervention allocation/randomization will be stratified according to the following factors:
1. Body mass index (≥30 versus <30 kg/m2)
2. Geographic region (North America, Europe, Asia-Pacific, Other). Details of the regions 
will be provided in a separate supplemental document for randomization.
6.3.3
Blinding
During the Placebo Run-in period, participants only will be blinded to the study intervention 
(ie, single-blind). Following the Placebo Run-in period, a double-blinding technique with in-
house blinding will be used. Gefapixant and placebo will be packaged identically so that the 
blind is maintained throughout the duration of the study. The participant, the investigator, 
and Sponsor personnel or delegate(s) who are involved in the study intervention
administration or clinical evaluation of the participants are unaware of the intervention 
assignments.
Details on the analyses and in-house blinding are provided in Section 9.2.
See Section 8.1.11 for a description of the method of unblinding a participant during the 
study, should such action be warranted.
6.4
Study Intervention Compliance
Records of intervention compliance for each participant will be kept during the study. The 
clinical research associates will review intervention compliance during investigational site 
visits and at the completion of the study. Compliance should be based on participant 
reporting (and supplemented 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 (compliance <80% between study 
visits, based on review with the participant) require consultation between the investigator and 
the Sponsor and written documentation of the collaborative decision on participant 
management.
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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 
medications or vaccinations 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 or vaccination rests 
with the investigator and/or the participant’s primary physician. However, the decision to 
continue the participant on study intervention requires the mutual agreement of the 
investigator, the Sponsor, and the participant.
For participants who receive study intervention, any medication (including over-the-counter 
medications) or therapy administered to the participant during the course of the study will be 
recorded on the Prior and Concomitant Therapy CRF. Treatments for chronic cough and SUI 
received by the participant will also be recorded. The investigator(s) will record any AE on 
the AEs CRF for which a concomitant medication/therapy was administered.
Listed below are specific restrictions for prior/concomitant therapy during the course of the 
study:
Chronic Cough
1. Opioids (including codeine) for the treatment of cough are not allowed from 1 week prior 
to Placebo Run-in/Visit 2 through completion of the study. 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 Placebo Run-in/Visit 2
and, in the opinion of the investigator, is likely to remain on the stable treatment regimen 
through completion of the study.
2. Pregabalin, gabapentin, amitriptyline, or nortriptyline for the treatment of cough is not 
allowed from 2 weeks prior to Placebo Run-in/Visit 2 through completion of the study.
Pregabalin, gabapentin, amitriptyline, or nortriptyline for indications other than chronic 
cough are permitted provided the participant is receiving a stable treatment regimen for at 
least 2 weeks prior to Placebo Run-in/Visit 2 and, in the opinion of the investigator, is 
likely to remain on the stable treatment regimen through completion of the study.
3. Dextromethorphan, guaifenesin, benzonatate and any other over the counter or 
prescription medication for the treatment of cough are not allowed from 2 weeks prior to 
Placebo Run-in/Visit 2 through completion in the study. 
4. Lozenges/drops, teas/drinks, natural/herbal remedies, and other similar treatments which 
do not contain an active antitussive or expectorant are allowed, provided they have been 
used on a regular basis for at least 2 weeks prior to Placebo Run-in/Visit 2. 
Lozenges/drops, teas/drinks, and natural/herbal remedies should not be initiated during 
the study. The Sponsor should be consulted for further information.
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5. Treatments for conditions associated with chronic cough, such as GERD, asthma, UACS
(formerly called postnasal drip), or non-asthmatic eosinophilic bronchitis, are permitted 
provided that participants have been treated for at least 2 months for these co-morbid 
conditions associated with chronic cough and are receiving a stable treatment regimen for 
at least 2 weeks prior to Placebo Run-in/Visit 2 and, in the opinion of the investigator, are 
likely to remain on the stable treatment regimen through completion of the study. 
Possible treatments are provided in Table 2. Note, this list is not meant to be 
comprehensive. The Sponsor should be consulted for further information.
Table 2
Examples of Concomitant Treatment 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
Non-asthmatic 
eosinophilic bronchitis
Inhaled/oral corticosteroids
GERD = gastroesophageal reflux disease 
Note: the treatments included in this table are not exhaustive, but examples of treatment class. The guidelines 
in bullet #5 above the table should be referred to when determining appropriate concomitant treatment use 
during the study.
6. Non-pharmacologic treatments (eg, physiotherapy, speech and language therapy) for 
cough are not allowed from 3 months prior to Screening/Visit 1 through completion of 
the study.
Stress Urinary Incontinence
Excluded medications and therapies are detailed in Section 5.2.
Other Conditions
Angiotensin converting enzyme inhibitors are not allowed within 3 months of 
Screening/Visit 1 through completion of the study.
6.5.1
Rescue Medications and Supportive Care
No rescue or supportive medications are specified for use in this study.
6.6
Dose Modification
No dose modification is allowed in this study.
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6.7
Intervention After the End of the Study
There is no study-specified intervention following the end of the study.
6.8
Clinical Supplies Disclosure
The emergency unblinding call center will use the intervention/randomization schedule for 
the study to unblind participants and to unmask study intervention identity . The emergency 
unblinding call center should only be used in cases of emergency (see Section 8.1.10). In the 
event that the emergency unblinding call center is not available for a given site in this study, 
the central electronic intervention allocation/randomization system (IRT) should be used to 
unblind participants and to unmask study intervention identity. The Sponsor will not provide 
random code/disclosure envelopes or lists with the clinical supplies.
See Section 8.1.11 for a description of the method of unblinding a participant during the 
study, should such action be warranted.
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL
7.1
Discontinuation of Study Intervention
Discontinuation of study intervention does not represent withdrawal from the study.
As certain data on clinical events beyond study intervention discontinuation may be 
important to the study, they must be collected through the participant’s last scheduled follow-
up, even if the participant has discontinued study intervention. Therefore, all participants 
who discontinue study intervention prior to completion of the protocol-specified treatment 
period will still continue to participate in the study as specified in Section 1.3 and 
Section 8.10.3.
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 8.1.10.
A participant must be discontinued from study intervention but continue to be monitored in 
the study for any of the following reasons:
•
The participant or participant’s legally acceptable representative requests to discontinue 
study intervention.
•
The participant’s treatment assignment has been unblinded by the investigator, MSD 
subsidiary, or through the emergency unblinding call center.
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•
The participant has a medical condition or personal circumstance which, in the opinion of 
the investigator and/or Sponsor, places the participant at unnecessary risk from continued 
administration of the study intervention.
•
The participant has a confirmed positive serum pregnancy test.
•
In case of clinically significant and potentially drug-related rash or signs and/or 
symptoms consistent with allergic drug reaction or anaphylaxis to study intervention.
•
Chronic failure to comply with the dosing, evaluations, or other requirements of the 
study, despite documentation at the site of repeated efforts to reinforce compliance.
For participants who discontinue study intervention early, refer to Section 8.10.4.
Discontinuation from study intervention is “permanent.” Once a participant is discontinued, 
he/she shall not be allowed to restart study intervention.
7.2
Participant Withdrawal From the Study
A participant must be withdrawn from the study if the participant or participant’s legally 
acceptable representative withdraws consent from the study.
If a participant withdraws from the study, they will no longer receive study intervention or be 
followed at scheduled protocol visits.
Specific details regarding procedures to be performed at the time of withdrawal from the 
study, as well as specific details regarding withdrawal from future biomedical research, are 
outlined in Section 8.1.10. The procedures to be performed should a participant repeatedly 
fail to return for scheduled visits and/or if the study site is unable to contact the participant 
are outlined in Section 7.3.
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.
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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 (by education, training, and experience) staff. Delegation of study 
site personnel responsibilities will be documented in the Investigator Trial File Binder (or 
equivalent).
•
All study-related medical decisions must be made by an investigator who is a qualified 
physician.
•
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
•
Procedures conducted as part of the participant’s routine clinical management (eg, chest 
x-ray) 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. The Sponsor may provide protocol-specific 
guidance and/or guidance for special circumstances.
•
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 maximum amount of blood collected from each participant over the duration of the study
(based on the SoA) will not exceed 40 mL (Appendix 2). Repeat or unscheduled samples 
may be taken for safety reasons or for technical issues with the samples; blood volumes for 
these repeat or unscheduled samples are not included in the above calculation of maximum 
amount of blood collected. Some local regulations require blood samples to be drawn for 
additional serology testing; blood volumes for these samples are also not included in the 
maximum amount of blood collected (Section 10.7).
8.1
Administrative and General Procedures
8.1.1
Informed Consent
The investigator or medically qualified designee (consistent with local requirements) must 
obtain documented informed consent from each potential participant (or their legally 
acceptable representative) prior to participating in this clinical study or future biomedical 
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research. If there are changes to the participant’s status during the study (eg, health or age of 
majority requirements), the investigator or medically qualified designee must ensure the 
appropriate documented informed consent is in place.
8.1.1.1
General Informed Consent
Informed consent given by the participant or their legally acceptable representative must be 
documented on a consent form. The form must include the trial protocol number, trial 
protocol title, dated signature, and /agreement of the participant (or his/her legally acceptable 
representative) and of the person conducting the consent discussion.
A copy of the signed and dated informed consent form should be given to the participant (or 
their legally acceptable representative) before participation in the study.
The initial ICF, any subsequent revised ICF, and any written information provided to the 
participant must receive the IRB/IEC’s approval/favorable opinion in advance of use. The 
participant or his/her legally acceptable representative should be informed in a timely manner 
if new information becomes available that may be relevant to the participant’s willingness to 
continue participation in the study. The communication of this information will be provided 
and documented via a revised consent form or addendum to the original consent form that 
captures the participant’s or the participant’s legally acceptable representative’s dated 
signature.
Specifics about the study and the study population are to be included in the study informed 
consent form. 
Informed consent will adhere to IRB/IEC requirements, applicable laws and regulations, and 
Sponsor requirements.
8.1.1.2
Consent and Collection of Specimens for Future Biomedical Research
The investigator or medically qualified designee will explain the future biomedical research 
consent to the participant, or the participant’s legally acceptable representative, answer all of 
his/her questions, and obtain documented informed consent before performing any procedure 
related to future biomedical research. A copy of the informed consent will be given to the 
participant before performing any procedure related to future biomedical research.
8.1.2
Inclusion/Exclusion Criteria
Inclusion and exclusion criteria for this study are defined in Section 5.1 and Section 5.2, 
respectively.
All inclusion and exclusion criteria will be reviewed by the investigator, who is a qualified 
physician, to ensure that the participant qualifies for the study. If the participant is referred to 
a specialist for evaluation of any of the entry criteria, such as the SUI criteria, the specialist 
must be a medically qualified health care professional, and should document and share the 
evaluation findings with the investigator so that a collaborative decision may be made on the 
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participant’s eligibility for the study. Source documentation for all eligibility criteria needs to 
be maintained at the study site.
For Inclusion Criteria 2 and 3 (see Section 5.1 for details), a combination of medical records 
and/or verbal history from the participant can be used to fulfill these criteria if documented in 
the participant study file by the investigator.
For participants with eGFR ≥30 mL/min/1.73 m2 and <50 mL/min/1.73 m2 at 
Screening/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 
Screening/Visit 1), documentation of stable serum creatinine must be retained as source 
documentation at the study site.
8.1.3
Participant Identification Card
All participants will be given a participant identification card identifying them as participants 
in a research study. The card will contain study site contact information (including direct 
telephone numbers) to be used in the event of an emergency. The investigator or qualified 
designee will provide the participant with a participant identification card immediately after 
the participant provides documented informed consent. At the time of intervention
(randomization), site personnel will add the treatment/randomization number to the 
participant identification card.
The participant identification card also contains contact information for the emergency 
unblinding call center so that a healthcare provider can obtain information about study 
intervention in emergency situations where the investigator is not available.
8.1.4
Medical History
A medical history will be obtained by the investigator or qualified designee (refer to eCRF 
entry guidelines).
8.1.5
Medical Epidemiological and Social Aspects of Aging (MESA) Questionnaire
The MESA is a 15-item validated questionnaire adapted from the MESA survey [Diokno, A. 
C., et al 1999]. The MESA is used to identify participants with symptoms of urge and/or 
stress incontinence. Item response options are: never (0), rarely (1), sometimes (2), or often 
(3). The stress score is comprised of 9 items with a total score ranging from 0 to 27; the urge 
score is comprised of 6 items with a total score ranging from 0 to 18. The MESA will be used 
in this study to identify participants with pure or predominant stress incontinence as indicated 
by meeting the following 3 criteria: a stress total score ≥7, an urge total score ≤12, and a 
stress score ratio greater than the urge score ratio. The MESA questionnaire (along with the 
Cough Severity VAS) will be completed by participants at the clinic at Screening/Visit 1.
Participants must also have a history of cough-induced SUI, based on their responses to the 
following questions on the MESA: response of ‘sometimes’ or ‘often’ to the question, “Does 
coughing gently cause you to lose urine?” OR to the question, “Does coughing hard cause 
you to lose urine?”.
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8.1.6
Prior and Concomitant Medications Review
8.1.6.1
Prior Medications
The investigator or qualified designee will review prior medication use at Screening/Visit 1
(see Section 6.5 and refer to eCRF entry guidelines).
8.1.6.2
Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the participant 
during the study.
8.1.7
Assignment of Screening Number
All consented participants will be given a unique screening number that will be used to 
identify the participant for all procedures that occur prior to randomization. Each participant 
will be assigned only 1 screening number. Screening numbers must not be re-used for 
different participants.
8.1.8
Assignment of Treatment/Randomization Number
All eligible participants will be randomly allocated and will receive a 
treatment/randomization number. The treatment/randomization number identifies the 
participant for all procedures occurring after treatment allocation/randomization. Once a 
treatment/randomization number is assigned to a participant, it can never be re-assigned to 
another participant.
A single participant cannot be assigned more than 1 treatment/randomization number.
8.1.9
Study Intervention Administration
The distribution of study intervention will be performed by the investigator and/or study staff 
at the study site visits. 
At Placebo Run-in/Visit 2, study intervention (placebo only for all participants) will be 
dispensed by the study site.
Then, according to when the clinic visit is during the day, the participant will take the first 
dose of study intervention either in the morning or in the evening. Subsequent dosing should 
be performed by the participant BID approximately 12 hours apart and approximately at the 
same time each day for the duration of the study. 
At Randomization, gefapixant 45 mg BID or placebo will be dispensed by the study site. 
Participants should be instructed to follow the same dosing schedule as described for the 
Placebo Run-in period.
Note: While the study site will be aware that the participants are receiving placebo during the 
Placebo Run-in period, the participants themselves must not be informed that they are 
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receiving placebo at the Placebo Run-in/Visit 2, nor must they be told that there may be a 
change of treatment (or that they are entering a different treatment phase) at 
Randomization/Visit 3 (Section 8.10.2 and Section 8.10.3).
The last dose of study intervention will be on the evening prior to Visit 6. Study intervention 
supplies will be collected and accountability will be performed at Visit 3, Visit 4, Visit 5, and 
Visit 6.
8.1.9.1
Timing of Dose Administration
Study intervention will be administered orally, BID, approximately 12 hours apart for 
approximately 12 weeks (84 days) during the study.
A missed dose may be taken if it is <4 hours after the expected dosing time. If it is ≥4 hours 
after the expected dosing time, then the dose can be skipped, and the regular schedule 
resumed.
8.1.10
Discontinuation and Withdrawal
Participants who discontinue study intervention prior to completion of the intervention period
should be encouraged to continue to be followed for all remaining study visits as outlined in 
the SoA (Section 1.3) and Section 8.10.3.
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.
8.1.10.1
Withdrawal From Future Biomedical Research
Participants may withdraw their consent for future biomedical research. Participants may 
withdraw consent at any time by contacting the investigator for the main study. If medical 
records for the main study are still available, the investigator will contact the Sponsor using 
the designated mailbox (clinical.specimen.management@merck.com). Subsequently, the 
participant's consent for future biomedical research will be withdrawn. A letter will be sent 
from the Sponsor to the investigator confirming the withdrawal. It is the responsibility of the 
investigator to inform the participant of completion of withdrawal. Any analyses in progress 
at the time of request for withdrawal or already performed prior to the request being received 
by the Sponsor will continue to be used as part of the overall research study data and results. 
No new analyses would be generated after the request is received.
In the event that the medical records for the main study are no longer available (eg, if the 
investigator is no longer required by regulatory authorities to retain the main study records) 
or the specimens have been completely anonymized, there will no longer be a link between 
the participant’s personal information and their specimens. In this situation, the request for 
specimen withdrawal cannot be processed.
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8.1.11
Participant Blinding/Unblinding
STUDY INTERVENTION IDENTIFICATION INFORMATION IS TO BE UNMASKED 
ONLY IF NECESSARY FOR THE WELFARE OF THE PARTICIPANT. EVERY 
EFFORT SHOULD BE MADE NOT TO UNBLIND.
For emergency situations, where the investigator or medically qualified designee (consistent 
with local requirements) needs to identify the intervention used by a participant and/or the 
dosage administered, he/she will contact the emergency unblinding call center by telephone 
and make a request for emergency unblinding. As requested by the investigator or medically 
qualified designee, the emergency unblinding call center will provide the information to 
him/her promptly and report unblinding to the Sponsor. Prior to contacting the emergency 
unblinding call center to request unblinding of a participant’s intervention assignment, the 
investigator, who is a qualified physician, should make reasonable attempts to enter the 
intensity of the AEs observed, the relation to study intervention, the reason thereof, etc, in the 
medical chart. If it is not possible to record this assessment in the chart prior to the 
unblinding, the unblinding should not be delayed.
In the event that unblinding has occurred, the circumstances around the unblinding (eg, date, 
reason, and person performing the unblinding) must be documented promptly, and the 
Sponsor Clinical Director notified as soon as possible.
Once an emergency unblinding has taken place, the investigator, site personnel, and Sponsor 
personnel may be unblinded so that the appropriate follow-up medical care can be provided 
to the participant.
Participants whose treatment assignment has been unblinded by the investigator or medically 
qualified designee and/or nonstudy treating physician must be discontinued from study 
intervention, but should continue to be monitored in the study.
Additionally, the investigator or medically qualified designee must go into the IRT system 
and perform the unblind in the IRT system to update drug disposition. In the event that the 
emergency unblinding call center is not available for a given site in this study, the IRT 
system should be used for emergency unblinding in the event that this is required for 
participant safety.
8.1.12
Calibration of Equipment
The investigator or qualified designee has the responsibility to ensure that any device or 
instrument used for a clinical evaluation/test during a clinical study that provides information 
about inclusion/exclusion criteria and/or safety or efficacy parameters shall be suitably 
calibrated and/or maintained to ensure that the data obtained are reliable and/or reproducible. 
Documentation of equipment calibration must be retained as source documentation at the 
study site.
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8.2
Efficacy Assessments
Compliance with the efficacy and safety assessments (along with study intervention use) and 
visit schedule is essential, and any noncompliance noted by the investigator or designee 
should result in consultation with the participant on corrective measures needed to ensure 
compliance.
8.2.1
Patient-reported Outcomes
At Screening/Visit 1, each participant will be dispensed and instructed on the use of an 
electronic diary (e-Diary) for completing the ePRO measures. Participants should bring their 
e-Diary device for all study visits and should be contacted and reminded to do so (eg, by 
telephone or text) before each study visit.
Between clinic visits, participants will be instructed to complete the Incontinence Diary 
throughout each day at the time of each SUI episode, and then again with the other ePRO 
measures (in the following order: Incontinence Diary, CSD, and Cough Severity VAS) at 
approximately the same time each evening. The Incontinence Diary should be completed for 
the 7 days prior to a study visit, and the CSD and Cough Severity VAS should be completed 
daily between Visits 1 and 6 (as outlined in the SoA, Section 1.3). If a participant fails to 
complete the Incontinence Diary, CSD and/or Cough Severity VAS ePRO measure(s), the 
e-Diary will allow the participant, based on recall, to complete these missed measures the 
next day (also see vendor’s site manual for further details). Participants will be prompted 
within the e-Diary to complete the missed measures first, prior to the measures for the current 
day.
At the clinic visits, participants will be asked to complete ePRO measures (in the following 
order: Cough Severity VAS, I-QoL, PGIC, and WPAI) as outlined in the SoA (also see 
vendor’s site manual for further details). All Visit 1, 2, and 3 ePRO measures MUST be 
activated and completed prior to the first dose of study intervention/Randomization (see 
vendor’s site manual for further details).
Electronic PRO measures must be activated, as outlined in the SoA. More details on PRO 
measures are given in Section 4.2.1.1.
Participants who discontinue study intervention early will continue to be monitored in the 
study and should be encouraged to continue to complete the ePRO measures for the 
remaining visits (as outlined in the SoA) through the end of the study.  At the discontinuation 
visit, participants will be asked to complete ePRO measures (in the following order: I-QoL, 
PGIC, and WPAI), as outlined in the SoA (also see vendor’s site manual for further details).
Compliance with daily completion of the eDiaries should be monitored by the investigator or 
designee. Each investigator site will contact individual participants who are non-compliant in 
order to retrain and/or remind them to complete their assessments as per the SoA 
(Section 1.3). Discussion with the participant and retraining will be performed if any 
question on any e-Diary is missing and/or if any e-Diary scheduled for completion per the 
SoA is missing, in error.
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Once a participant has completed the study (or discontinued from the study), the participant 
should return the e-Diary to the study site and all ePRO measures should be deactivated.
Data collection for all ePRO measures will be dependent on ePRO device and software 
availability.
8.2.1.1
Incontinence Diary
The Incontinence Diary is designed as an event diary to be completed each time a participant 
experiences a urine leak. A “urine leak” is defined as an accidental leakage of urine of any 
amount. The participant is required to report EVERY urine leak, even if the leak is a small 
amount (for example, a few drops), and to record the main cause of the urine leak as follows:
a.
“Coughing” – the participant will choose this option if coughing or a coughing fit was 
the main cause of their urine leak.
b. “Another stress reason” – the participant will choose this option if another 
stress-related activity such as sneezing, laughing, lifting something heavy, moving 
too quickly, or other physical activity was the main cause of their urine leak.
c.
“Other cause” – the participant will choose this option if the main cause of their urine 
leak was something other than coughing or another stress-related activity.
In the evening, the e-Diary will provide participants with a summary of the urine leaks they 
have reported during that day and will prompt them to enter any urine leaks they may have 
forgotten to report. The following morning, the e-Diary will again prompt the participant to 
report any urine leaks during the night that were not yet reported.
The Incontinence Diary should be completed throughout each day as each urine leak occurs 
for the 7 days prior to the first dose of study intervention in the Placebo Run-in/Visit 2 period 
and for the 7 days prior to each subsequent study visit, as outlined in the SoA (Section 1.3).
A reminder telephone call to the participant will be scheduled prior to each 7-day collection 
period.
Should the participant have to reschedule a visit, and the rescheduling occurs after 
completing the Incontinence Diary for 7 days, they should continue to complete diary entries 
for every additional day until the visit. If the rescheduled visit is delayed beyond 7 additional 
days, the Sponsor/Clinical Research Associate should be contacted for further guidance.
Should a participant not complete all 7 days prior to any visit, they will be retrained in how 
to complete the Incontinence Diary to improve compliance during the rest of the study.
Please note: participants must have at least 4 days of Incontinence Diary data during the 
7-day eligibility period prior to each of Placebo Run-in/Visit 2 and Randomization/Visit 3 to 
be eligible for study participation.
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8.2.1.2
Cough Severity Diary
Participants will complete the CSD daily at approximately the same time each evening before 
going to bed, as outlined in the SoA (Section 1.3). 
8.2.1.3
Cough Severity Visual Analog Scale 
Participants will be asked to rate the severity of their cough over the past 24 hours using a 
100-mm Cough Severity VAS single-item questionnaire, with the response ranging from 0 
(“No Cough”) to 100 (“Extremely Severe Cough”).
At Screening/Visit 1, participants will complete a single Cough Severity VAS questionnaire 
at the study visit in order to assess the eligibility criteria. For the remainder of the study
(Visits 1 through 6), participants will complete the Cough Severity VAS daily at 
approximately the same time each evening before going to bed, as outlined in the SoA
(Section 1.3).
In order to confirm participant eligibility, study site staff will be required to review/confirm 
the participant met the Cough Severity VAS eligibility criteria from the measurement done at
Screening/Visit 1 at the clinic and the measurement done the evening before Placebo 
Run-in/Visit 2 (or from the morning of Placebo Run-in/Visit 2, prior to conducting any 
Visit 2 procedures, if the evening measurement was missed). A score of ≥40 mm on the 
Cough Severity VAS for both Screening/Visit 1 and Placebo Run-in/Visit 2 is required for 
randomization into the study.
8.2.1.4
Incontinence Quality of Life Questionnaire
Participants are required to complete the I-QoL at the clinic visits, as outlined in the SoA
(Section 1.3).
8.2.1.5
Patient Global Impression of Change Questionnaire
Participants are required to complete the PGIC at the clinic visits, as outlined in the SoA
(Section 1.3).
8.2.1.6
Work Productivity and Activity Impairment Questionnaire
The WPAI questionnaire will be used to assess impairment and productivity at work.
Participants will be asked to indicate if they are currently employed and to respond to a series 
of work-related questions referring to “the past 7 days” (Section 4.2.1.1).
Participants are required to complete the WPAI at the clinic visits, as outlined in the SoA
(Section 1.3).
8.3
Safety Assessments
Details regarding specific safety procedures/assessments to be performed in this study are 
provided in this section. 
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The total amount of blood/tissue to be drawn/collected over the course of the study (from 
prestudy to poststudy visits), including approximate blood/tissue volumes drawn/collected by 
visit and by sample type per participant, can be found in the introduction to Section 8.
Planned time points for all safety assessments are provided in the SoA.
8.3.1
Chest Radiography/Computed Tomography Thorax Scan
A chest radiograph or computed tomography scan of the thorax should be performed locally 
for participants at Screening/Visit 1, if this has not been done within the last 5 years, and 
after the onset of chronic cough. The chest radiograph or computed tomography scan of the 
thorax should not demonstrate any abnormality considered to be significantly contributing to 
the chronic cough or any other clinically significant lung disease, in the opinion of the 
principal investigator (or subinvestigator, see Inclusion Criterion 1, Section 5.1).
8.3.2
Physical Examinations
A complete physical examination will be performed at Screening/Visit 1 and will include 
assessments of the following: general appearance; skin and lymphatic; eyes, ears, nose, 
throat; cardiovascular system; respiratory system; abdomen/gastrointestinal system; 
musculoskeletal and neurological systems. Other body systems may be examined at the 
discretion of the investigator. 
Any clinically significant abnormalities in physical examinations noted after 
Screening/Visit 1 will be recorded as AEs in the eCRF. 
A brief directed physical examination will be performed at Visit 6 or the Discontinuation
Visit. 
A brief directed physical examination may be performed at any study visit that does not 
already include a physical examination if deemed necessary by the investigator due to 
signs/symptoms. A physical examination (complete or directed) can be performed at any 
unscheduled visit if deemed necessary by the investigator.
Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
8.3.3
Pelvic Examination
A pelvic examination will be performed during Screening/Visit 1. The examination must be 
sufficiently thorough to evaluate the participant for gynecological abnormalities including,
but not limited to, pelvic organ prolapse. Note: participants with Grade 3 or higher pelvic 
organ prolapse are excluded from the study (see Exclusion Criterion 10, Section 5.2).
The pelvic examination should be performed by medically qualified personnel (eg, urologist, 
gynecologist, urogynecologist, other physician, nurse practitioner) who routinely perform 
pelvic examinations, including evaluation for, and grading of, pelvic organ prolapse.
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Abnormal findings should be recorded on eCRFs as medical history (if identified during the 
screening period between Screening/Visit 1 and Placebo Run-in/Visit 2).
8.3.4
Cough Stress Test
The cough stress test is commonly used as a diagnostic test for SUI; however, there is no 
standardized method for conducting the procedure. This study will use a modified version of 
the 1-3-5 cough test [Grigoriadis, T., et al 2016] to determine study eligibility (see Inclusion 
Criterion 9, Section 5.1). Participants should attend Screening/Visit 1 (or the visit at which 
the cough stress test is performed) with a comfortably full bladder. The participant will be 
asked to stand over an incontinence pad, towel, or other protective floor covering with legs
apart and cough forcefully one time. Visualization of fluid loss from the urethra simultaneous 
with the cough is considered a positive stress test and diagnostic of SUI. If no fluid loss is 
observed simultaneous with the 1 cough, the participant should wait approximately 1 to 2 
minutes, then cough forcefully 3 consecutive times in quick succession. If no fluid loss is 
observed simultaneous with any of the 3 coughs, the participant should wait approximately 1 
to 2 minutes, then cough forcefully 5 consecutive times in quick succession. If no fluid loss is 
observed simultaneous with any of the 5 coughs, then the cough stress test is considered 
negative and the subject is not eligible for the study.
The cough stress test should be performed by medically qualified personnel (eg, urologist, 
gynecologist, urogynecologist, other physician, nurse practitioner).
8.3.5
Vital Signs
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 will be collected, as outlined in the SoA (Section 1.3). All blood pressure 
measurements should be performed on the same arm, preferably by the same person. Height 
and weight will also be collected as per the SoA (Section 1.3). 
Any clinically significant abnormalities in vital signs noted after Screening/Visit 1 will be 
recorded as AEs in the eCRF.
8.3.6
Electrocardiograms
A 12-lead ECG will be performed at Screening/Visit 1 using local standard procedures. 
Clinically significant abnormal findings should be recorded in the AE eCRF.
8.3.7
Spirometry
A spirometry assessment will be performed locally at Screening/Visit 1 using a calibrated 
spirometer to determine study eligibility (Exclusion Criterion 4, Section 5.2). Assessments 
will include FEV1, FVC, and FEV1/FVC ratio.
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Spirometry should be performed in accordance with guidelines established by the American 
Thoracic Society / European Respiratory Society (Available from: 
http://www.thoracic.org/statements/). For safety reasons, spirometry should be performed 
with the participant sitting, using a chair with arms and without wheels; however, if 
necessary to undertake the testing with the participant standing or in another position, this 
should be noted in the participant’s study file.
Spirometry performed within the past year of Screening is acceptable to assess eligibility if 
the investigator confirms that spirometry was done during a period where the participant was 
clinically stable (eg, not during an upper respiratory infection) and documentation of the 
spirometry is available in the participant medical records and/or study file.
8.3.8
Clinical Safety Laboratory Assessments
Refer to Appendix 2 for the list of clinical laboratory tests to be performed and to the SoA for 
the timing and frequency.
•
The investigator or medically qualified designee (consistent with local requirements) 
must review the laboratory report, document this review, and record any clinically 
relevant changes occurring during the study in the AE section of the case report form 
(CRF). The laboratory reports must be filed with the source documents. Clinically 
significant abnormal laboratory findings are those which are not associated with the 
underlying disease, unless judged by the investigator to be more severe than expected for 
the participant's condition.
•
All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the laboratory manual and the SoA (Section 1.3).
•
If laboratory values from nonprotocol-specified laboratory assessments performed at the 
institution’s local laboratory require a change in study participant management or are 
considered clinically significant by the investigator (eg, SAE or AE or dose 
modification), then the results must be recorded in the appropriate CRF (eg, SLAB).
•
For any laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 7 days after the last dose of study intervention, every 
attempt should be made to perform repeat assessments until the values return to normal or 
baseline or if a new baseline is established as determined by the investigator.
8.3.9
Renal and Urological Safety Assessments
Safety assessments will be performed in all participants in order to monitor renal and 
urological safety during the course of the study. Participants will be monitored for hematuria 
and urinary crystals through urinalysis (performed at the central laboratory). 
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8.3.9.1
Screening
If, during screening, a participant has unexplained hematuria (defined as, for example, 
participants without a history of recent menses, urinary tract infection, or recent 
procedure/instrumentation that would explain the hematuria), the participant should not be 
enrolled. (Note: Any other explanation for hematuria finding must be reviewed with the 
Sponsor).
If, during screening, a participant has crystalluria, 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.

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.
8.3.9.2
Visit 6/Discontinuation
At Visit 6 or Discontinuation Visit, a urine sample will be collected from all participants, as 
outlined in the SoA. If unexplained hematuria and/or urinary crystals are identified and 
deemed to be clinically significant by the investigator, the participant should be considered 
for further evaluation. If an investigator deems it necessary to perform an unscheduled 
urinalysis at any time during the study (after randomization), the same procedures for 
collection/preparation of the urine sample and evaluation of hematuria (as explained or 
unexplained) described for Visit 6 or Discontinuation Visit should be performed.
8.4
Adverse Events (AEs), Serious Adverse Events (SAEs), and Other Reportable 
Safety Events
The definitions of an AE or SAE, as well as the method of recording, evaluating, and 
assessing causality of AE and SAE and the procedures for completing and transmitting AE, 
SAE, and other reportable safety event reports can be found in Appendix 3.
Adverse events, SAEs, and other reportable safety events will be reported by the participant 
(or, when appropriate, by a caregiver, surrogate, or the participant's legally authorized 
representative).
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The investigator and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE as well as other reportable safety events. 
Investigators remain responsible for following up AEs, SAEs, and other reportable safety 
events for outcome according to Section 8.4.3.
The investigator, who is a qualified physician, will assess events that meet the definition of 
an AE or SAE as well as other reportable safety events with respect to seriousness, 
intensity/toxicity and causality.
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other Reportable 
Safety Event Information
All AEs, SAEs, and other reportable safety events that occur after the participant provides 
documented informed consent but before intervention randomization must be reported by the 
investigator if the participant is receiving Placebo Run-in or other run-in treatment, if the 
event causes the participant to be excluded from the study, or is the result of a protocol-
specified intervention, including but not limited to washout or discontinuation of usual 
therapy, diet, or a procedure.
From the time of intervention randomization through 14 days following cessation of 
treatment, 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 starts from completion of 
the safety follow-up telephone call following cessation of intervention until the last study-
related off-intervention telephone call.
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 related to study intervention.
Investigators are not obligated to actively seek AEs or SAEs or other reportable safety events 
in former study participants. However, if the investigator learns of any SAE, including a 
death, at any time after a participant has been discharged from the study, and he/she 
considers the event to be reasonably related to the study intervention or study participation, 
the investigator must promptly notify the Sponsor.
All initial and follow-up AEs, SAEs, and other reportable safety events will be recorded and 
reported to the Sponsor or designee within the time frames as indicated in Table 3.
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Table 3
Reporting Time Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events
Type of Event
Reporting Time 
Period:
Consent to 
Randomization/ 
Allocation
Reporting Time 
Period:
Randomization/ 
Allocation through 
Protocol-specified 
Follow-up Period
Reporting Time Period:
After the Protocol-
specified Follow-up 
Period
Time Frame to 
Report Event 
and Follow-up 
Information to 
Sponsor:
Nonserious 
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 
Exposurea
Report if:
- due to intervention
- causes exclusion
Report alla
Previously reported –
Follow to 
completion/termination; 
report outcome
Within 24 hours 
of learning of 
event
Event of Clinical 
Interest (require 
regulatory 
reporting)
Report if:
- due to intervention
- causes exclusion
Reporta
- Potential drug-
induced liver injury 
(DILI)
- Require regulatory 
reporting
Not required
Within 24 hours 
of learning of 
event
Event of Clinical 
Interest (do not 
require regulatory 
reporting)
Report if:
- due to intervention
- causes exclusion
Reporta
- non-DILI ECIs 
and those not 
requiring regulatory 
reporting
Not required
Within 5 
calendar days of 
learning of event
Cancer
Report if:
- due to intervention
- causes exclusion
Report all
Not required
Within 5 
calendar days of 
learning of event
Overdose
Report if:
- receiving placebo 
run-in or other run-in 
medication 
Report alla
Not required
Within 5 
calendar days of 
learning of event
DILI = drug-induced liver injury; ECI = event of clinical interest.
a
Participants who discontinue study intervention and are continuing to be monitored in the study do not 
require the reporting of ECIs, pregnancy/lactation exposure, and overdose. Previously reported 
pregnancies/lactations exposure need to be followed for completion/termination; report outcome.
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8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events
Care will be taken not to introduce bias when detecting AEs and/or SAEs and other 
reportable safety events. Open-ended and nonleading verbal questioning of the participant is 
the preferred method to inquire about AE occurrence.
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All AEs, SAEs, and other reportable safety events,
including pregnancy and exposure during breastfeeding, events of clinical interest (ECIs), 
cancer, and overdose will be followed until resolution, stabilization, until the event is 
otherwise explained, or the participant is lost to follow-up (as defined in Section 7.3). In 
addition, the investigator will make every attempt to follow all nonserious AEs that occur in
randomized participants for outcome. Further information on follow-up procedures is given 
in Appendix 3.
8.4.4
Regulatory Reporting Requirements for SAE
Prompt notification (within 24 hours) by the investigator to the Sponsor of SAE is essential 
so that legal obligations and ethical responsibilities towards the safety of participants and the 
safety of a study intervention under clinical investigation are met.
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
Sponsor will comply with country-specific regulatory requirements and global laws and 
regulations relating to safety reporting to regulatory authorities, IRB/IECs, and investigators.
Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSARs) according to local regulatory requirements and Sponsor policy and 
forwarded to investigators as necessary.
An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAE) from the Sponsor will file it 
along with the IB and will notify the IRB/IEC, if appropriate according to local requirements.
8.4.5
Pregnancy and Exposure During Breastfeeding
Although pregnancy and infant exposure during breastfeeding are not considered AEs, any
pregnancy or infant exposure during breastfeeding in a participant (spontaneously reported to 
the investigator or their designee) that occurs during the study are reportable to the Sponsor.
All reported pregnancies must be followed to the completion/termination of the pregnancy. 
Pregnancy outcomes of spontaneous abortion, missed abortion, benign hydatidiform mole, 
blighted ovum, fetal death, intrauterine death, miscarriage, and stillbirth must be reported as 
serious events (Important Medical Events). If the pregnancy continues to term, the outcome 
(health of infant) must also be reported.
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Reporting time periods and time frames are fully detailed in Table 3.
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying as 
AEs or SAEs
There are no disease-related events and/or disease-related outcomes not qualifying as AEs or 
SAEs.
8.4.7
Events of Clinical Interest (ECIs)
Selected nonserious and SAEs are also known as ECIs and must be reported to the Sponsor.
Events of clinical interest for this study include:

An elevated AST or ALT lab value that is greater than or equal to 3X the upper limit 
of normal and an elevated total bilirubin lab value that is greater than or equal to 2X 
the upper limit of normal and, at the same time, an alkaline phosphatase lab value that 
is less than 2X the upper limit of normal, as determined by way of protocol-specified 
laboratory testing or unscheduled laboratory testing.*
*Note: These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may require 
an additional evaluation for an underlying etiology. The study site guidance for 
assessment and follow-up of these criteria can be found in the Investigator Study File 
Binder (or equivalent).
Reporting time periods and time frames are fully detailed in Table 3.
8.5
Treatment of Overdose
In this study, an overdose is any dose >1 tablet BID (Section 4.3.2). Study intervention 
should be taken once in the morning and once in the evening. If more than the 
protocol-specified intervention is taken within a 1-day period (ie, >2 tablets/day), 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 gefapixant IB). Overdose should be treated according to the participant’s 
clinical signs and symptoms.
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the Sponsor Clinical Director based on the clinical evaluation of the 
participant.
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8.6
Pharmacokinetics
8.6.1
Blood Collection for Plasma Gefapixant
A blood sample will be collected, as outlined in the SoA (Section 1.3). A pharmacokinetic 
blood sample should be collected within approximately 96 hours of the final dose of study 
medication. If the discontinuation or final visit is scheduled to occur greater than 96 hours 
following the final dose of study medication, please contact the Sponsor for guidance.
The date and time for the last dose of study intervention taken prior to the study visit on 
which the sample was collected should be recorded in the eCRF. In addition, the date and 
time of the sample collection should also be recorded in the eCRF.
Gefapixant plasma concentrations will be determined using a validated LC-MS/MS assay. 
Sample collection, storage and shipment instructions for plasma samples will be provided in 
the operations/laboratory manual for the study.
8.7
Pharmacodynamics
Pharmacodynamic parameters will not be evaluated in this study.
8.8
Biomarkers
Collection of samples for other biomarker research is also part of this study. The following 
samples for biomarker research are required and will be collected from all randomized
participants, as specified in the SoA (Section 1.3):
•
Blood for Genetic Analysis 
8.8.1
Planned Genetic Analysis Sample Collection
The planned genetic analysis sample should be drawn for planned analysis of the association 
between genetic variants in DNA and drug response. This sample will not be collected at the 
site if there is either a local law or regulation prohibiting collection, or if the IRB/IEC does 
not approve the collection of the sample for these purposes. If the sample is collected, 
leftover extracted DNA will be stored for future biomedical research if the participant 
provides documented informed consent for future biomedical research. If the planned genetic
analysis is not approved, but future biomedical research is approved and consent is given, 
this sample will be collected for the purpose of future biomedical research.
Sample collection, storage, and shipment instructions for planned genetic analysis samples 
will be provided in the operations/laboratory manual.
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8.9
Future Biomedical Research Sample Collection
If the participant provides written documented informed consent for future biomedical 
research, the following specimens will be obtained as part of future biomedical research:
•
Leftover DNA for future research
8.10
Visit Requirements
Visit requirements are outlined in Section 1.3. Specific procedure-related details are provided 
in Section 8.
8.10.1
Screening
Approximately 3 to 8 weeks (including the 2-week Placebo Run-in period) prior to 
intervention randomization, potential participants will be evaluated to determine whether
they fulfill the entry requirements as set forth in Section 5.  
Participants who are consented will complete the Cough Severity VAS and MESA on the day 
of Screening/Visit 1 at the clinic, prior to completing other screening procedures (in order to 
first determine if the participant meets the Screening/Visit 1 Cough Severity VAS and MESA 
entry criteria). 
Washout of concomitant medication is permitted after signing informed consent; participants 
may wash out of these therapies during the screening period (ie, at least 2 weeks prior to the
start of Placebo Run-in/Visit 2) and remain off of them through the completion of the study.
The investigator should evaluate the participant’s medical history and overall condition in 
making the decision as to whether participants can withdraw from medications in order to 
participate in the study.
Participants will be contacted prior to the 7-day Incontinence Diary assessment period before 
Placebo Run-in/Visit 2 to remind them to complete the Incontinence Diary for the 7 days 
prior to the next study visit.
Participants are to be reminded to bring their e-Diary device with them to the next visit.
8.10.2
Single-blind Placebo Run-in Period
During the 2-week, single-blind, Placebo Run-in period (approximately 2 weeks prior to
intervention randomization), participants will again be evaluated to determine that they fulfill
the entry requirements outlined in Section 5. Upon fulfilling participation requirements, 
participants will be provided with placebo study intervention to be taken BID for 2 weeks.
(Note: only participants will be blinded to the study intervention during the Placebo Run-in 
period).
While the study site will be aware that the participants are receiving placebo during the 
Placebo Run-in period, the participants themselves must not be informed that they are 
receiving placebo at the Placebo Run-in/Visit 2.
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The participants must not be told that this study consists of a single-blind period and a 
double-blind period, or that they need to meet eligibility criteria to enter the double-blind 
period. 
Participants will be contacted prior to the 7-day Incontinence Diary assessment period before
Randomization/Visit 3 to remind them to complete the Incontinence Diary for the 7 days 
prior to the next study visit.
Participants are to be reminded to bring their e-Diary device with them to the next visit.
8.10.3
Double-blind Treatment Period
At Randomization/Visit 3, participants will again be evaluated for eligibility to participate in 
the study based on the requirements outlined in Section 5. The participant must not be told 
that they are entering the double-blind period, or that the study intervention may change 
during this time. Once randomized, participants will receive either gefapixant 45 mg or 
placebo BID for 12 weeks. Both the participants and study personnel will be blinded to the 
study intervention.
Participants will be contacted prior to the 7-day Incontinence Diary assessment period before
Visits 4 to 6 to remind them to complete the Incontinence Diary for the 7 days prior to the 
next study visit. Participants will be contacted by telephone on Day 7 (+3 days; following 
Randomization/Visit 3) to review any AEs that may have occurred and concomitant 
medications taken, instructions on/compliance with study drug administration, and e-Diary 
completion (as necessary), and any questions the participant may have about the study.  
For all study site visits, participants are to be reminded to bring their e-Diary device with 
them to the next visit. Randomization/Visit 3 will be assigned as Day 1, and subsequent visit 
scheduling will be calculated from Day 1 (and not from the previous visit).
8.10.4
Discontinued Participants Continuing to be Monitored in the Study
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. 
If a participant is discontinued from the study intervention early:

the Discontinuation Visit should be performed as soon as possible;
If feasible, participants should be instructed to complete the Incontinence Diary and 
other PROs during the 7 days prior to the Discontinuation Visit.
Procedures, including e-Diary assessments, should be performed as outlined for the 
Discontinuation Visit in the SoA (Section 1.3).
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Note: If a participant discontinues at a regularly scheduled study visit, the procedures 
outlined for the Discontinuation Visit in the SoA should be followed in place of the 
procedures for the regularly scheduled study visit.

a safety follow-up telephone call should be conducted a minimum of 14 days (with an 
allowed variance of up to +7 days) after the last dose of study intervention; and

Study site visits should continue to be performed at timepoints that correspond to 
each remaining study visit. These visits will allow collection of follow-up 
information, limited to:
-
AEs;
-
Concomitant medication use; and 
-
e-Diary assessments, as outlined in the SoA (Section 1.3).  
Note: If the participant discontinues study intervention at a regularly scheduled study visit
but remains in the study, the Discontinuation Visit should be performed, and the regularly 
scheduled study visits should resume thereafter.  
For example: If a participant discontinues study intervention at the time of Visit 4, 
procedures for the Discontinuation Visit should be performed at that time. The next expected 
study visit would be Visit 5, followed by Visit 6.
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 those participants who have discontinued study intervention early and who miss 
remaining study visits, 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.
Additionally, the ICF will explain the importance of continued data collection from 
participants, including the use of continued contact by telephone.
8.10.5
Poststudy
All participants that complete the treatment period will be required to complete the safety
follow-up telephone call approximately 2 weeks (14 days, with an allowed variance of up to 
+7 days) after the last dose of study intervention to determine if any AEs have occurred since 
discontinuing study intervention.
Note: Participants that discontinue intervention and/or discontinue from the study should also 
complete the safety follow-up telephone call 14 days (+7 days) after the last dose of 
intervention. See Section 8.10.4 for further details.
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If the safety follow-up telephone contact occurs less than 14 days after the last dose of study 
intervention, a subsequent follow-up telephone call should be made at approximately 
2 weeks (14 days, with an allowed variance of up to +7 days) post the last dose of study 
intervention.
9
STATISTICAL ANALYSIS PLAN
This section outlines the statistical analysis strategy and procedures for the study. If, after the 
study has begun, but prior to any unblinding, there are changes made to the primary 
hypothesis, or the statistical methods related to this hypothesis, then the protocol will be 
amended (consistent with ICH Guidance for Industry E9). Changes to exploratory analyses 
made after the protocol has been finalized, but prior to unblinding, will be documented in a 
sSAP and referenced in the CSR for the study. Post-hoc exploratory analyses will be clearly 
identified in the CSR. Other planned analyses (ie, those specific to the analysis of 
pharmacokinetic data and planned genetic analysis) are beyond the scope of this document or
will be documented in separate analysis plans.
9.1
Statistical Analysis Plan Summary
Key elements of the statistical analysis plan are summarized below. The comprehensive plan 
is provided in Sections 9.2 through 9.12.
Study Design 
Overview
A Phase 3b, Randomized, Placebo Controlled, Multicenter Study 
to Evaluate the Efficacy and Safety of Gefapixant in Women 
with Chronic Cough and Stress Urinary Incontinence (P042)
Treatment Assignment
Participants will be randomized in a 1:1 ratio to 1 of 2 treatment 
groups: Gefapixant 45 mg BID or Placebo.
Analysis Populations
Efficacy: FAS population which consists of all randomized 
participants who have taken at least 1 dose of study intervention.
Safety: APaT population, which consists of all randomized 
participants who received at least 1 dose of study intervention.
Primary Endpoint
Episodes of cough-induced SUI
Key Secondary 
Endpoints
None
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Statistical Methods for 
Key Efficacy Analyses
The primary analysis will be based on the FAS population. The 
primary analysis approach will be conducted utilizing the 
longitudinal ANCOVA model. In this model, the response 
vector consists of percentage change from baseline in average 
daily cough-induced SUI episodes at each post-Baseline visit. 
The model will use all available post-Baseline cough-induced 
SUI episode data at Weeks 4, 8, and 12. The model will include 
the terms for treatment group, visit, the interaction between 
treatment group and visit, BMI group, and baseline average daily
cough-induced SUI episodes. Contrasts will be constructed to 
compare the Gefapixant group to the Placebo group at each post-
Baseline visit. The least squares mean % change from baseline 
with the associated standard errors will be displayed for each 
treatment group. An overall estimated treatment difference 
(Gefapixant − Placebo) along with corresponding CIs and p
value will also be presented for the entire follow-up period. 
Statistical Methods for 
Key Safety Analyses
The analysis of safety endpoints will follow a tiered approach. 
The tiers differ with respect to the analyses that will be 
performed. Tier 1 and Tier 2 safety endpoints will be evaluated 
via point estimates and 95% CIs for between-group 
comparisons, with p values provided for the Tier 1 safety 
endpoints. These analyses will be performed using the Miettinen 
and Nurminen method [Miettinen, O. and Nurminen, M. 1985]. 
Tier 3 safety endpoints will be evaluated via point estimates 
only.
Interim Analyses
One planned IA for efficacy and futility will be performed in this 
study. Results will be reviewed by an external DMC. The IA is 
summarized below. Details are provided in Section 9.7. 

Timing: To be performed when approximately 40% of 
participants (approximately the first 152 randomized 
participants) have either completed the study or 
discontinued the study intervention early. 

Testing: Efficacy and Futility boundaries based on the 
primary endpoint will be provided. 
Multiplicity
Since there is only one hypothesis testing for the primary 
endpoint, no multiplicity adjustment is planned other than the IA 
alpha adjustment to the primary efficacy endpoint.
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9.5
Analysis Populations
9.5.1
Efficacy Analysis Populations
The FAS population will serve as the primary population for the analysis of efficacy data in 
this study. The FAS population consists of all randomized participants who have taken at 
least 1 dose of study intervention. 
Participants will be included in the treatment group to which they are randomized for the 
analysis of efficacy data using the FAS population. 
9.5.2
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 1 dose of study 
intervention. Participants will be included in the treatment group corresponding to the study 
intervention they actually received for the analysis of safety data using the APaT population. 
For most participants, this will be the treatment group to which they are randomized. 
Participants who take incorrect study intervention for the entire treatment period will be 
included in the treatment group corresponding to the study intervention actually received.
Participants who take incorrect study intervention for during only a part of the treatment 
period and took at least 1 dose of active study intervention will be included in the active 
treatment group.
At least 1 laboratory or vital sign measurement obtained subsequent to at least 1 dose of 
study intervention is required for inclusion in the analysis of each specific parameter. To 
assess change from baseline, a Baseline measurement is also required.
9.6
Statistical Methods
This section describes the statistical methods that address the primary objective. Methods 
related to exploratory objectives and supportive analyses will be described in a separate 
analysis plan. Statistical testing and inference for efficacy and safety analyses are described 
in Sections 9.6.1 and 9.6.2, respectively. The statistical test of the primary efficacy 
endpoint will be conducted at the overall significance level of 0.05 (2-sided).
9.6.1
Statistical Methods for Efficacy Analyses
The analysis of efficacy endpoints will be based on the FAS population. Unless otherwise 
specified, all efficacy data from participants who have taken at least 1 dose of study 
intervention will be included in efficacy analyses.
Primary Efficacy Analysis 
Daily cough-induced SUI episodes will be recorded for the seven days prior to randomization 
and for the seven days prior to each post-Baseline visit at Weeks 4, 8, and 12. A participant 
will be considered evaluable for the primary endpoint at Week 12 if incontinence frequency 
is assessed at least four days in the 7-day period prior to the visit at Week 12.
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The primary efficacy endpoint of this study is the percentage change in average daily
cough -induced SUI episodes from baseline at Week 12. The primary analysis approach will 
be conducted utilizing the longitudinal ANCOVA model. In this model, the response vector 
consists of the percent change from baseline at each post-Baseline visit at Weeks 4, 8, and 
12. The model will include terms for treatment group (Gefapixant, Placebo), visit (Weeks 4,
8,12), the interaction of treatment by visit, BMI group (<30 kg/m2, ≥30 kg/m2), and the 
baseline cough-induced SUI episodes (continuous variable). The model will use all available
data from post-Baseline visits at Weeks 4, 8, and 12. Contrasts will be constructed to 
compare the Gefapixant treatment group to the Placebo group at each post-Baseline visit. The 
least squares mean change from baseline with the associated standard errors will be displayed 
for each treatment group. An overall estimated treatment differences (Gefapixant −Placebo) 
along with corresponding CIs and p-values will also be presented. 
Further details of the model specification, assumptions, and SAS implementation codes will 
be provided in the sSAP. 
Secondary Efficacy Analysis
There are no secondary efficacy analyses.
Exploratory Efficacy Analysis 
Details of the exploratory efficacy analysis, as well as any additional exploratory analyses 
that may be performed to supplement the primary and secondary analyses, will be described 
in a separate sSAP.
Handling of Missing Data 
A participant will be included in the assessment of the efficacy endpoint at each post-baseline 
visit if the diary is completed on at least 4 days during the 7-day period prior to the visit. The 
participants who have at least 1 baseline and at least 1 post-baseline endpoint assessment
during the treatment period will be included for the primary efficacy analysis.
All efficacy analyses will be conducted based on the observed data only. No imputation is 
planned for the missing diaries or missing questionnaire items. The pattern of missing is 
assumed to be MAR. The missing pattern will be inspected to determine if the MAR 
assumption is met. 
Depending on the proportion of missing values, sensitivity analyses will be implemented to 
explore the impact of departures from the assumption made in missing diaries. Additional 
sensitivity analyses with respect to the handling of missing data will be specified in the 
sSAP.
9.6.2
Statistical Methods for Safety Analyses
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
AEs, laboratory tests, and vital signs. 
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The analysis of safety results will follow a tiered approach (Table 4). The tiers differ with 
respect to the analyses that will be performed. Adverse events (specific terms as well as 
system organ class terms) and events that meet predefined limits of change in laboratory and 
vital signs are either pre-specified as “Tier 1” endpoints, or will be classified as belonging to 
"Tier 2" or "Tier 3" based on the observed proportions of participants with an event. 
Tier 1 Events
Safety parameters or adverse events of interest that are identified a priori constitute “Tier 1” 
safety endpoints that will be subject to inferential testing for statistical significance with 
p -values and 95% CIs to be provided for between-treatment differences in the proportion of 
participants with events; these analyses will be performed using the Miettinen and Nurminen 
(M&N) method (1985) [Miettinen, O. and Nurminen, M. 1985], an unconditional, asymptotic 
method. For this protocol, taste-related AEs (including dysgeusia, ageusia, and hypogeusia, 
as well as other related terms) are considered Tier 1 events. The definition of taste-related 
AEs will be finalized and documented before the database lock of the study.
Tier 2 Events
Tier 2 parameters will be assessed via point estimates and 95% CIs provided for differences 
in the proportion of participants with events. 
Inclusion in Tier 2 requires that at least 4 participants in any treatment group exhibit the 
event. The threshold of at least 4 events was chosen because the 95% confidence interval for 
the between-group difference in percent incidence will always include zero when treatment 
groups of equal size each have less than 4 events and thus would add little to the 
interpretation of potentially meaningful differences. Because many 95% confidence intervals 
for Tier 2 events may be provided without adjustment for multiplicity, the confidence 
intervals should be regarded as a helpful descriptive measure to be used in review, not a 
formal method for assessing the statistical significance of the between-group differences in 
adverse events and safety parameters that meet predefined limits of change.
In addition to individual events that occur in 4 or more participants in any treatment group, 
any oral paresthesia AE, any oral hypoesthesia AE, and the broad AE categories consisting of 
the proportion of participants with any AE, a drug-related AE, a serious AE, an AE which is 
both drug-related and serious, and discontinuation due to an AE will be considered Tier 2 
endpoints.
Tier 3 Events
Safety endpoints that are not Tier 1 or 2 events are considered Tier 3 events. Only point 
estimates by treatment group are provided for Tier 3 safety parameters. 
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Continuous Safety Measures
For continuous measures such as changes from baseline in laboratory and vital signs, 
summary statistics for baseline, on-treatment, and change from baseline values will be 
provided by intervention group in table format.
Table 4
Analysis Strategy for Safety Parameters
Safety 
Tier
Safety Endpointa
p-value
95% CI for 
Treatment 
Comparison
Descriptive 
Statistics
Tier 1
Any taste-related AE (including dysgeusia, 
ageusia, and hypogeusia, as well as other related 
terms)
X
X
X
Tier 2
Oral paresthesia AE
X
X
Oral hypoesthesia AE
X
X
Any AE
X
X
Any Serious AE
X
X
Any Drug-related AE
X
X
Any Serious and Drug-related AE
X
X
Discontinuation due to AE
X
X
Specific AEs, SOCs, or PDLCsb (incidence ≥4 
participants in 1 of the treatment groups)
X
X
Tier 3
Specific AEs, SOCs, or PDLCsb (incidence <4 
participants in all the treatment groups)
X
Change from baseline results (Labs, Vital Signs)
X
AE = adverse event; CI = confidence interval; PDLC = predefined limit of change; SOC = system organ class; 
X = results will be provided.
a
Adverse experience references refer to both clinical and laboratory AEs.
b
Includes only those endpoints not pre-specified as Tier 1 or not already pre-specified as Tier 2 endpoints.
9.6.3
Summaries of Baseline Characteristics, Demographics, and Other Analyses
9.6.3.1
Demographic and Baseline Characteristics 
The comparability of the treatment groups for each relevant demographic and baseline 
characteristic will be assessed by the use of tables and/or graphs. No statistical hypothesis 
tests will be performed on these characteristics. The number and percentage of participants 
screened and randomized and the primary reasons for screening failure and discontinuation 
will be displayed. Demographic variables (eg, age, gender, race, weight, and height), baseline 
characteristics, primary and secondary diagnoses, and prior and concomitant therapies will be 
summarized by treatment either by descriptive statistics or categorical tables.
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10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1
Code of Conduct for Clinical Trials
Merck Sharp and Dohme Corp., a subsidiary of Merck & Co., Inc. (MSD)
Code of Conduct for Interventional Clinical Trials
I. Introduction
A. Purpose
MSD, through its subsidiaries, conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, implementing, conducting, analyzing, and reporting these trials 
in compliance with the highest ethical and scientific standards. Protection of participants in clinical trials is the 
overriding concern in the design and conduct of clinical trials. In all cases, MSD clinical trials will be conducted 
in compliance with local and/or national regulations, and International Council for Harmonisation Good Clinical 
Practice (ICH-GCP), and also 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 (e.g., 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 (i.e., 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 (or individuals acting on behalf of MSD) 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 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, 
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scientific/research misconduct or serious GCP-non-compliance is suspected, the issues are investigated. 
When necessary, the clinical site will be closed, the responsible regulatory authorities and ethics review 
committees notified.
B. Publication and Authorship
Regardless of trial outcome, MSD commits to publish the primary and secondary results of its registered trials of 
marketed products in which treatment is assigned, according to the pre-specified 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. Regulatory Authority and Ethics Committee Review (Institutional Review Board [IRB]/Independent Ethics 
Committee [IEC])
All protocols and protocol amendments will be submitted by MSD for regulatory authority 
acceptance/authorization prior to implementation of the trial or amendment, in compliance with local and/or 
national regulations.
The protocol, protocol amendment(s), informed consent form, investigator’s brochure, and other relevant trial 
documents must be reviewed and approved by an IRB/IEC before being implemented at each site, in compliance 
with local and/or national regulations. Changes to the protocol that are required urgently to eliminate an 
immediate hazard and to protect participant safety may be enacted in anticipation of ethics committee approval.  
MSD will inform regulatory authorities of such new measures to protect participant safety, in compliance with 
local and/or national regulations.
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 individuals acting on behalf of MSD), 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.
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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 and medical evaluation to identify potentially eligible participants.
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 (e.g., to scientific meetings, investigator meetings, etc.) will be 
consistent with local guidelines and practices.
V. Investigator Commitment
Investigators will be expected to review MSD’s Code of Conduct as an appendix to the trial protocol, and in signing the 
protocol, agree to support these ethical and scientific standards.
10.1.2
Financial Disclosure
Financial Disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54). It is the 
Sponsor's responsibility to determine, based on these regulations, whether a request for 
Financial Disclosure information is required. It is the investigator's/subinvestigator's
responsibility to comply with any such request.
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21 
CFR Part 54, to provide his/her financial interests in and/or arrangements with the Sponsor to 
allow for the submission of complete and accurate certification and disclosure statements. 
The investigator/subinvestigator(s) further agree to provide this information on a 
Certification/Disclosure Form, commonly known as a financial disclosure form, provided by 
the Sponsor. The investigator/subinvestigator(s) also consent to the transmission of this 
information to the Sponsor in the United States for these purposes. This may involve the 
transmission of information to countries that do not have laws protecting personal data.
10.1.3
Data Protection
Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor will contain the identifier only; participant names 
or any information that would make the participant identifiable will not be transferred.
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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.
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 data. By signing the consent form, the participant agrees to this 
process. If study documents will be photocopied during the process of verifying 
worksheet/CRF information, the participant will be identified by unique code only; full 
names/initials will be masked prior to transmission to the Sponsor.
By signing this protocol, the investigator agrees to treat all participant data used and 
disclosed in connection with this study in accordance with all applicable privacy laws, rules 
and regulations.
10.1.3.3
Confidentiality of IRB/IEC Information
The Sponsor is required to record the name and address of each IRB/IEC that reviews and 
approves this study. The Sponsor is also required to document that each IRB/IEC meets 
regulatory and ICH GCP requirements by requesting and maintaining records of the names 
and qualifications of the IRB/IEC members and to make these records available for 
regulatory agency review upon request by those agencies.
10.1.4
Committees Structure
10.1.4.1
Scientific Advisory Committee (SAC)
This study was developed in collaboration with a SAC. The SAC is comprised of both 
Sponsor and non-Sponsor scientific experts who provide input with respect to study design, 
interpretation of study results, and subsequent peer-reviewed scientific publications.
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10.1.4.2
Executive Oversight Committee
The EOC is comprised of members of Sponsor Senior Management. The EOC will receive 
and decide upon any recommendations made by the DMC regarding the study.
10.1.4.3
External Data Monitoring Committee
To supplement the routine study monitoring outlined in this protocol, an external DMC will 
monitor the interim data from this study. The voting members of the committee are external 
to the Sponsor. The members of the DMC must not be involved with the study in any other 
way (eg, they cannot be study investigators) and must have no competing interests that could 
affect their roles with respect to the study.
The DMC will make recommendations to the EOC regarding steps to ensure both participant 
safety and the continued ethical integrity of the study. Also, the DMC will review interim 
study results, consider the overall risk and benefit to study participants (Section 9.7 [Interim 
Analysis]) and recommend to the EOC whether the study should continue in accordance with 
the protocol.
Specific details regarding composition, responsibilities, and governance, including the roles 
and responsibilities of the various members and the Sponsor protocol team; meeting
facilitation; the study governance structure; and requirements for and proper documentation 
of DMC reports, minutes, and recommendations will be described in the DMC charter that is 
reviewed and approved by all the DMC members.
10.1.5
Publication Policy
The results of this study may be published or presented at scientific meetings. The Sponsor 
will comply with the requirements for publication of study results. In accordance with 
standard editorial and ethical practice, the Sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data. In this case, a 
coordinating investigator will be designated by mutual agreement.
If publication activity is not directed by the Sponsor, the investigator agrees to submit all 
manuscripts or abstracts to the Sponsor before submission. This allows the Sponsor to protect 
proprietary information and to provide comments.
Authorship will be determined by mutual agreement and in line with International Committee 
of Medical Journal Editors authorship requirements.
10.1.6
Compliance with Study Registration and Results Posting Requirements
Under the terms of the Food and Drug Administration Amendments Act (FDAAA) of 2007 
and the European Medicines Agency (EMA) clinical trial Directive 2001/20/EC, the Sponsor 
of the study is solely responsible for determining whether the study and its results are subject
to the requirements for submission to http://www.clinicaltrials.gov, 
www.clinicaltrialsregister.eu or other local registries. MSD, as Sponsor of this study, will 
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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.
10.1.7
Compliance with Law, Audit, and Debarment
By signing this protocol, the investigator agrees to conduct the study in an efficient and 
diligent manner and in conformance with this protocol; generally accepted standards of GCP
(eg, International Council on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use GCP: Consolidated Guideline and other generally accepted 
standards of GCP); and all applicable federal, state and local laws, rules and regulations 
relating to the conduct of the clinical study.
The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by MSD, is provided in this appendix 
under the Code of Conduct for Clinical Studies.
The investigator agrees not to seek reimbursement from participants, their insurance 
providers, or from government programs for procedures included as part of the study 
reimbursed to the investigator by the Sponsor.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this study.
The investigator agrees to provide the Sponsor with relevant information from inspection 
observations/findings to allow the Sponsor to assist in responding to any citations resulting 
from regulatory authority inspection and will provide the Sponsor with a copy of the 
proposed response for consultation before submission to the regulatory authority. 
Persons debarred from conducting or working on clinical studies by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s studies. The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the study is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
10.1.8
Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the Sponsor or designee electronically (eg, laboratory data). The investigator 
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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 participants’ documented informed consent, pertaining to 
the conduct of this study must be retained by the investigator for 15 years after study 
completion unless local regulations or institutional policies require a longer retention period. 
No records may be destroyed during the retention period without the written approval of the 
Sponsor. No records may be transferred to another location or party without written 
notification to the Sponsor.
10.1.9
Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. The investigator/institution should maintain adequate and 
accurate source documents and study records that include all pertinent observations on each 
of the site’s participants. Source documents and data should be attributable, legible, 
contemporaneous, original, accurate, and complete. Changes to source data should be 
traceable, should not obscure the original entry, and should be explained if necessary (eg, via 
an audit trail). 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 
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investigator/institution may need to request previous medical records or transfer records, 
depending on the study. Also, current medical records must be available.
10.1.10
Study and Site Closure
The Sponsor or its designee may stop the study or study site participation in the study for 
medical, safety, regulatory, administrative, or other reasons consistent with applicable laws, 
regulations, and GCP.
In the event the Sponsor prematurely terminates a particular study site, the Sponsor or 
designee will promptly notify that study site’s IRB/IEC as specified by applicable regulatory 
requirement(s).
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10.2
Appendix 2: Clinical Laboratory Tests
•
The tests detailed in Table 5 will be performed by the study site or central laboratory.
•
Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5 of the protocol.
•
Additional tests may be performed at any time during the study as determined necessary 
by the investigator or required by local regulations.
•
Pregnancy testing:
-
Pregnancy testing requirements for study inclusion are described in Section 5.1.
-
Additional serum or urine pregnancy tests may be performed, as determined 
necessary by the investigator or required by local regulation, to establish the absence 
of pregnancy at any time during the subject's participation in the study.
Table 5
Protocol-required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet Count 
WBC count with Differential:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
RBC Count
Hemoglobin
Hematocrit
Chemistry
Electrolytes
Sodium
Potassium
Chloride
Bicarbonate
Calcium
Phosphorous
Liver function tests
AST/ SGOT
ALT/ SGPT
Alkaline phosphatase
Total bilirubin (and direct bilirubin, if total bilirubin is elevated 
above the upper limit of normal)
Renal function tests
Blood Urea Nitrogen
Creatinine
eGFR calculation
-eGFR will be calculated with each serum creatinine 
measurement (using the Chronic Kidney Disease Epidemiology 
Collaboration formula [http://mdrd.com/])
Other
Glucose (nonfasting)
Albumin
Total Protein
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Laboratory 
Assessments
Parameters
Routine 
Urinalysis

Routine urinalysis will be performed at a central laboratory for all participants and 
include: specific gravity, pH, glucose, protein, and blood. Microscopic examination
will also be performed (crystals will be characterized).
Other Screening 
Tests

Serum or urine β-hCG pregnancy test (as needed for women of childbearing potential)
- Urine pregnancy test will be performed at site in women of child bearing potential. 
Refer to Section 1.3.
ALT = alanine aminotransferase; AST = aspartate aminotransferase; β-hCG = β-human chorionic gonadotropin;
eGFR = estimated glomerular filtration rate; RBC = red blood cell; SGOT = serum glutamic-oxaloacetic transaminase;
SGPT = serum glutamic-pyruvic transaminase; WBC = white blood cell.
The investigator (or medically qualified designee) must document their review of each 
laboratory safety report.
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10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
10.3.1
Definition of AE
AE definition
•
An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of study intervention, whether or not considered related to the 
study intervention.
•
NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study intervention.
•
NOTE: For purposes of AE definition, study intervention (also referred to as Sponsor’s 
product) includes any pharmaceutical product, biological product, vaccine, diagnostic 
agent, or protocol specified procedure whether investigational or marketed (including 
placebo, active comparator product, or run-in intervention), manufactured by, licensed 
by, provided by, or distributed by the Sponsor for human use in this study.
Events meeting the AE definition
•
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the medical 
and scientific judgment of the investigator.
•
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.
•
New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study.
•
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.
•
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication.
•
For all reports of overdose (whether accidental or intentional) with an associated AE, the 
AE term should reflect the clinical symptoms or abnormal test result. An overdose 
without any associated clinical symptoms or abnormal laboratory results is reported using 
the terminology “accidental or intentional overdose without adverse effect.”
•
Any new cancer or progression of existing cancer.
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Events NOT meeting the AE definition
•
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE.
•
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).
•
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.
•
Surgery planned prior to informed consent to treat a pre-existing condition that has not 
worsened.
•
Refer to Section 8.4.6 for protocol-specific exceptions.
10.3.2
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met.
An SAE is defined as any untoward medical occurrence that, at any dose:
a.     Results in death
b.     Is life-threatening
    The term “life-threatening” in the definition of “serious” refers to an event in which 
the participant was at risk of death at the time of the event. It does not refer to an 
event, which hypothetically might have caused death, if it were more severe.
c.    Requires inpatient hospitalization or prolongation of existing hospitalization
    Hospitalization is defined as an inpatient admission, regardless of length of stay, 
even if the hospitalization is a precautionary measure for continued observation. 
(Note: Hospitalization for an elective procedure to treat a pre-existing condition that 
has not worsened is not an SAE. A pre-existing condition is a clinical condition that 
is diagnosed prior to the use of an MSD product and is documented in the 
participant’s medical history.)
d.    Results in persistent or significant disability/incapacity
    The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.
    This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
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and accidental trauma (eg, sprained ankle) that may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
e.    Is a congenital anomaly/birth defect
In offspring of participant taking the product regardless of time to diagnosis.
f.    Other important medical events
    Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 
1 of the other outcomes listed in the above definition. These events should usually be 
considered serious.
Examples of such events include invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions 
that do not result in hospitalization, or development of drug dependency or drug abuse.
10.3.3
Additional Events Reported
Additional events that require reporting
In addition to the above criteria, AEs meeting either of the below criteria, although not 
serious per ICH definition, are reportable to the Sponsor.
    Is a cancer
    Is associated with an overdose
10.3.4
Recording AE and SAE
AE and SAE recording
    When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) related to 
the event.
    The investigator will record all relevant AE/SAE information on the AE 
CRFs/worksheets at each examination.
    It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to the Sponsor in lieu of completion of the AE CRF page.
    There may be instances when copies of medical records for certain cases are requested by 
the Sponsor. In this case, all participant identifiers, with the exception of the participant 
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number, will be blinded on the copies of the medical records before submission to the 
Sponsor.
    The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.
Assessment of intensity
    An event is defined as “serious” when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, not when it is rated as severe.
    The investigator will make an assessment of intensity for each AE and SAE (and other 
reportable safety event) reported during the study and assign it to 1 of the following 
categories:
-    Mild: An event that is easily tolerated by the participant, causing minimal discomfort, 
and not interfering with everyday activities (for pediatric studies, awareness of 
symptoms, but easily tolerated).
-    Moderate: An event that causes sufficient discomfort to interfere with normal 
everyday activities (for pediatric studies, definitely acting like something is wrong).
-    Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with an SAE. Severe is a category used for rating the 
intensity of an event; and both AE and SAE can be assessed as severe (for pediatric 
studies, extremely distressed or unable to do usual activities).
Assessment of causality
•
Did the Sponsor’s product cause the AE?
•
The determination of the likelihood that the Sponsor’s product caused the AE will be 
provided by an investigator who is a qualified physician. The investigator’s signed/dated 
initials on the source document or worksheet that supports the causality noted on the AE 
form, ensures that a medically qualified assessment of causality was done. This initialed 
document must be retained for the required regulatory time frame. The criteria below are 
intended as reference guidelines to assist the investigator in assessing the likelihood of a 
relationship between the test product and the AE based upon the available information.
•
The following components are to be used to assess the relationship between the 
Sponsor’s product and the AE; the greater the correlation with the components and 
their respective elements (in number and/or intensity), the more likely the Sponsor’s 
product caused the AE:
- Exposure: Is there evidence that the participant was actually exposed to the 
Sponsor’s product such as: reliable history, acceptable compliance assessment (pill 
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count, diary, etc.), expected pharmacologic effect, or measurement of 
drug/metabolite in bodily specimen?
- Time Course: Did the AE follow in a reasonable temporal sequence from 
administration of the Sponsor’s product? Is the time of onset of the AE compatible 
with a drug-induced effect (applies to studies with investigational medicinal 
product)?
- Likely Cause: Is the AE not reasonably explained by another etiology such as 
underlying disease, other drug(s)/vaccine(s), or other host or environmental factors.
- Dechallenge: Was the Sponsor’s product discontinued or dose/exposure/frequency 
reduced?
◦
If yes, did the AE resolve or improve?
◦
If yes, this is a positive dechallenge.
◦
If no, this is a negative dechallenge.
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent 
disability; (2) the AE resolved/improved despite continuation of the Sponsor’s 
product; (3) the study is a single-dose drug study; or (4) Sponsor’s product(s) is/are 
only used 1 time.)
- Rechallenge: Was the participant re-exposed to the Sponsor’s product in this study?
◦
If yes, did the AE recur or worsen?
◦
If yes, this is a positive rechallenge.
◦
If no, this is a negative rechallenge.
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or 
permanent disability, or (2) the study is a single-dose drug study; or (3) Sponsor’s 
product(s) is/are used only 1 time.)
NOTE: IF A RECHALLENGE IS PLANNED FOR AN AE THAT WAS SERIOUS AND 
MAY HAVE BEEN CAUSED BY THE SPONSOR’S PRODUCT, OR IF RE-EXPOSURE 
TO THE SPONSOR’S PRODUCT POSES ADDITIONAL POTENTIAL SIGNIFICANT 
RISK TO THE PARTICIPANT THEN THE RECHALLENGE MUST BE APPROVED IN 
ADVANCE BY THE SPONSOR CLINICAL DIRECTOR, AND IF REQUIRED, THE 
IRB/IEC.
•
Consistency with study intervention profile: Is the clinical/pathological presentation of 
the AE consistent with previous knowledge regarding the Sponsor’s product or drug class 
pharmacology or toxicology?
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•
The assessment of relationship will be reported on the case report forms/worksheets by 
an investigator who is a qualified physician according to his/her best clinical judgment, 
including consideration of the above elements.
•
Use the following scale of criteria as guidance (not all criteria must be present to be 
indicative of a Sponsor’s product relationship).
- Yes, there is a reasonable possibility of Sponsor’s product relationship:
◦
There is evidence of exposure to the Sponsor’s product. The temporal sequence 
of the AE onset relative to the administration of the Sponsor’s product is 
reasonable. The AE is more likely explained by the Sponsor’s product than by 
another cause.
- No, there is not a reasonable possibility of Sponsor’s product relationship:
◦
Participant did not receive the Sponsor’s product OR temporal sequence of the 
AE onset relative to administration of the Sponsor’s product is not reasonable 
OR the AE is more likely explained by another cause than the Sponsor’s 
product. (Also entered for a participant with overdose without an associated 
AE.)
•
For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality.
•
There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to the Sponsor. However, it is very important 
that the investigator always make an assessment of causality for every event before the 
initial transmission of the SAE data to the Sponsor.
•
The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality assessment.
•
The causality assessment is 1 of the criteria used when determining regulatory reporting 
requirements.
Follow-up of AE and SAE
    The investigator is obligated to perform or arrange for the conduct of supplemental
measurements and/or evaluations as medically indicated or as requested by Sponsor to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals.
    New or updated information will be recorded in the CRF.
    The investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information.
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10.3.5
Reporting of AEs, SAEs, and Other Reportable Safety Events to the Sponsor
AE, SAE, and other reportable safety event reporting to Sponsor via electronic data 
collection tool
    The primary mechanism for reporting to the Sponsor will be the electronic data collection 
(EDC) tool.
-    Electronic reporting procedures can be found in the EDC data entry guidelines (or 
equivalent).
-    If the electronic system is unavailable for more than 24 hours, then the site will use 
the paper AE Reporting form.
-    Reference Section 8.4.1 for reporting time requirements.
    The site will enter the SAE data into the electronic system as soon as it becomes 
available.
    After the study is completed at a given site, the EDC tool will be taken off-line to prevent 
the entry of new data or changes to existing data.
    If a site receives a report of a new SAE from a study participant or receives updated data 
on a previously reported SAE after the EDC tool has been taken off-line, then the site can 
report this information on a paper SAE form or by telephone (see next section).
    Contacts for SAE reporting can be found in the Investigator Study File Binder (or 
equivalent).
SAE reporting to the Sponsor via paper CRF
    If the EDC tool is not operational, facsimile transmission or secure e-mail of the SAE 
paper CRF is the preferred method to transmit this information to the Sponsor.
    In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service.
    Initial notification via telephone does not replace the need for the investigator to complete 
and sign the SAE CRF pages within the designated reporting time frames.
    Contacts and instructions for SAE reporting and paper reporting procedures can be found 
in the Investigator Study File Binder (or equivalent).
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10.4
Appendix 4: Device Events, Adverse Device Events, and Medical Device 
Incidents: Definitions, Collection, and Documentation
Not applicable.
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10.5
Appendix 5: Contraceptive Guidance
10.5.1
Definitions
Women of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile.
Women in the following categories are not considered WOCBP:

Premenarchal

Premenopausal female with 1 of the following:
o
Documented hysterectomy
o
Documented bilateral salpingectomy
o
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
o
A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause.

A high FSH level in the postmenopausal range may be used to confirm a 
postmenopausal state in women not using hormonal contraception or HRT. However, 
in the absence of 12 months of amenorrhea, confirmation with 2 FSH measurements 
in the postmenopausal range is required.
o
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.
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10.5.2
Contraception Requirements
Female participants of childbearing potential are eligible to participate if they agree to use 
one of the contraception methods described in Table 6 consistently and correctly during the 
protocol-defined time frame in Section 5.1.
Table 6
Contraceptive Methods
Highly Effective Contraceptive Methods That Are User Dependenta
Failure rate of <1% per year when used consistently and correctly.
●Combined (estrogen- and progestogen- containing) hormonal contraceptionb
○
Oral
○
Intravaginal
○
Transdermal
○
Injectable
●Progestogen only hormonal contraceptionb
○
Oral
○
Injectable
Highly Effective Methods That Have Low User Dependency
Failure rate of <1% per year when used consistently and correctly.
●Progestogen- only contraceptive implantb
●Intrauterine hormone-releasing system b
●Intrauterine device 
●Bilateral tubal occlusion
●Vasectomized partner
A vasectomized partner is a highly effective contraception method provided that the partner is the sole male 
sexual partner of the WOCBP and the absence of sperm has been confirmed. If not, an additional highly 
effective method of contraception should be used.
●Sexual abstinence
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study intervention. The reliability of sexual 
abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual lifestyle 
of the participant.
Notes:
Use should be consistent with local regulations regarding the use of contraceptive methods for participants of clinical 
studies.
a.
Typical use failure rates are higher than perfect-use failure rates (ie, when used consistently and correctly).
b.
If locally required, in accordance with Clinical Trial Facilitation Group guidelines, acceptable hormonal contraceptives 
are limited to those which inhibit ovulation.
WOCBP = women of childbearing potential
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10.5.3
Pregnancy Testing
Women of childbearing potential should only be included after a negative highly sensitive 
urine or serum pregnancy test.
Pregnancy testing will be performed at Screening/Visit 1 (in WOCBP) and after 
Screening/Visit 1 whenever an expected menstrual cycle is missed or when pregnancy is 
otherwise suspected. Testing can also be performed as necessary based on local 
requirements.
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10.6
Appendix 6: Collection and Management of Specimens for Future Biomedical 
Research
1.  Definitions
a.   Biomarker: A biological molecule found in blood, other body fluids, or tissues that is a 
sign of a normal or abnormal process or of a condition or disease. A biomarker may be 
used to see how well the body responds to a treatment for a disease or condition.1
b.   Pharmacogenomics: The investigation of variations of DNA and RNA characteristics as 
related to drug/vaccine response.2
c.   Pharmacogenetics: A subset of pharmacogenomics, pharmacogenetics is the influence of 
variations in DNA sequence on drug/vaccine response.2
d.   DNA: Deoxyribonucleic acid.
e.   RNA: Ribonucleic acid.
2.  Scope of Future Biomedical Research
The specimens consented and/or collected in this study as outlined in Section 8.9 will be used 
in various experiments to understand:
◦
The biology of how drugs/vaccines work
◦
Biomarkers responsible for how a drug/vaccine enters and is removed by the body
◦
Other pathways drugs/vaccines may interact with
◦
The biology of disease
The specimen(s) may be used for future assay development and/or drug/vaccine 
development.
It is now well recognized that information obtained from studying and testing clinical 
specimens offers unique opportunities to enhance our understanding of how individuals 
respond to drugs/vaccines, enhance our understanding of human disease and ultimately 
improve public health through development of novel treatments targeted to populations with 
the greatest need. All specimens will be used by the Sponsor or those working for or with the 
Sponsor.
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 future 
biomedical research.
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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 intervention outcomes are critical to 
understanding clinical context of analytical results.
To maintain privacy of information collected from specimens obtained for future biomedical 
research, the Sponsor has developed secure policies and procedures. All specimens will be 
single-coded per ICH E15 guidelines as described below.
At the clinical study site, unique codes will be placed on the future biomedical research 
specimens. This code is a random number which does not contain any personally identifying 
information embedded within it. The link (or key) between participant identifiers and this 
unique code will be held at the study site. No personal identifiers will appear on the specimen 
tube.
5.  Biorepository Specimen Usage
Specimens obtained for the Sponsor will be used for analyses using good scientific practices. 
Analyses utilizing the future biomedical research specimens may be performed by the 
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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 future biomedical research protocol and consent. 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 investigator for the main study. If medical records for the main 
study are still available, the investigator will contact the Sponsor using the designated 
mailbox (clinical.specimen.management@merck.com). Subsequently, the participant's 
specimens will be flagged in the biorepository and restricted to main study use only. If 
specimens were collected from study participants specifically for future biomedical research, 
these specimens will be removed from the biorepository and destroyed. Documentation will 
be sent to the investigator confirming withdrawal and/or destruction, if applicable. It is the 
responsibility of the investigator to inform the participant of completion of the withdrawal 
and/or destruction, if applicable. Any analyses in progress at the time of request for 
withdrawal/destruction or already performed prior to the request being received by the 
Sponsor will continue to be used as part of the overall research study data and results. No 
new analyses would be generated after the request is received.
In the event that the medical records for the main study are no longer available (eg, if the 
investigator is no longer required by regulatory authorities to retain the main study records) 
or the specimens have been completely anonymized, there will no longer be a link between 
the participant’s personal information and their specimens. In this situation, the request for 
withdrawal of consent and/or destruction cannot be processed.
7.  Retention of Specimens
Future biomedical research specimens will be stored in the biorepository for potential 
analysis for up to 20 years from the end of the main study. Specimens may be stored for 
longer if a regulatory or governmental authority has active questions that are being answered. 
In this special circumstance, specimens will be stored until these questions have been 
adequately addressed.
Specimens from the study site will be shipped to a central laboratory and then shipped to the 
Sponsor-designated biorepository. If a central laboratory is not utilized in a particular study, 
the study site will ship directly to the Sponsor-designated biorepository. The specimens will 
be stored under strict supervision in a limited access facility which operates to assure the 
integrity of the specimens. Specimens will be destroyed according to Sponsor policies and 
procedures and this destruction will be documented in the biorepository database.
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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 Council on Harmonisation [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
10.7.1
Argentina
Section 8.10.1 Screening
All participants at study sites in Argentina must be tested for hepatitis B, hepatitis C, and 
HIV at Screening prior to randomization.
Section 10.5.3 Pregnancy Testing
Women of childbearing potential at study sites in Argentina must have a pregnancy test 
performed before the start of the study and monthly during the treatment period and for the 
duration of the post-study contraception requirements.
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10.8
Appendix 8: Abbreviations
Abbreviation
Expanded Term
AE
adverse event 
ACCP
American College of Chest Physician
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
APaT
all participants as treated
AST
aspartate aminotransferase
ATP
adenosine triphosphate
BID
twice daily
BMI
body mass index
BOTOX®
onabotulinumtoxin A
CI
confidence interval
CONSORT
Consolidated Standards of Reporting Trials 
COVID-19
coronavirus infectious disease 2019
CP
conditional power
CRF
Case Report Form 
CSD
Cough Severity Diary
CSR
Clinical study report
Ctrough
the concentration of study drug at the end of the dosage interval
DILI
drug-induced liver injury
DMC
Data Management Committee
DNA
deoxyribonucleic acid 
ECG
electrocardiogram 
ECIs
events of clinical interest
eCRF
electronic Case Report Form
EDC
electronic data collection 
e-Diary
electronic diary
eGFR
estimated glomerular filtration rate
ePRO
electronic Patient-reported Outcome
EMA
European Medicines Agency
EOC
Executive Oversight Committee
FAS
full analysis set
FEV1
forced expiratory volume in 1 second
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Amendments Act
FSH
follicle stimulating hormone 
FVC
forced vital capacity
GCP
Good Clinical Practice 
GERD
gastroesophageal reflux disease
HIV
human immunodeficiency virus
HRT
hormone replacement therapy
IA
interim analysis
IB
Investigator’s Brochure 
ICF
Informed Consent Form 
ICH
International Council on Harmonisation
ICMJE
International Committee of Medical Journal Editors 
IEC
Independent Ethics Committee
IND
Investigational New Drug 
I-QoL
Incontinence Quality of Life
IRB
Institutional Review Board 
IRT
interactive response technology
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Abbreviation
Expanded Term
LC-MS/MS
liquid chromatography-mass spectrometry/mass spectrometry
MAR
missing at random
MESA
Medical Epidemiological and Social Aspects of Aging
PGIC
Patient Global Impression of Change
PRO
Patient-reported Outcome
RNA
ribonucleic acid
SAC
Scientific Advisory Committee
SAE
serious adverse event 
SARS-CoV-2
severe acute respiratory syndrome coronavirus 2
SD
standard deviation
SGPT
serum glutamic-pyruvic transaminase
SGOT
serum glutamic-oxaloacetic transaminase
SoA
schedule of activities
SOC
system organ class
sSAP
supplemental statistical analysis plan
SUI
stress urinary incontinence
SUSAR
suspected unexpected serious adverse reaction
UACS
upper airway cough syndrome
US
United States
VAS
visual analog scale
WBC
white blood cell
WOCBP
woman/women of childbearing potential 
WPAI
Work Productivity and Activity Impairment
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