Clinical trial NCT03282591
Conditions: Refractory Chronic Cough
Sponsor: Vyne Therapeutics Inc.
Start date: 2017-10-03; Completion date: 2018-09-06
Enrollment: 185 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Study of the efficacy, safety, and tolerability of serlopitant for the treatment of refractory chronic cough

Detailed description:

Arms: arm 1: Serlopitant Tablets arm 2: Placebo Tablets
Interventions: intervention 1: 5 mg Serlopitant Tablets intervention 2: Matching Placebo Tablets
Intervention descriptions: intervention 1: Serlopitant Tablets intervention 2: Placebo Tablets

Protocol documents:
Prot_000.pdf: 
Menlo Therapeutics Inc. 
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Protocol MTI-110 
Version 2.0 
 
Page 1  
CLINICAL STUDY PROTOCOL 
 
 
TITLE:  
A RANDOMIZED, DOUBLE-BLIND, PLACEBO-
CONTROLLED STUDY OF THE EFFICACY, SAFETY, 
AND TOLERABILITY OF SERLOPITANT FOR THE 
TREATMENT OF REFRACTORY CHRONIC COUGH  
 
IND No.: 
 
 
135540 
 
ClinicalTrials.gov ID: 
TBD 
 
EudraCT Number:  
2017-003250-16 
 
Protocol No.:  
 
MTI-110 
 
Protocol Version / Date: 
Version 2.0 / 28-AUG-2017 
 
Development Phase:  
Phase 2 
 
Sponsor: 
 
 
Menlo Therapeutics Inc. 
4085 Campbell Avenue, Suite 200 
Menlo Park, CA 94025 
USA 
 
 
Confidentiality Statement: 
This document is a confidential communication of Menlo Therapeutics Inc. As such, the 
recipients agree not to disclose or reproduce, without prior written approval, this document 
and any attachments, except to appropriate Institutional Review Boards, Ethics Committees, 
representatives of the US Food and Drug Administration, other regulatory agencies or as 
otherwise required by applicable laws or regulations. 


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Protocol MTI-110 
   
 
Version 2.0 
 
Page 2 
SIGNATURE PAGE FOR INVESTIGATOR(S) 
 
 
TITLE:  
A RANDOMIZED, DOUBLE-BLIND, 
PLACEBO-CONTROLLED STUDY OF THE EFFICACY, 
SAFETY, AND TOLERABILITY OF SERLOPITANT FOR 
THE TREATMENT OF REFRACTORY CHRONIC COUGH 
 
IND No.: 
 
 
135540 
 
ClinicalTrials.gov ID: 
TBD 
 
EudraCT Number:  
2017-003250-16 
 
Protocol No.:  
 
MTI-110 
 
Protocol Version / Date: 
Version 2.0 / 28-AUG-2017 
 
Development Phase:  
Phase 2 
 
Sponsor: 
 
 
Menlo Therapeutics Inc. 
4085 Campbell Avenue, Suite 200 
Menlo Park, CA 94025 
USA 
 
 
I have read the protocol and agree to conduct this study in accordance with the protocol, all 
relevant laws and regulations in force at the time, International Conference on Harmonisation 
Guidelines for Good Clinical Practices, and the Declaration of Helsinki.  
 
 
 
Principal Investigator’s printed name 
 
 
 
 
 
 
Principal Investigator’s signature 
 
Date (DD-MMM-YYYY) 


Menlo Therapeutics lnc. 
Protocol MTl-110 
Confidential 
SPONSOR PROTOCOL APPROVAL SIGNATURE(S) 
TITLE: 
A RANDOMIZED, DOUBLE-BLIND, PLACEBO-
CONTROLLED STUDY OF THE EFFICACY, SAFETY, 
AND TOLERABILITY OF SERLOPITANT FOR THE 
TREATMENT OF REFRACTORY CHRONIC COUGH 
IND No.: 
135540 
ClinicalTrials.gov ID: 
TBD 
EudraCT Number: 
2017-003250-16 
Protocol No.: 
MTI-110 
Protocol Version I Date: 
Version 2.0 I 28-AUG-2017 
Development Phase: 
Phase 2 
Sponsor: 
Menlo Therapeutics Inc. 
Approved by: 
Chief Medical Officer 
Version 2.0 
4085 Campbell A venue, Suite 200 
Menlo Park, CA 94025 
USA 
Page 3 


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PROTOCOL SYNOPSIS 
Study Title: 
A Randomized, Double-Blind, Placebo-Controlled Study of the Efficacy, 
Safety, and Tolerability of Serlopitant for the Treatment of Refractory Chronic 
Cough 
Protocol Number: 
MTI-110 
Sponsor: 
Menlo Therapeutics Inc. 
Study Centers: 
Approximately 45 sites in the USA and UK 
Development Phase: 
Phase 2 
Study Objectives: 
The primary objective of this study is to assess the effectiveness of serlopitant 
for the treatment of refractory chronic cough after 12 weeks of treatment in 
reducing 24-hour objective cough frequency. 
The secondary objectives are as follows: 
• To evaluate the effectiveness of serlopitant as compared to placebo after 4 
and 8 weeks of treatment in reducing 24-hour objective cough frequency 
• To evaluate the effectiveness of serlopitant as compared to placebo after 4, 
8 and 12 weeks of treatment in reducing awake objective cough frequency 
• To evaluate the effectiveness of serlopitant as compared to placebo after 4, 
8 and 12 weeks of treatment in reducing sleep objective cough frequency 
• To evaluate the effectiveness of serlopitant in: 
◦ 
Reducing the cough severity measured by a Visual Analog Scale 
(VAS) 
◦ 
Improving cough-specific quality of life (LCQ) 
• To assess the safety and tolerability of repeated oral doses of serlopitant in 
subjects with treatment refractory chronic cough 
Study Design: 
This is a 12-week randomized, parallel-group, double-blind, placebo-controlled 
study of serlopitant in subjects with treatment refractory chronic cough. 
Approximately 170 subjects who meet entry criteria will be randomly assigned 
to serlopitant 5 mg or matching placebo in a 1:1 ratio for up to 84 days. The 
randomization will be stratified by country and gender. 
The study will consist of three periods, for a total study period of approximately 
18 weeks: 
• Screening period: 14 days 
• Treatment period: 84 days 
• Follow-up period: 28 days 
 
During the screening period, subjects will undergo eligibility evaluations. 
Subjects must be willing to comply with restrictions on allowable concomitant 
therapies for the duration of the study. 
At the Baseline visit, eligible subjects will be randomly assigned to one of two 
treatment groups and will have baseline cough monitoring conducted. One day 
after the Baseline visit, subjects will take a loading dose (3 tablets taken orally) 
in the morning on the first day of the treatment period (Study Day 1). Starting 


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on Study Day 2, subjects will take one tablet per day taken orally in the 
morning. Subjects will be instructed to take all doses at approximately the same 
time each day and no sooner than 2 hours before or after a meal. 
The primary efficacy endpoint will be assessed at Day 84 of treatment.  
After completion of the 84-day treatment period, all subjects will enter a 28-day 
follow-up period. Subjects who discontinue treatment early at any time during 
the treatment period will have an Early Treatment Discontinuation (ETD) visit 
within 7 days after their last dose of study drug in addition to a follow-up visit. 
Planned Sample Size: 
Approximately 170 subjects will be randomized. 
Study Population: 
The study will consist of adults with a history of treatment refractory chronic 
cough.  
Inclusion Criteria: 
Subjects who meet all of the following criteria will be included in the study: 
1. Female and males between 18 and 80 years of age inclusive, at Screening 
2. Chest radiograph or computed tomography (CT) Thorax within the last 
5 years not demonstrating any abnormality considered to be significantly 
contributing to the chronic cough in the opinion of the Principal 
Investigator and Menlo Therapeutics Medical Monitor 
3. Have a diagnosis of treatment refractory chronic cough or unexplained 
cough for at least one year (see American College of Chest 
Physicians/British Thoracic Society (ACCP/BTS) guidelines in 
Appendix C)  
4. At Screening have a score of ≥ 40mm on the Cough Severity VAS  
5. At Baseline (Day 0) have a score of ≥ 40mm on the Cough Severity VAS  
6. All female subjects who are of childbearing potential must practice highly 
effective contraception (i.e., pregnancy prevention method with a failure 
rate of < 1% per year) from the time of the initial screening visit until 
4 weeks after last dose of study drug. Please refer to Section 7.1.5 for 
acceptable methods of contraception 
7. Have provided written informed consent 
8. Are willing and able to comply with all aspects of the protocol 
 
Exclusion Criteria: 
1. Prior treatment with serlopitant or other neurokinin-1 receptor (NK1-R) 
antagonists (e.g., aprepitant, orvepitant) 
2. Current smoker or individuals who have given up smoking within the past 
12 months 
3. FEV1/FVC < 60% 
4. Body mass index (BMI) <18 kg/m2 or ≥ 40 kg/m2 at Screening 
5. History of upper or lower respiratory tract infection or recent significant 
change in pulmonary status within 4 weeks of the Baseline Visit (Day 0) 
6. History of cystic fibrosis 
7. History of opioid use within 1 week of the Baseline Visit (Day 0) 


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8. Requiring concomitant therapy with prohibited medications (see 
Section 5.7) 
9. Treatment with biologic therapies within 8 weeks or 5 half-lives prior to the 
Baseline Visit (Day 0), whichever is longer 
10. Treatment with strong CYP3A4 inhibitors within 4 weeks prior to the 
Baseline Visit (Day 0) (see Appendix B) 
11. Treatment with any investigational therapy within 4 weeks (investigational 
biologic therapies within 8 weeks) prior to the Baseline Visit (Day 0)  
12. Serum creatinine, total bilirubin, alanine aminotransferase (ALT) or 
aspartate aminotransferase (AST) > 2x the upper limit of normal (ULN) 
during screening 
13. Positive test for any drug of abuse 
14. History of malignancy within 5 years prior to the Baseline Visit (Day 0), 
with the exception of completely treated and non-metastatic basal cell 
carcinoma or squamous cell carcinoma of the skin 
15. Any known psychiatric diagnosis meeting DSM-5 criteria which may 
confound the assessment of serlopitant safety or efficacy, or interfere with 
the subject’s ability to comply with protocol-mandated activities, within 
3 years prior to randomization. Examples of such DSM-5 diagnoses include 
but are not limited to major depressive disorder, bipolar disorder, 
schizophrenia, psychotic disorder, intellectual disability, severe alcohol use 
disorder. 
16. Known active hepatitis infection 
17. Known history of human immunodeficiency virus (HIV) infection 
18. History of hypersensitivity to serlopitant or any of its components 
19. Currently pregnant or breastfeeding female subject 
20. Females of childbearing potential who are unable or unwilling to practice 
highly effective contraception (pregnancy prevention) 
21. Presence of any medical condition or disability that, in the investigator’s 
opinion, could interfere with the assessment of safety or efficacy in this 
trial or compromise the safety of the subject, including clinically significant 
ECG abnormalities during screening 
22. Planned or anticipated major surgical procedure or other activity that would 
interfere with the subject’s ability to comply with protocol-mandated 
assessments (e.g., extended international travel) during the subject’s 
participation in the study 
Study Drug: 
Serlopitant 5 mg oral tablets and matching placebo. 
Dosage:  
Serlopitant: 5 mg once daily by mouth for 84 days, following a 3-tablet loading 
dose on the first day of the treatment period. 
Matching placebo: Once daily by mouth for 84 days, following a 3-tablet 
loading dose on the first day of the treatment period. 


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Prohibited Concomitant 
Therapy 
The following therapies are excluded from 1 week prior to the Baseline Visit 
(Day 0) through the follow-up period: 
• Opioids (including codeine). Opioids (including codeine), if required for 
other indications, are permitted provided that subjects are receiving a stable 
dose for at least one week prior to the Baseline Visit (Day 0) and still 
experiencing a troublesome cough. Subjects must remain on a stable dose 
for the duration of the treatment period. 
The following cough therapies are excluded from 2 weeks prior to the Baseline 
Visit (Day 0) through the end of the treatment period: 
• Dextromethorphan 
• Guaifenesin 
• Chlorpheniramine maleate extended release tablets 
• Benzonatate 
 
The following therapies are excluded from 2 weeks prior to the Baseline Visit 
(Day 0) through the follow-up period: 
• Pregabalin, gabapentin, thalidomide, or amitriptyline for the treatment of 
cough. Pregabalin, gabapentin, thalidomide, or amitriptyline if required for 
other indications, is permitted if subjects are receiving a stable dose and 
still experiencing a troublesome cough. Subjects must remain on a stable 
dose for the duration of the treatment period. 
 
The following therapies are excluded from 4 weeks prior to the Baseline Visit 
(Day 0) through the follow-up period: 
• Systemic immunosuppressive/immunomodulatory therapies (including but 
not limited to PDE4 inhibitors, cyclosporine, mycophenolate-mofetil, 
methotrexate, azathioprine, or phototherapy) 
• Strong CYP3A4 inhibitors (See Appendix B) 
• Any investigational therapy 
 
The following therapies are excluded from 8 weeks prior to the Baseline Visit 
(Day 0) through the follow-up period: 
• Biologic therapies 
• Investigational biologic therapies 
 
The following therapy is excluded from 12 weeks prior to the Baseline Visit 
(Day 0) through the follow-up period: 
• Treatment with an ACE-inhibitor 


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Primary Efficacy 
Endpoint: 
The primary efficacy endpoint is: 
Change from Baseline in 24-hour objective cough frequency after 12 weeks 
(Day 84) of treatment. 
Secondary Efficacy 
Endpoints: 
Key Secondary 
• Change from Baseline in awake objective cough frequency after 12 weeks 
(Day 84) of treatment 
• Proportion of subjects with ≥ 30% reduction in 24-hour objective cough 
frequency per hour at Week 12 (Day 84) 
• Proportion of subjects with ≥30% reduction in awake objective cough 
frequency per hour at Week 12 (Day 84) 
• Change from Baseline in Cough Severity Visual Analog Scale (VAS) at 
Week 12 (Day 84) 
 
Other Secondary 
• Change from Baseline in 24-hour objective cough frequency after 4 and 
8 weeks (Days 28 and 56) of treatment 
• Change from Baseline in awake objective cough frequency after 4 and 
8 weeks (Days 28 and 56) of treatment 
• Change from Baseline in 24-hour objective cough frequency at the 
Follow-Up visit (Day 112) 
• Change from Baseline in sleep objective cough frequency after 4, 8 and 
12 weeks (Days 28, 56 and 84) of treatment 
• Change from Baseline in Cough Severity Visual Analog Scale (VAS) at 
Weeks 4 and 8 (Days 28 and 56) 
• Change from Baseline in Leicester Cough Questionnaire (LCQ) individual 
Domain and Total scores 
• Patient's Global Impression of Change (PGIC) 
• Clinician's Global Impression of Change (CGIC) 
Safety Endpoints: 
Safety Assessments 
Safety will be assessed through monitoring of adverse events (AEs), physical 
examinations (including vital signs), electrocardiograms (ECGs), and laboratory 
tests. Safety assessment frequency is shown in the Schedule of Assessments and 
Procedures. 
 
Safety endpoints include the following: 
• Incidence of treatment-emergent adverse events (TEAEs) and serious 
adverse events (SAEs) 
• Change in clinical laboratory parameters following study drug exposure 
• Changes in vital sign and ECG parameters following study drug exposure 
• Plasma concentrations of serlopitant and metabolites 


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Decision Rule and 
Sample Size 
A total of 170 subjects (85/arm) in 1:1 ratio of serlopitant 5 mg or placebo will 
provide 90% power to detect a 25% relative reduction (placebo-adjusted ratio of 
0.75) in 24-hour objective cough frequency or awake objective cough frequency 
using a two-sample t-test at a one-sided significance level of 0.05. This assumes 
that 24-hour cough frequency or awake cough frequency follows a log-normal 
distribution with a CV of 0.64. This sample size also considers an expected 
dropout rate of 15%.  
The comparisons related to the primary and key secondary objectives will be 
done in a hierarchical manner to control the familywise error rate. The testing 
procedure will start by testing the primary endpoint and then proceed to the key 
secondary endpoints by following the order as specified in Section 8.9.4. 
Analysis Sets: 
Efficacy Analysis Sets 
Full Analysis Set (FAS) – All randomized subjects who have taken at least one 
dose of study medication and provided at least one baseline and at least one 
post-baseline primary endpoint observation during the treatment period. 
Participants will be analyzed according to the treatment group to which they are 
randomized. 
Safety Analysis Sets 
The safety analysis set will consist of all subjects randomized who receive at 
least one dose of study medication. Subjects will be classified based upon the 
treatment received. 
PK Analysis Set 
The PK analysis set will consist of all subjects who receive ≥ 1 dose of 
serlopitant and who have at least 1 post-dose PK blood sample available for 
analysis. 
Statistical Methods: 
Efficacy Analyses: 
The FAS population will serve as the primary population for the analysis of 
efficacy data in this study.  
The primary efficacy endpoint of this study is change from Baseline in 24-hour 
objective cough frequency after 12 weeks (84 days) of treatment.  
As the change in 24-hour cough frequency may have a skewed and wide 
distribution, the primary analysis for the primary endpoint will be analyzed on 
the natural log scale. The difference between serlopitant (5 mg) and placebo 
will be estimated using a mixed effect repeated measures (MMRM) model. The 
model will include factors for treatment, visit, country, sex, the interaction of 
treatment by visit; and the log-transformed baseline value as a covariate. The 
MMRM model will use all available 24-hour cough frequency data on Day 28, 
56, and 84. The geometric mean of the 24-hour coughs per hour will be 
presented by treatment and by visit. The percent difference change between 
serlopitant and placebo will be estimated by 100*(ediff - 1), where diff is the 
difference provided by the analysis of the log transformed variable.  
In order to evaluate the robustness of efficacy results and assess the effect of 
missing data, additional sensitivity analyses for the primary efficacy variables 
will be employed. 
Safety Analyses: 
The incidence of all AEs and treatment-related AEs will be tabulated by 
treatment received. These AEs will be classified by system organ class and 
preferred term using the Medical Dictionary for Regulatory Activities 
(MedDRA). For incidence reporting, if a subject reported more than one AE 
that was coded to the same system organ class or preferred term, the subject will 


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be counted only once for that specific system organ class or preferred term. An 
overview of AEs, which includes subject incidence of AEs, treatment-related 
AEs, AEs by severity, SAEs, deaths, and AEs leading to discontinuation, will 
be presented.  
Clinical safety laboratory values will be measured by a central laboratory. 
Summary statistics for actual values and for changes from Baseline will be 
tabulated for laboratory results by scheduled visit.  
Subjects with clinical laboratory values outside of the normal reference range at 
any post-baseline assessment will be summarized. Shifts from Baseline 
laboratory values will be tabulated. 
The observed vital signs and ECG data and change from Baseline for each 
measurement day will be summarized with descriptive statistics. 
Expected Duration of 
Subject’s Participation 
Approximately 126 days: 14 days of screening, 84 days of treatment, and a 
follow-up period of 28 days. 
This study will be conducted in accordance with the Guidelines of Good Clinical Practices (GCPs). 


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TABLE OF CONTENTS 
CLINICAL STUDY PROTOCOL ............................................................................................1 
SIGNATURE PAGE FOR INVESTIGATOR(S) .....................................................................2 
SPONSOR PROTOCOL APPROVAL SIGNATURE(S) .........................................................3 
PROTOCOL SYNOPSIS ..........................................................................................................4 
TABLE OF CONTENTS .........................................................................................................11 
LIST OF APPENDICES ..........................................................................................................14 
LIST OF FIGURES .................................................................................................................14 
LIST OF TABLES ...................................................................................................................14 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..........................................15 
1 
INTRODUCTION .................................................................................................16 
1.1 
Refractory Chronic Cough ...............................................................................16 
1.2 
Substance P and the Neurokinin-1 Receptor in Cough ....................................16 
1.3 
Serlopitant ........................................................................................................17 
1.3.1 
Serlopitant Background .......................................................................17 
1.3.2 
Serlopitant Clinical Data in Phase 1 and Non-Pruritus Studies ...........17 
1.3.3 
Serlopitant in Pruritus-Related Studies ................................................18 
1.3.4 
Serlopitant in Chronic Cough ..............................................................19 
2 
STUDY OBJECTIVES ..........................................................................................19 
3 
STUDY DESIGN...................................................................................................19 
3.1 
Overall Study Design .......................................................................................19 
3.2 
Rationale for Study Design and Dose Selection ..............................................20 
3.3 
Study Endpoints ...............................................................................................21 
3.3.1 
Primary Efficacy Endpoint ..................................................................21 
3.3.2 
Key Secondary Efficacy Endpoints .....................................................21 
3.3.3 
Additional Secondary Efficacy Endpoints ...........................................21 
3.3.4 
Safety Endpoints ..................................................................................22 
3.4 
Safety Review ..................................................................................................22 
3.4.1 
Safety Monitoring Team ......................................................................22 
4 
SELECTION OF STUDY POPULATION ...........................................................22 
4.1 
Study Population ..............................................................................................22 
4.2 
Inclusion Criteria .............................................................................................23 
4.3 
Exclusion Criteria ............................................................................................23 
5 
STUDY DRUG ......................................................................................................25 
5.1 
Study Drug Supply, Route of Administration, and Storage.............................25 
5.2 
Labeling and Study Drug Accountability ........................................................25 
5.3 
Dosing Regimen...............................................................................................25 
5.4 
Dose Modification ...........................................................................................25 


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5.5 
Missed or Delayed Doses.................................................................................25 
5.6 
Study Drug Discontinuation ............................................................................26 
5.7 
Concomitant and Excluded Therapies .............................................................26 
5.7.1 
Allowed Therapies ...............................................................................26 
5.7.2 
Excluded Therapies ..............................................................................27 
5.7.3 
Use of Excluded Therapies During the Treatment Period ...................28 
5.8 
Assignment to Treatment .................................................................................28 
5.8.1 
Randomization .....................................................................................28 
5.8.2 
Blinding................................................................................................28 
5.9 
Treatment Compliance .....................................................................................28 
6 
STUDY SCHEDULE AND ASSESSMENTS ......................................................29 
6.1 
Efficacy Parameters .........................................................................................29 
6.1.1 
Objective Cough Frequency ................................................................29 
6.1.2 
Cough Severity Visual Analogue Scale (VAS) ...................................29 
6.1.3 
Leicester Cough Questionnaire (LCQ) ................................................29 
6.1.4 
Patient’s Global Impression of Change (PGIC)...................................29 
6.1.5 
Clinician’s Global Impression of Change (CGIC)...............................29 
6.2 
Safety Parameters.............................................................................................29 
6.2.1 
Vital Signs ............................................................................................29 
6.2.2 
Physical Examination...........................................................................29 
6.2.3 
Clinical Laboratory Assessments .........................................................30 
6.2.4 
Electrocardiogram ................................................................................30 
6.3 
Pharmacokinetics Measurements .....................................................................30 
6.4 
Subject Flow Diagram .....................................................................................30 
6.5 
Study Visits ......................................................................................................31 
6.5.1 
Informed Consent.................................................................................32 
6.5.2 
Screening Visit/Period .........................................................................32 
6.5.3 
Baseline Visit (Day 0) ..........................................................................32 
6.5.4 
Day 1 Visit ...........................................................................................33 
6.5.5 
Day 14 Visit (Telephone Visit) ............................................................34 
6.5.6 
Day 28 Visit .........................................................................................34 
6.5.7 
Day 56 Visit .........................................................................................35 
6.5.8 
Day 84 Visit .........................................................................................36 
6.5.9 
Day 85/Early Treatment Discontinuation Visit ...................................37 
6.5.10 
Day 112 Follow-up Visit .....................................................................38 
6.5.11 
Day 113 Follow-up Visit .....................................................................38 
6.6 
Early Termination ............................................................................................39 
7 
ASSESSMENT OF SAFETY ................................................................................39 


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7.1 
Definitions........................................................................................................39 
7.1.1 
Adverse Event ......................................................................................39 
7.1.2 
Serious Adverse Event .........................................................................39 
7.1.3 
Abnormal Physical Exam, Laboratory, Vital Sign, and 
Electrocardiogram Findings .................................................................40 
7.1.4 
Deaths ..................................................................................................41 
7.1.5 
Pregnancies and Contraception Requirements .....................................41 
7.2 
Methods and Timing for Recording and Reporting Adverse Events ...............42 
7.2.1 
Adverse Event Reporting Period .........................................................42 
7.2.2 
Eliciting Adverse Events......................................................................42 
7.2.3 
Assessment of Severity ........................................................................42 
7.2.4 
Assessment of Causality ......................................................................43 
7.3 
Follow-up of Adverse Events and Serious Adverse Events ............................44 
7.4 
Reporting Serious Adverse Events to the Sponsor and Institutional Review 
Board or Ethics Committee ..............................................................................44 
7.5 
Reporting Serious Adverse Events to Regulatory Authorities and Study 
Investigators .....................................................................................................44 
7.6 
Emergency Unblinding ....................................................................................45 
8 
STATISTICAL METHODS ..................................................................................45 
8.1 
Decision Rule and Sample Size .......................................................................45 
8.2 
Handling of Missing Data and Excluded Therapy Use ...................................45 
8.3 
Derivations of Efficacy Variables ....................................................................45 
8.4 
Analysis Populations ........................................................................................46 
8.5 
Subject Disposition ..........................................................................................47 
8.6 
Subject Characteristics .....................................................................................47 
8.7 
Concomitant Medications ................................................................................47 
8.8 
Treatment Compliance and Extent of Exposure ..............................................47 
8.9 
Efficacy Analyses ............................................................................................48 
8.9.1 
Statistical Hypotheses and Tests ..........................................................48 
8.9.2 
Primary Endpoint .................................................................................48 
8.9.3 
Secondary Endpoints ...........................................................................49 
8.9.4 
Multiplicity Adjustment .......................................................................52 
8.10 
Safety Analyses ................................................................................................52 
8.10.1 
Adverse Events ....................................................................................52 
8.10.2 
Clinical Safety Laboratory Results ......................................................52 
8.10.3 
Vital Signs ............................................................................................53 
8.10.4 
Electrocardiograms ..............................................................................53 
8.11 
Pharmacokinetics Analysis ..............................................................................53 
9 
ADMINISTRATIVE ASPECTS ...........................................................................53 


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9.1 
Changes to the Protocol ...................................................................................53 
9.2 
Study Termination ...........................................................................................53 
9.3 
Monitoring and Auditing Procedures...............................................................54 
9.4 
Transfer of Obligations ....................................................................................54 
9.5 
Informed Consent.............................................................................................54 
9.6 
Communication with the Institutional Review Board or Ethics Committee ...54 
9.7 
Disclosure and Confidentiality ........................................................................54 
9.8 
Records and Electronic Case Report Forms ....................................................55 
9.9 
Good Clinical Practices and Ethical Study Conduct........................................55 
9.10 
End of Study Notification ................................................................................56 
9.11 
Publication of Results ......................................................................................56 
9.12 
Final Report .....................................................................................................56 
10 
REFERENCES ......................................................................................................57 
 
LIST OF APPENDICES 
Appendix A 
Schedule of Activities and Assessments ..........................................................59 
Appendix B 
List of Strong CYP3A4 Inhibitors ...................................................................62 
Appendix C 
ACCP/BTS Guidelines ....................................................................................63 
 
LIST OF FIGURES 
Figure 1 
Subject Flow Diagram ...............................................................................31 
 
LIST OF TABLES 
Table 1 
Adverse Event Grading ..............................................................................43 
Table 2 
Analysis Strategy for Primary and Key Secondary Efficacy Endpoints....51 
Table 3 
Schedule of Visit Activities .......................................................................59 
Table 4 
Schedule of Cough Monitoring and Patient Reported Outcomes 
(PROs)........................................................................................................61 
 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
ACCP 
American College of Chest Physicians 
AE 
Adverse event 
ALT 
Alanine aminotransferase  
AMH 
Anti-Mullerian Hormone 
ANOVA 
Analysis of variance 
AST 
Aspartate aminotransferase 
ATC 
Anatomical Therapeutic Classification 
BMI 
Body Mass Index 
BTS 
British Thoracic Society 
CGIC 
Clinician’s Global Impression of Change 
COPD 
Chronic Obstructive Pulmonary Disease 
CT 
Computed Tomograghy 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
ETD 
Early treatment discontinuation 
FAS 
Full Analysis Set 
iDMC 
Independent Data Monitoring Committee 
DSM 
Diagnostic Statistical Manual 
ICF 
Informed Consent Form 
IRB 
Institutional Review Board 
IVRS 
Interactive Voice Response System 
IWRS 
Interactive Web Response System  
LCQ 
Leicester Cough Questionnaire 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
NK1-R 
Neurokinin-1 receptor 
PGIC 
Patient Global Impression of Change 
PK 
Pharmacokinetics 
QoL 
Quality of life 
RO 
Receptor Occupancy 
SAE 
Serious adverse event 
SOC 
System organ class 
SP 
Substance P 
TEAE 
Treatment-emergent adverse event 
UK 
United Kingdom 
USA 
United States of America 
VAS 
Visual Analog Scale 


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1 
INTRODUCTION 
1.1 
Refractory Chronic Cough 
Cough is a common symptom frequently associated with other conditions such as an upper 
respiratory infection, chronic obstructive pulmonary disease (COPD), or asthma. In cough 
guidelines, such as those published by the American College of Chest Physicians, cough is 
characterized by the length of time a patient is coughing: Acute - up to 3 weeks, Sub Acute - 
from 3 to 8 weeks, and Chronic - greater than 8 weeks (Irwin 2006). Patients who present to 
a physician for a persistent cough are evaluated and treated for obvious and common causes 
of cough. If a patient continues to cough, he/she is evaluated for conditions that are 
commonly associated with chronic cough. These are asthma, gastroesophageal reflux disease 
(GERD), and upper airway cough syndrome (UACS) (Dicpinigaitis 2011). According to the 
cough guidelines, a patient may be evaluated for less common diseases based on the patient’s 
history, other symptoms, or physical findings. Patients in whom no treatable cause of their 
cough can be found are characterized as having “refractory chronic cough” (Gibson 2016). 
Patients with refractory chronic cough may represent up to 12% of the general population. 
Patients are most commonly women (approximately 2/3-3/4 of patients are women) of 
approximately 45 to 75 years of age. Patients most commonly cough while awake for 
approximately 20 times per hour to as much as several hundred times per hour 
(Abdulqawi 2014). The cough may last for many years with some patients reporting having 
coughed for a median of 12 years in a recent study (Abdulqawi 2014). Patients with 
refractory chronic cough report that their condition is frequently disabling and has a marked 
effect on their quality of life as measured by instruments such as the Leicester Cough 
Questionnaire (LCQ) (Birring 2003, Kelsall 2008).  
Treatment options for refractory chronic cough are very limited. There are no approved drug 
treatments for this disease. Patients and clinicians frequently try over-the-counter agents such 
as dextromethorphan, guaifenesin, and antihistamines with little benefit. Prescription options 
in the U.S. include codeine and related opiate products and benzonatate, and in the U.K. 
low-dose oral morphine. Studies have evaluated amitriptyline (Dicpinigaitis 2014) and 
gabapentin with some patients having some benefit but with some important adverse events 
(Ryan 2012). Importantly, there have been no FDA approvals for a novel pharmaceutical 
agent to treat cough in over 50 years. 
1.2 
Substance P and the Neurokinin-1 Receptor in Cough  
As the study of cough and the search for agents that can control the coughing in patients with 
refractory chronic cough advance, there has been a greater appreciation for the role of the 
abnormalities in the neuronal pathways that control cough. These pathways include 
peripheral sensory C and Aδ fibers that are contained in vagal afferent nerves 
(LaVinka 2013, Mazzone 2007). These nerves have their ganglia in the jugular and nodose 
ganglion and project their terminals into the nucleus tractus solitarius of the brainstem. It has 
been proposed by Canning et al that while there are multiple stimuli in the periphery that are 
involved with the cough reflex, in the central nervous system there are few mediators of the 
cough (Canning 2009). One of these is through substance P/neurokinin pathway. Neurokinin 


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A1 antagonists have been found to inhibit cough in several animal models of cough 
(Canning 2009, Grobman 2016, Mazzone 2005). Therefore, it is proposed that NK1-R 
antagonism may play a key role in controlling cough. There have been two recently reported 
studies with an NK1-R antagonist in controlling cough. Aprepitant, which is commercially 
available as an antiemetic, was successful in reducing cough in patients with lung cancer 
(Harle 2015). Similarly, a study of orvepitant in subjects with refractory chronic cough also 
showed benefit after one month of treatment (Smith 2017). 
1.3 
Serlopitant  
1.3.1 
Serlopitant Background 
Serlopitant is a small molecule, highly selective NK1-R antagonist that is administered orally 
and metabolized by CYP3A4, with a plasma half-life of 45–86 hours. It binds with high 
affinity to the human NK1-R with a dissociation constant (Kd) of 46 pM; displacing SP 
binding with a half-maximal inhibition concentration (IC50) of 61 pM. Serlopitant is a potent 
functional antagonist of SP-induced inositol phosphate generation. 
Serlopitant has been extensively studied in animal toxicology studies, including chronic 
toxicology and carcinogenicity studies. In non-clinical chronic toxicology studies in rats, 
mice and dogs, treatment related findings of potential clinical significance included increased 
salivation, decreased body weight gain and food consumption, slight changes in hematology 
and serum biochemistry parameters, mild increases in liver weight and mild 
histomorphologic changes. The histomorphologic changes were seen only in rats (not in dogs 
or mice) and included: very slight ovarian interstitial cell hypertrophy, mammary gland and 
uterine atrophy; decreased corpora lutea; increased histiocytes in lung and mesenteric lymph 
nodes; slight skeletal and cardiac muscle degeneration; slight increased hematopoiesis in 
bone marrow; and slight to moderate vacuolation in kidney tubules. These nonclinical 
findings occurred at systemic exposures exceeding those anticipated to provide efficacy of 
serlopitant for pruritus indications in humans (1 to 5 mg tablet daily). No cardiac lesions have 
been observed in dog toxicity studies up to 9 months in duration nor in a 3-month mouse 
range-finding study and 2-year mouse carcinogenicity study at exposure higher than the 
lowest level which caused cardiotoxicity in rats. The no observed adverse effect level 
(NOAEL) in rats for histomorphological changes in the reproductive tract, mammary gland 
and bone marrow provides a 2.5-fold margin for the maximum-targeted exposure 
(5 mg tablet daily). The rat NOAEL for histomorphological changes in muscle and kidney 
provides a 5-fold margin for the maximum-targeted exposure (5 mg tablet daily).  
In summary, the nonclinical toxicity noted with serlopitant provides no contraindications to 
the continuation of clinical trials via the oral route. Findings in the developmental toxicity 
studies support inclusion of women of childbearing potential in clinical trials in accordance 
with the study protocol and local regulatory guidances. 
1.3.2 
Serlopitant Clinical Data in Phase 1 and Non-Pruritus Studies 
In humans, serlopitant has been administered to over 1000 individuals. Single doses up to 
400 mg have been well tolerated in healthy young males. Multiple doses of up to 50 mg a 


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day for 4 weeks have been well tolerated in healthy young males, and a single (loading) dose 
of 15 mg followed by daily doses of 5 mg for 2 weeks have been well tolerated in elderly 
males and females. Forty-one (41) subjects received 4 mg liquid filled capsule (LFC) daily 
(exposure comparable to 5 mg tablets) for 1 year. Plasma concentrations of serlopitant 
appear to increase in a dose-proportional fashion in both young males and elderly subjects 
(males and females). Peak plasma concentrations after a single oral dose occurred at ~2 to 
4 hours in both young and elderly subjects. 
In a Phase 2 study examining treatment of overactive bladder (Study P003), the most 
common AEs during the initial 8-week base period across all treatment groups were 
headache (5.7%), diarrhea (5.2%), urinary tract infection (4.7%), dry mouth (4.5%), 
nasopharyngitis (4.5%), upper respiratory tract infection (4.3%), fatigue (4.1%), dizziness 
(3.8%), back pain (2.9%), nausea (2.3%), and peripheral edema (2.2%). 
1.3.3 
Serlopitant in Pruritus-Related Studies 
Serlopitant has been evaluated in two completed Phase 2 studies of subjects with chronic 
pruritus (TCP-101 and TCP-102). In TCP-101, a Phase 2 study of 256 adult subjects 18 to 
65 years of age with chronic pruritus), treatment-emergent AEs (TEAEs) were reported for 
25.4% of subjects in the placebo group and 32.8%, 36.9%, and 37.5% of subjects in the 
serlopitant 0.25, 1, and 5 mg groups, respectively. Overall, headache was the most commonly 
reported TEAE, reported for 6.3% of subjects in the placebo group and 1.6%, 4.6%, and 
1.6% of subjects in the serlopitant 0.25, 1, and 5 mg groups, respectively. Somnolence and 
diarrhea were the TEAEs with the highest overall incidence in the serlopitant groups. Most 
TEAEs were mild or moderate in severity. Six subjects discontinued study drug due to a 
TEAE; the events considered treatment-related in the serlopitant groups were diarrhea and 
gastrointestinal (GI) pain. There was no evidence of meaningful trends in laboratory 
abnormalities or changes in vital signs.  
In TCP-102, a Phase 2 study of 127 adult subjects 18 to 80 years of age with PN, TEAEs 
were reported for 61.9% of subjects in the placebo group and 71.9% of subjects in the 
serlopitant 5 mg group. The most common TEAEs in the serlopitant group were 
nasopharyngitis (17.2% serlopitant, 3.2% placebo), diarrhea (10.9% serlopitant, 4.8% 
placebo), and fatigue (9.4% serlopitant, 6.3% placebo). Most TEAEs were mild or moderate 
in severity. Five subjects (3 serlopitant, 2 placebo) had serious adverse events (SAEs); those 
considered possibly related to study drug in the serlopitant group were depression, dizziness, 
and vertigo. Nine subjects discontinued study drug due to a TEAE; those considered 
treatment-related in the serlopitant groups were pruritus, neurodermatitis, headache, 
dizziness, and vertigo. No clinically relevant changes were observed in chemistry, 
hematology, vital signs, or electrocardiogram (ECG) results. 
Additional studies are currently ongoing in pruritus associated with atopic dermatitis and 
epidermolysis bullosa. 


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1.3.4 
Serlopitant in Chronic Cough 
Other NK1-R antagonists (aprepitant and orvepitant) have reported success in pilot studies in 
treating chronic cough. A study in subjects with lung cancer and cough showed a favorable 
benefit of treatment with aprepitant (Harle 2015). Similarly, a study of orvepitant in subjects 
with refractory cough also showed benefit after 1 month of treatment (Smith 2017). 
Therefore, it is reasonable to study serlopitant in this indication. Serlopitant has several 
advantages over the other NK1-R antagonists especially considering its long half-life and 
favorable safety profile. This study will explore the effectiveness of serlopitant in subjects 
with refractory chronic cough. 
2 
STUDY OBJECTIVES  
The primary objective of this study is to assess the effectiveness of serlopitant for the 
treatment of refractory chronic cough after 12 weeks of treatment in reducing 24-hour 
objective cough frequency. 
The secondary objectives are as follows: 
• To evaluate the effectiveness of serlopitant as compared to placebo after 4 and 8 weeks of 
treatment in reducing 24-hour objective cough frequency 
• To evaluate the effectiveness of serlopitant as compared to placebo after 4, 8 and 
12 weeks of treatment in reducing awake objective cough frequency 
• To evaluate the effectiveness of serlopitant as compared to placebo after 4, 8 and 
12 weeks of treatment in reducing sleep objective cough frequency 
• To evaluate the effectiveness of serlopitant in: 
◦ 
Reducing the cough severity measured by a Visual Analog Scale (VAS) 
◦ 
Improving cough-specific quality of life (LCQ) 
• To assess the safety and tolerability of repeated oral doses of serlopitant in subjects with 
treatment refractory chronic cough 
 
3 
STUDY DESIGN 
3.1 
Overall Study Design 
This is a 12-week randomized, parallel-group, double-blind, placebo-controlled study of 
serlopitant in subjects with treatment refractory chronic cough. 
Approximately 170 subjects who meet entry criteria will be randomly assigned to serlopitant 
5 mg or matching placebo in a 1:1 ratio for up to 84 days. The randomization will be 
stratified by country and gender. 


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The study will consist of three periods, for a total study period of approximately 18 weeks: 
• Screening period: 14 days 
• Treatment period: 84 days 
• Follow-up period: 28 days 
 
Informed consent will occur prior to any protocol-mandated procedures, including the 
stopping of any excluded therapies. This may occur prior to the initial Screening visit. During 
the screening period, subjects will undergo eligibility evaluation and will have baseline 
cough monitoring conducted. Subjects must be willing to comply with restrictions on 
allowable concomitant therapies for the duration of the study. 
At the baseline visit, eligible subjects will be randomly assigned to receive serlopitant 5 mg 
or placebo. Subjects will take a loading dose (3 tablets taken orally) in the morning on the 
first day of the treatment period (Study Day 1). Starting on Study Day 2, subjects will take 
one tablet per day taken orally in the morning. Subjects will be instructed to take all doses at 
approximately the same time each day and no sooner than 2 hours before or after a meal. 
The primary efficacy endpoint will be assessed at Day 84 of treatment.  
After completion of the 84-day treatment period, all subjects will enter a 28-day follow-up 
period. Subjects who discontinue treatment early at any time during the treatment period will 
have an Early Treatment Discontinuation (ETD) visit within 7 days after their last dose of 
study drug in addition to a follow-up visit. 
3.2 
Rationale for Study Design and Dose Selection 
Serlopitant has not been studied in patients with refractory chronic cough. However, 
serlopitant has been studied extensively in other indications. It is currently being advanced 
into Phase 3 studies in pruritus.  
In the TCP-101 study, serlopitant 5 mg and 1 mg taken daily for 6 weeks were superior to 
placebo for the reduction of pruritus. Similarly, in the TCP-102 study in patients with prurigo 
nodularis, serlopitant 5 mg taken daily for 8 weeks was superior to placebo for the reduction 
of pruritus. In both the TCP-102 and TCP-101 studies, serlopitant was generally 
well-tolerated and demonstrated an overall favorable safety profile at the doses evaluated. 
Serlopitant demonstrated superior efficacy compared to placebo for the treatment of chronic 
pruritus in a broad population of subjects (N = 257), including subjects with atopic diathesis 
(i.e. history of atopic dermatitis, asthma, and/or allergic rhinitis). The superior efficacy was 
observed at multiple timepoints with both the serlopitant 1 mg and 5 mg doses, but not with 
the serlopitant 0.25 mg dose. Safety profiles between the three serlopitant doses were 
comparable, and serlopitant was generally well-tolerated at the doses evaluated. 


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The serlopitant 5 mg dose was selected for this study based on the following factors: 
• The favorable efficacy, safety, and tolerability profile of serlopitant at the 5 mg dose 
level, as demonstrated in the TCP-101 and TCP-102 studies. These data are supported by 
safety experience across the serlopitant clinical development program. Over 250 subjects 
have been exposed to serlopitant at doses equivalent to the 5 mg tablet daily for at least 
6 weeks, and ~40 subjects have been exposed for up to one year. 
• Human CNS PET receptor occupancy (RO) data for serlopitant in healthy young males 
(Study P002) demonstrated a plasma concentration - RO relationship fitted with a 
maximum effect (Emax) model resulting in an Emax of 97%, EC50 of 22.9 nM, and EC90 of 
294 nM. Based on this modeling the steady state trough concentration in adults taking 
serlopitant 5 mg tablets once-daily is predicted to achieve ~93% RO. In previous 
dose-ranging experience with the NK1-R antagonist aprepitant, optimal clinical efficacy 
for the relief of chemotherapy-induced nausea and vomiting (CINV) was achieved at 
dose levels resulting in > 90% CNS NK1 RO. 
 
3.3 
Study Endpoints 
3.3.1 
Primary Efficacy Endpoint 
The primary efficacy endpoint is the change from Baseline in 24-hour Cough Frequency after 
12 weeks (Day 84) of treatment. 
3.3.2 
Key Secondary Efficacy Endpoints 
• Change from Baseline in awake objective cough frequency after 12 weeks (Day 84) of 
treatment 
• Proportion of subjects with ≥ 30% reduction in 24-hour objective cough frequency per 
hour at Week 12 (Day 84) 
• Proportion of subjects with ≥ 30% reduction in awake objective cough frequency per 
hour at Week 12 (Day 84) 
• Change from Baseline in Cough Severity Visual Analog Scale (VAS) at Week 12 
(Day 84) 
 
3.3.3 
Additional Secondary Efficacy Endpoints 
Additional secondary efficacy endpoints include the following: 
• Change from Baseline in 24-hour objective cough frequency after 4 and 8 weeks 
(Days 28 and 56) of treatment 


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• Change from Baseline in awake objective cough frequency after 4 and 8 weeks (Days 28 
and 56) of treatment 
• Change from Baseline in 24-hour objective cough frequency at the Follow-Up visit 
(Day 112) 
• Change from Baseline in sleep objective cough frequency after 4, 8 and 12 weeks 
(Days 28, 56 and 84) of treatment 
• Change from Baseline in Cough Severity Visual Analog Scale (VAS) at Weeks 4 and 8 
(Days 28 and 56) 
• Change from Baseline in Leicester Cough Questionnaire (LCQ) individual Domain and 
Total scores 
• Patient's Global Impression of Change (PGIC) 
• Clinician's Global Impression of Change (CGIC) 
 
3.3.4 
Safety Endpoints 
Safety endpoints include the following: 
• Incidence of TEAEs and SAEs 
• Changes in clinical laboratory parameters following study drug exposure 
• Changes in vital sign and ECG parameters following study drug exposure 
• Plasma concentrations of serlopitant and metabolites  
 
3.4 
Safety Review 
3.4.1 
Safety Monitoring Team 
An internal safety monitoring team consisting of representatives from Menlo Therapeutics 
Inc. and its designees will monitor blinded safety data on a regular basis throughout the 
study. 
4 
SELECTION OF STUDY POPULATION 
4.1 
Study Population 
Approximately 170 adult subjects with a history of treatment refractory chronic cough will 
be randomized into this study. 


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4.2 
Inclusion Criteria 
Subjects must meet the following criteria to be randomized into the study: 
1. Female and males between 18 and 80 years of age inclusive, at Screening 
2. Chest radiograph or CT Thorax within the last 5 years not demonstrating any abnormality 
considered to be significantly contributing to the chronic cough in the opinion of the 
Principal Investigator and Menlo Therapeutics Medical Monitor 
3. Have a diagnosis of treatment refractory chronic cough or unexplained cough for at least 
one year (see ACCP/BTS guidelines in Appendix C)  
4. At Screening have a score of ≥ 40mm on the Cough Severity VAS  
5. At Baseline (Day 0) have a score of ≥ 40mm on the Cough Severity VAS  
6. All female subjects who are of childbearing potential must practice highly effective 
contraception (i.e., pregnancy prevention method with a failure rate of < 1% per year) 
from the time of the initial Screening visit until 4 weeks after last dose of study drug. 
Please refer to Section 7.1.5 for acceptable methods of contraception 
7. Have provided written informed consent 
8. Are willing and able to comply with all aspects of the protocol 
 
4.3 
Exclusion Criteria 
Subjects who meet any of the following criteria are not eligible for participation in the study: 
1. Prior treatment with serlopitant or other neurokinin-1 receptor (NK1-R) antagonists (e.g., 
aprepitant, orvepitant) 
2. Current smoker or individuals who have given up smoking within the past 12 months 
3. FEV1/FVC < 60% 
4. Body mass index (BMI) < 18 kg/m2 or ≥ 40 kg/m2 at Screening 
5. History of upper or lower respiratory tract infection or recent significant change in 
pulmonary status within 4 weeks of the Baseline Visit (Day 0) 
6. History of cystic fibrosis 
7. History of opioid use within 1 week of the Baseline Visit (Day 0) 
8. Requiring concomitant therapy with prohibited medications (see Section 5.7) 
9. Treatment with biologic therapies within 8 weeks or 5 half-lives prior to the Baseline 
Visit (Day 0), whichever is longer 
10. Treatment with strong CYP3A4 inhibitors within 4 weeks prior to the Baseline Visit 
(Day 0) (see Appendix B) 
11. Treatment with any investigational therapy within 4 weeks (investigational biologic 
therapies within 8 weeks) prior to the Baseline Visit (Day 0) 


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12. Serum creatinine, total bilirubin, alanine aminotransferase (ALT) or aspartate 
aminotransferase (AST) > 2x the upper limit of normal (ULN) during screening 
13. Positive test for any drug of abuse 
14. History of malignancy within 5 years prior to the Baseline Visit (Day 0), with the 
exception of completely treated and non-metastatic basal cell carcinoma or squamous cell 
carcinoma of the skin 
15. Any known psychiatric diagnosis meeting DSM-5 criteria which may confound the 
assessment of serlopitant safety or efficacy, or interfere with the subject’s ability to 
comply with protocol-mandated activities, within 3 years prior to randomization. 
Examples of such DSM-5 diagnoses include but are not limited to major depressive 
disorder, bipolar disorder, schizophrenia, psychotic disorder, intellectual disability, 
severe alcohol use disorder 
16. Known active hepatitis infection 
17. Known history of human immunodeficiency virus (HIV) infection 
18. History of hypersensitivity to serlopitant or any of its components 
19. Currently pregnant or breastfeeding female subject 
20. Females of childbearing potential who are unable or unwilling to practice highly effective 
contraception (pregnancy prevention) 
21. Presence of any medical condition or disability that, in the investigator’s opinion, could 
interfere with the assessment of safety or efficacy in this trial or compromise the safety of 
the subject, including clinically significant ECG abnormalities during screening 
22. Planned or anticipated major surgical procedure or other activity that would interfere with 
the subject’s ability to comply with protocol-mandated assessments (e.g., extended 
international travel) during the subject’s participation in the study 
 


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5 
STUDY DRUG 
5.1 
Study Drug Supply, Route of Administration, and Storage 
The study drug in this study is serlopitant 5 mg or placebo, in a film-coated tablet 
formulation for oral administration. The serlopitant tablets contain microcrystalline cellulose, 
mannitol, croscarmellose sodium, silicon dioxide, sodium lauryl sulfate, and magnesium 
stearate, and are film coated with Opadry™ Brown. The placebo tablets contain 
microcrystalline cellulose, lactose monohydrate, and magnesium stearate, and are film coated 
with Opadry™ Brown.  
The study drug will be provided in bottles that can be stored at room temperature (59–86°F). 
The tablets will be supplied in bottles, with 18 tablets per bottle. Two bottles will be issued 
via Interactive Web Response System (IWRS) at Baseline and at the Day 28 and Day 56 
visits, for a total of 6 bottles dispensed for subjects completing 84 days of study drug 
treatment. 
Additional details regarding study drug supplies can be found in the Pharmacy Manual. 
5.2 
Labeling and Study Drug Accountability 
The study drug will be appropriately packaged and labeled in bottles with 18 tablets per 
bottle. The study drug supplied for this study is not to be used for any purpose other than this 
study, and study drug accountability must be maintained for all bottles distributed to the 
investigative site. 
Additional details regarding study drug labeling and accountability can be found in the 
Pharmacy Manual. 
5.3 
Dosing Regimen 
Subjects will take a loading dose (3 tablets taken orally) in the morning on the first day of the 
treatment period (Study Day 1). Starting on Study Day 2, subjects will take one tablet per day 
taken orally in the morning. Subjects will be instructed to take all doses at approximately the 
same time each day and no sooner than 2 hours before or after a meal. 
5.4 
Dose Modification 
No dose modification of study drug will be allowed during this study. 
5.5 
Missed or Delayed Doses 
Each dose of study drug after the first dose must be administered once daily in the morning, 
no sooner than 2 hours before or after a meal. If the morning dose is missed or delayed by 
8 or more hours, that dose should be skipped, and the following dose should be taken in the 
morning of the following day. The skipped dose will be considered and documented as a 
missed dose.  


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5.6 
Study Drug Discontinuation 
Subjects will be discontinued from study drug treatment in the following events: 
• A female subject becomes pregnant 
• Subject decision to discontinue study drug treatment, or subject decision to withdraw 
consent from the study 
• The subject receives a strong CYP3A4 inhibitor 
• Any medical condition that may jeopardize the subject’s safety if study drug is continued, 
in the investigator’s and/or Sponsor’s opinion 
• Discontinuation is deemed to be in the best interest of the subject, in the investigator’s 
and/or Sponsor’s opinion 
• The subject experiences a NCI CTCAE Grade 2 or higher treatment emergent AE that is 
assessed as likely related to study drug 
 
The Sponsor or designee should be contacted within 24 hours of investigator’s awareness of 
any study drug treatment discontinuation. Investigators should make every effort to contact 
the Sponsor or designee before discontinuing study drug treatment, if possible.  
Subjects who discontinue treatment with study drug prior to completing the treatment period 
will have a Follow-up visit 28 days after their last dose of study drug (see Section 6.5.11). 
Every effort should be made for subjects to complete the Follow-up visit after a subject has 
discontinued from study drug. 
5.7 
Concomitant and Excluded Therapies 
Concomitant therapies include any therapies (including over-the-counter medications) used 
by a subject from initiation of study drug treatment through the follow-up period. A record of 
all medications used will be maintained for each subject throughout the study. Reported 
information will include a description of the type of drug, treatment period, dosing regimen, 
the route of administration, and drug indication. 
5.7.1 
Allowed Therapies 
Subjects using oral contraceptives, hormone-replacement therapy, or other maintenance 
therapies that are not Excluded Therapies (Section 5.7.2) may continue their use during the 
study.  
A record of all concomitant therapies will be maintained for each subject. 


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5.7.2 
Excluded Therapies 
The following therapies are excluded from 1 week prior to the Baseline Visit (Day 0) through 
the follow-up period: 
• Opioids (including codeine). Opioids (including codeine), if required for other 
indications, are permitted provided that subjects are receiving a stable dose for at least 
one week prior to the Baseline Visit (Day 0) and still experiencing a troublesome 
cough. Subjects must remain on a stable dose for the duration of the treatment period. 
 
The following cough therapies are excluded from 2 weeks prior to the Baseline Visit (Day 0) 
through the end of the treatment period: 
• Dextromethorphan 
• Guaifenesin 
• Chlorpheniramine maleate extended release tablets 
• Benzonatate 
 
The following therapies are excluded from 2 weeks prior to the Baseline Visit (Day 0) 
through the follow-up period: 
• Pregabalin, gabapentin, thalidomide, or amitriptyline for the treatment of cough. 
Pregabalin, gabapentin, thalidomide, or amitriptyline if required for other indications, is 
permitted if subjects are receiving a stable dose and still experiencing a troublesome 
cough. Subjects must remain on a stable dose for the duration of the treatment period. 
 
The following therapies are excluded from 4 weeks prior to the Baseline Visit (Day 0) 
through the follow-up period: 
• Systemic immunosuppressive/immunomodulatory therapies (including but not limited to 
PDE4 inhibitors, cyclosporine, mycophenolate-mofetil, methotrexate, azathioprine, or 
phototherapy) 
• Strong CYP3A4 inhibitors (See Appendix B) 
• Any investigational therapy 
The following therapies are excluded from 8 weeks prior to the Baseline Visit (Day 0) 
through the follow-up period: 
• Biologic therapies 
• Investigational biologic therapies 
The following therapy is excluded from 12 weeks prior to the Baseline Visit (Day 0) through 
the follow-up period: 


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• Treatment with an ACE-inhibitor 
 
5.7.3 
Use of Excluded Therapies During the Treatment Period  
Use of any excluded therapies will be recorded for subjects who receive them. 
5.8 
Assignment to Treatment  
5.8.1 
Randomization 
Eligible subjects will be randomized to receive serlopitant 5 mg or placebo in a 1:1 ratio. 
Stratified permuted block randomization will be used. Randomization will be stratified by 
country and gender. 
An IWRS will be used to perform the randomization.  
5.8.2 
Blinding 
This study will be conducted as a double-blind study with the treatment assignment 
concealed from the subjects, the investigators and their staff, the Sponsor, and any designees 
of the Sponsor who interact directly with investigative sites. The placebo will be formulated 
to be indistinguishable from the active study product(s). Study materials will be packaged 
and issued in a manner designed to maintain the blind for subjects and all study personnel 
involved in the direction and execution of study procedures, study assessments, and 
collection of data. The randomization code for each subject will be available to the sites for 
use only in an emergency situation. For details of the procedure for unblinding of individual 
subjects in cases of emergency see Section 7.6.  
5.9 
Treatment Compliance 
Records of study drug used, dosages administered, and intervals between visits will be kept 
during the study. Dosing dates and times will be recorded. Subjects will be asked to return all 
partially used and empty bottles to the study site at each visit. The site staff will count and 
record the number of remaining tablets in each returned bottle. The site staff will assess the 
subject’s compliance with dosing by reviewing the subject’s dosing diary (available on the 
IWRS website) and the number of remaining study drug tablets relative to the number of 
days since the bottle was dispensed. A subject who has deviated significantly from the 
once-daily dosing regimen will be counseled. 


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6 
STUDY SCHEDULE AND ASSESSMENTS  
6.1 
Efficacy Parameters 
6.1.1 
Objective Cough Frequency 
Objective cough frequency will be measured as 24-hour sound recordings as outlined in 
Appendix A using a custom-built digital recording device (VitaloJAK, Vitalograph, Ltd). 
6.1.2 
Cough Severity Visual Analogue Scale (VAS) 
A cough severity VAS scored on a 100mm visual analogue scale will be measured at the time 
points outlined in Appendix A. 
6.1.3 
Leicester Cough Questionnaire (LCQ) 
The LCQ is a cough specific quality of life assessment that will be completed at the time 
points outlined in Appendix A. 
6.1.4 
Patient’s Global Impression of Change (PGIC) 
The PGIC is an instrument used by subjects to assess their overall status since the start of the 
study. It consists of a 7-point scale ranging from ‘very much improved’ to very much worse’. 
The PGIC will be assessed at the time points outlined in Appendix A. 
6.1.5 
Clinician’s Global Impression of Change (CGIC) 
The CGIC is an instrument used to assess subjects’ overall status since the start of the study. 
It consists of a 7-point scale ranging from ‘very much improved’ to very much worse’. The 
CGIC will be assessed at the time points outlined in Appendix A. 
6.2 
Safety Parameters 
Safety assessments will consist of monitoring and recording protocol-defined AEs and SAEs; 
vital signs; physical examinations; clinical laboratory assessments; ECGs; pharmacokinetics 
(PK) measurements; and other protocol-specified tests that are deemed critical to the safety 
evaluation of the study drug. 
6.2.1 
Vital Signs 
Vital signs will include measurements of heart rate, sitting blood pressure, respiration rate, 
and temperature. Vital signs will be assessed as outlined in Appendix A and at unscheduled 
study visits when clinically indicated. The subjects’ height and weight will be measured as 
outlined in Appendix A. 
6.2.2 
Physical Examination 
Physical examinations will be performed as outlined in Appendix A and at unscheduled 
study visits when clinically indicated. 


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6.2.3 
Clinical Laboratory Assessments 
Samples for hematology, chemistry, urinalysis, and serum pregnancy testing (when 
necessary) will be collected as outlined in Appendix A and at unscheduled study visits when 
clinically indicated, and analyzed at a central laboratory unless otherwise specified. Detailed 
instructions regarding sample collection, preparation, and shipment can be found in the 
laboratory manual. Laboratory assessments will include the following: 
• Hematology: hematocrit, hemoglobin, red blood cell count, red blood cell indices, 
platelets, white blood cell count, white blood cell differential (neutrophils, lymphocytes, 
monocytes, basophils, eosinophils) 
• Chemistry: sodium, potassium, chloride, bicarbonate, glucose, blood urea nitrogen, 
creatinine, calcium, phosphorus, magnesium, albumin, ALT, AST, alkaline phosphatase, 
total bilirubin, LDH, uric acid, total protein, lipid panel  
• Pregnancy testing: all females of childbearing potential will have a local urine pregnancy 
test performed. Positive or equivocal urine pregnancy test results will be confirmed by a 
serum pregnancy test analyzed at a central laboratory. A serum pregnancy test will be 
done at Screening. 
• Urinalysis: color, clarity, pH, specific gravity, bilirubin, glucose, ketones, leukocytes, 
nitrite, blood, protein, urobilinogen, microscopic analysis 
• Endocrine: TSH, free T4, cortisol, corticotropin  
• Reproductive endocrinology (for all female subjects under 55 years of age at consent): 
serum FSH, LH, estradiol, progesterone, Anti-Mullerian hormone (AMH)  
 
6.2.4 
Electrocardiogram 
A standard 12-lead ECG will be performed as outlined in Appendix A and at unscheduled 
study visits when clinically indicated.  
6.3 
Pharmacokinetics Measurements 
PK samples will be collected at the time points outlined in Appendix A. The date and time of 
dosing prior to PK sample collection and date and time of PK sample collection will be 
recorded in the eCRF. Detailed instructions regarding PK sample collection, preparation, and 
shipment can be found in the laboratory manual. 
6.4 
Subject Flow Diagram 
The visit schedule and assessments are summarized in Appendix A. The following subject 
flow diagram provides a summary of assessments and decision points for each subject. The 
IVRS/IWRS dosing diary is performed throughout the study and is not confined to scheduled 
visits. Refer to Appendix A for frequency and duration of these assessments. 


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Figure 1 
Subject Flow Diagram 
 
 
6.5 
Study Visits 
The following sections describe the procedures and assessments to be performed at each 
study visit. Details of each procedure and assessment can be found in Sections 6.1, 6.2, and 
6.3. 
Unscheduled visits may be performed as necessary, and may include procedures or 
assessments as deemed necessary by the investigator. 
The IVRS/IWRS dosing diary is performed throughout the Treatment Period and is not 
confined to scheduled visits. Refer to Appendix A for frequency and duration of these 
assessments. 


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6.5.1 
Informed Consent 
Informed consent will occur prior to any protocol-mandated procedures, including the 
stopping of any excluded therapies. This may occur prior to the initial Screening visit. 
6.5.2 
Screening Visit/Period 
Screening assessments may be conducted over a 14-day period prior to the Baseline visit. 
The Screening Period may be extended beyond 14 days if the Medical Monitor requires 
additional follow-up on findings from any of the Screening assessments.  
The following screening procedures are to be performed: 
• Inclusion/exclusion criteria review 
• Cough severity VAS  
• Medical history (including chronic cough history, history of any medications within 
30 days prior to Screening and chronic cough treatments within 1 year prior to Screening) 
• Complete physical examination 
• Vital signs (including height and weight) 
• ECG 
• Spirometry 
• Chest radiograph or CT Thorax (if not done within the past 5 years) 
• Contact IWRS to register subject 
• Laboratory tests 
◦ 
Reproductive endocrine labs for females under 55 years of age at time of consent 
◦ 
Serum pregnancy test for females of childbearing potential 
◦ 
Endocrine 
◦ 
Hematology 
◦ 
Chemistry 
◦ 
Urinalysis 
◦ 
Urine drug screen 
• Schedule the Baseline visit 
 
6.5.3 
Baseline Visit (Day 0) 
At the Baseline visit, the following procedures and assessments are to be performed: 


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• Inclusion/exclusion criteria review  
• Update medical history 
• Cough severity VAS 
• Randomize (via IWRS) subject if all inclusion and exclusion criteria are met 
• Contact IWRS to obtain study drug bottles for Days 1–28 
• Distribute study drug bottles in a lock box for subjects who will NOT return to the 
clinic for the Day 1 visit.  
• HOLD the study drug bottles AT THE CLINIC for subjects who will return to 
clinic for the Day 1 visit.  
• Attach and activate the Day 0 cough monitor (preferably before 10 am)  
• Vital signs 
• Urine pregnancy test for females of childbearing potential 
• LCQ 
• Record all concomitant medication use  
• Schedule Day 1 visit at clinic or at subject’s home 
• Schedule Day 28 visit at clinic. 
 
6.5.4 
Day 1 Visit 
At least 24 hours after the cough monitor had been attached (preferably before 10 am), the 
following activities will be performed by clinic staff or a mobile research nurse will visit the 
subject to: 


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• Measure vital signs (sitting systolic and diastolic blood pressure, pulse, respiration rate, 
temperature)  
• Collect the Baseline cough monitor 
• Distribute study drug Days 1–28 bottles for subjects who have returned to the clinic 
for the Day 1 visit 
• Administer the first dose of study drug (before 10am) 
• Conduct IVRS/IWRS training for dosing diary and instruct subjects to complete each day  
• Record all AEs 
• Record all concomitant medication use 
• Remind subject about Day 28 visit at clinic 
 
6.5.5 
Day 14 Visit (Telephone Visit) 
The following evaluations will be performed by telephone on Day 14 (± 3 days): 
• Review IVRS/IWRS Days 1-13 dosing diary entries 
• Instruct subjects to continue recording IVRS/IWRS dosing diary entries for Days 14–28 
• Record all AEs 
• Record all concomitant medication use  
 
6.5.6 
Day 28 Visit 
The following procedures and evaluations will be performed at the clinic on Day 28 
(± 3 days): 
• Cough severity VAS 
• LCQ 
• PGIC 
• Vital signs 
• Weight 
• ECG (12-lead) 
• PK sample  


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• Study drug dosing 
◦ 
Observe AM dose (before 10 am) 
• Attach and activate Day 28 cough monitor (AFTER DOSING) 
◦ 
Cough monitor will be collected the following day by a courier service and 
delivered to the clinic 
• Laboratory tests  
◦ 
Hematology 
◦ 
Chemistry 
◦ 
Urinalysis 
◦ 
Urine pregnancy test for females of childbearing potential 
◦ 
Urine drug screen 
• Study Drug 
◦ 
Collect/perform accountability for Days 1–28 bottles  
◦ 
Contact IWRS to obtain study drug bottles for Days 29–56 and dispense to 
subject 
• Review IVRS/IWRS Days 1-28 dosing diary entries 
• Instruct subjects to continue recording IVRS/IWRS dosing diary entries for Days 29–56  
• Record all AEs 
• Record all concomitant medication use  
• Schedule Day 56 visit at clinic 
 
6.5.7 
Day 56 Visit 
The following procedures and evaluations will be performed at the clinic on Day 56 
(± 3 days): 
• Cough severity VAS 
• LCQ 
• PGIC 
• Vital signs  
• Weight 
• ECG (12-lead) 


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• PK sample  
• Study drug dosing 
◦ 
Observe AM dose (before 10 am) 
• Attach and activate Day 56 cough monitor (AFTER DOSING) 
◦ 
Cough monitor will be collected the following day by a courier service and 
delivered to the clinic 
• Laboratory tests 
◦ 
Hematology 
◦ 
Chemistry 
◦ 
Urinalysis 
◦ 
Urine pregnancy test for females of childbearing potential 
◦ 
Urine drug screen 
• Study drug 
◦ 
Collect/perform accountability for Days 29–56 bottles  
◦ 
Contact IWRS to obtain study drug bottles for Days 57–84 and dispense to 
subject  
• Review IVRS/IWRS Days 29–56 dosing diary entries 
• Instruct subjects to continue recording IVRS/IWRS dosing diary entries for Days 57–84 
• Record all AEs 
• Record all concomitant medication use  
• Schedule Day 84 visit at clinic 
 
6.5.8 
Day 84 Visit 
The following procedures and evaluations may be performed at the clinic or at the subject’s 
home by the mobile research nurse on Day 84 (± 3 days): 
• Cough severity VAS 
• Vital signs  
• Study drug dosing 
◦ 
Observe AM dose (before 10 am) 
• Attach and activate Day 84 cough monitor (AFTER DOSING) 


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• Study Drug - collect/perform accountability for Days 57–84 bottles  
• Review IVRS/IWRS Days 57–84 dosing diary entries 
• Record all AEs 
• Record all concomitant medication use 
• Remind subject about Day 85 Visit at clinic 
 
6.5.9 
Day 85/Early Treatment Discontinuation Visit 
The following procedures and evaluations will be performed at the clinic on Day 85 or within 
7 days of the last dose of study drug for subjects who discontinue study drug treatment early.  
At this visit, the following procedures and assessments are to be performed:  
• Cough severity VAS 
• PGIC 
• LCQ 
• Vital signs  
• Weight 
• Collect Day 84 cough monitor  
• Complete physical exam  
• ECG (12 lead) 
• Laboratory tests 
◦ 
Reproductive endocrine labs for females under 55 years of age at time of consent 
◦ 
Endocrine 
◦ 
Hematology 
◦ 
Chemistry 
◦ 
Urinalysis 
◦ 
Urine pregnancy test for females of childbearing potential 
◦ 
Urine drug screen 
• Contact IWRS to register Day 85 end of treatment visit 
• Review IVRS/IWRS Days 57–84 dosing diary entries 
• The following will be completed by the Investigator (MD or DO): 


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◦ 
CGIC 
◦ 
Study drug - collect/perform accountability for Days 57–84 bottles (early 
treatment discontinuation visit only) 
◦ 
Record all AEs 
◦ 
Record all concomitant medication use  
◦ 
Schedule Day 112 visit at clinic or at subject’s home 
◦ 
Schedule Day 113 visit at clinic 
 
6.5.10 
Day 112 Follow-up Visit 
Subjects will return to the clinic or be visited by a mobile research nurse on Day 112 
(± 3 days) for the following procedures and evaluations: 
• Cough severity VAS 
• Record all AEs 
• Record all concomitant medication use 
• Attach and activate cough monitor 
◦ 
Cough monitor will be collected the following day by a courier service and 
delivered to the clinic  
• Contact IWRS to register the Day 112 Follow-up visit 
• Remind subject about Day 113 visit at clinic 
 
6.5.11 
Day 113 Follow-up Visit 
Subjects will return to the clinic on Day 113 for the following procedures and evaluations: 
• Vital signs  
• Collect Day 112 cough monitor  
• Cough severity VAS 
• LCQ 
• Contact IWRS to register the Day 113 Follow-up visit 
• Complete physical exam  
• ECG (12-lead) 


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• Laboratory tests 
◦ 
Reproductive endocrine labs for females under 55 years of age at time of consent 
◦ 
Endocrine 
◦ 
Hematology 
◦ 
Chemistry 
◦ 
Urinalysis 
◦ 
Urine pregnancy test for females of childbearing potential 
◦ 
Urine drug screen 
• Record all AEs  
• Record all concomitant medication use 
 
6.6 
Early Termination 
Early termination from the study may occur due to loss to follow-up or withdrawal of 
consent by the subject. In accordance with legal requirements and International Conference 
on Harmonisation (ICH) – Good Clinical Practice (GCP) guidelines, every subject or his/her 
legal representative has the right to withdraw from the study at any time and without 
providing reasons. If a subject is willing to provide a reason for withdrawal, this will be 
recorded in the electronic Case Report Form (eCRF). 
7 
ASSESSMENT OF SAFETY 
7.1 
Definitions 
7.1.1 
Adverse Event 
An AE is any untoward medical occurrence associated with the use of a drug in humans, 
whether or not considered drug related. An AE can be any unfavorable and unintended sign 
(e.g. an abnormal laboratory finding), symptom, or disease temporally associated with the 
use of a drug, without any judgment about causality. 
AEs include exacerbations of pre-existing illnesses and AEs that occur as a result of 
protocol-mandated interventions. 
7.1.2 
Serious Adverse Event  
An SAE is considered “serious” if it results in any of the following outcomes: 
• Death 


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• Life-threatening AE (i.e. the subject was at immediate risk of death from the event as it 
occurred. An event that might have led to death if it had occurred with greater severity is 
not “life-threatening”) 
• Inpatient hospitalization or prolongation of existing hospitalization  
• Persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
• Congenital anomaly/ birth defect 
• Important medical event (i.e. an event that may not result in death, be life-threatening, or 
require hospitalization, but which may be considered serious by the investigator or 
Sponsor, as it may jeopardize the subject and may require medical/surgical intervention 
to prevent one of the outcomes listed above). Examples of such medical events include 
allergic bronchospasm requiring intensive treatment in an emergency room or at home, 
blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse. 
 
The following are not considered SAEs: a visit to the emergency room or other hospital 
department < 24 hours that does not result in admission (unless considered an important 
medical or life-threatening event), an elective surgery planned prior to signing consent, 
admission as per protocol for planned medical/surgical procedure, and/or routine health 
assessments requiring admission for baseline/trending of health status (e.g. routine 
colonoscopy). 
The terms “severe” and “serious” are not synonymous. Severity refers to the intensity of an 
AE (e.g. mild, moderate, or severe pain); the event itself may be of minor medical 
significance (e.g. severe back pain). “Serious” is a regulatory definition, as defined above. 
Seriousness (not severity) serves as the basis for defining regulatory reporting obligations.  
Severity and seriousness should be independently assessed when recording AEs and SAEs on 
the eCRF. 
7.1.3 
Abnormal Physical Exam, Laboratory, Vital Sign, and Electrocardiogram 
Findings  
Abnormal physical exam findings that are clinically significant and are identified prior to the 
first dose of study drug should be recorded as medical history. New or worsening clinically 
significant abnormal physical exam findings identified after the first dose of study drug 
should be recorded as AEs.  
Only abnormal laboratory, vital sign, and ECG findings that are considered clinically 
significant by the investigator (e.g. require active management or are associated with 
accompanying symptoms/signs) will be recorded as medical history or AEs on the eCRF. 
Abnormal laboratory, vital sign, and ECG findings that occur prior to the first dose of study 


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drug should be recorded as medical history, and abnormal findings that occur after the first 
dose of study drug should be recorded as AEs. 
If the clinically significant laboratory, vital sign, or ECG abnormality is a sign associated 
with a confirmed disease or condition (e.g. elevated creatinine in a subject diagnosed with 
chronic kidney disease), only the diagnosis (chronic kidney disease) needs to be recorded on 
the AE eCRF.  
Separate instances of the same clinically significant laboratory, vital sign, or ECG 
abnormality across visits should not be recorded as separate AEs or SAEs. 
7.1.4 
Deaths  
Any deaths that occur from the time of informed consent to the follow-up visit, regardless of 
attribution, must be reported within 24 hours of investigator’s awareness of the death. See 
SAE and Pregnancy Form Completion Guidelines for complete instructions. 
The Sponsor should be provided a copy of any post-mortem findings and/or relevant medical 
reports, including histopathology. 
7.1.5 
Pregnancies and Contraception Requirements 
For the purposes of this study, a female of childbearing potential is defined as any female 
who has experienced menarche and is pre-menopausal; a postmenopausal state is defined as 
no menses for 12 months without an alternative medical cause in a previously menstruating 
female.  
For the purposes of this study, acceptable contraception is defined below based on 
Nonclinical Safety Studies for the Conduct of Human Clinical Trials and Marketing 
Authorization for Pharmaceuticals: ICH M3(R2) dated January 2010, and other available 
guidelines (“U.S. Medical Eligibility Criteria for Contraceptive Use, 2010” 2010; 
“Recommendations related to contraception and pregnancy testing in clinical trials” 2014; 
“M3(R2) Nonclinical Safety Studies for the Conduct of Human Clinical Trials and Marketing 
Authorization for Pharmaceuticals” 2010): 
a) All female subjects of childbearing potential must use highly effective contraception, 
which includes the use of one or more of the following acceptable methods:  
i. 
Surgical sterilization (e.g., bilateral tubal occlusion or ligation, hysterectomy, 
bilateral salpingectomy, bilateral oophorectomy) 
ii. 
Total (as opposed to periodic or cyclic) abstinence 
iii. 
Hormonal contraception associated with consistent inhibition of ovulation; 
these may include (but are not necessarily limited to) oral, intravaginal, 
implantable, injectable, or transdermal delivery methods.  
i. Progesterone only oral contraceptives are excluded as a highly 
effective method, as they do not consistently inhibit ovulation. 
iv. 
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v. 
Exclusive monogamous heterosexual intercourse with a sterilized (i.e., 
vasectomized) or otherwise non-fertile (e.g., castrated) male partner  
 
Any pregnancy occurring in a female subject or the female partner of a male subject, from 
the first study drug administration through the 4-week follow-up visit must be reported 
within 24 hours of the investigator’s awareness of the pregnancy. See SAE and Pregnancy 
Form Report Completion Guidelines for complete instructions.  
The investigator will follow the pregnancy to delivery or other pregnancy outcome.  
Pregnancy in a female clinical trial subject or female partner of a male clinical trial subject is 
not an SAE per se. Complications of such pregnancies (for example, spontaneous abortion) 
may qualify as SAEs and should be reported as such even if they occur after the Follow-up 
visit. Any congenital anomalies/birth defects must be recorded and reported as SAEs. See 
SAE and Pregnancy Form Report Completion Guidelines for complete instructions.  
7.2 
Methods and Timing for Recording and Reporting Adverse Events 
7.2.1 
Adverse Event Reporting Period 
Any AE occurrence during the study must be recorded on source documentation and eCRF at 
the site, in accordance with protocol instructions.  
AEs and SAEs will be recorded from the first study drug administration through the 
follow-up visit. After the 4-week follow-up visit, only SAEs that are believed to be drug-
related should be reported. 
After informed consent but prior to initiation of study drug, only SAEs considered by the 
investigator to be caused by a protocol-mandated intervention will be collected (e.g. SAEs 
related to invasive procedures such as blood collection). These procedure-related SAEs 
should only be reported on the SAE form, not on the AE form of the eCRF. Subjects who 
undergo screening procedures but are not randomized into the study will not have SAEs 
recorded in the clinical database. 
7.2.2 
Eliciting Adverse Events 
Investigators will seek information on AEs and SAEs at each subject contact through the 
follow-up visit. All AEs and SAEs, whether reported by the subject or noted by authorized 
study personnel, will be recorded in the subject’s medical record and on the AE eCRF page, 
and, if serious, on the SAE form. For each AE and SAE recorded, the investigator will make 
an assessment of seriousness, severity, and causality. 
7.2.3 
Assessment of Severity 
All AEs entered into the eCRF will be graded for severity using the National Cancer Institute 
Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.03 


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(“Common Terminology Criteria for Adverse Events (CTCAE)” 2010) to describe the 
maximum intensity of the AE.  
If the AE cannot be found in the event-specific NCI CTCAE grading criteria, the investigator 
should use the definitions for Grade 1, 2, 3, and 4 in Table 1. 
Table 1 
Adverse Event Grading 
Grade 
Severity 
Alternate Descriptiona 
1 
Mild (apply event-specific NCI 
CTCAE grading criteria) 
Asymptomatic or mild symptoms; clinical or 
diagnostic observations only; intervention not 
indicated. 
2 
Moderate (apply event-specific NCI 
CTCAE grading criteria) 
Minimal, local or noninvasive intervention 
indicated; limiting age-appropriate 
instrumentation activities of daily living 
(ADL)b 
3 
Severe (apply event-specific NCI 
CTCAE grading criteria) 
Severe or medically significant but not 
immediately life-threatening; hospitalization 
or prolongation of hospitalization indicated; 
disabling; limiting self care ADLc 
4 
Very severe, life threatening, or 
disabling (apply event-specific NCI 
CTCAE grading criteria) 
Life-threatening consequences; urgent 
intervention indicated. 
5 
Death related to AE 
 
aUse these alternative definitions for Grade 1, 2, 3, and 4 events when the observed or reported AE is not in 
the NCI CTCAE listing. A semi-colon indicates ‘or’ within the alternate description of the grade. 
bInstrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, 
managing money, etc. 
cSelf care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, 
and not bedridden. 
Source: National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.03 
(“Common Terminology Criteria for Adverse Events (CTCAE)” 2010) 
 
Note that severity, a measure of intensity, is not equivalent to seriousness, a regulatory 
definition of outcome. Regardless of severity, some AEs may meet the criteria for 
seriousness. See Section 7.1.2 for the definition of an SAE. 
If an adverse event changes in severity during the same study period (e.g., treatment period), 
only the highest severity grade will be recorded on the eCRF. 
7.2.4 
Assessment of Causality 
The investigator’s assessment of causality must be provided for all AEs (serious and 
non-serious). An investigator’s causality assessment is the determination of whether there 
exists a reasonable possibility that the investigational product caused or contributed to an AE. 
Causality of an AE will be assessed by the investigator using the following terms: 


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• Likely Related: A reaction that follows a reasonable temporal sequence from 
administration of the study drug; that follows a known or expected response pattern to the 
suspected study drug; and for which other potential etiologies are considered less likely 
factors than the study drug. 
• Likely Unrelated: A reaction that, considering all potential etiologies, is most likely due 
to factors other than the study drug. 
 
7.3 
Follow-up of Adverse Events and Serious Adverse Events 
The investigator must make every effort to follow all AEs and SAEs regardless of attribution 
until judged resolved or stabilized, the subject is lost to follow-up, or it has been determined 
that study drug treatment or participation in the study is not the cause of the AE or SAE. 
7.4 
Reporting Serious Adverse Events to the Sponsor and Institutional 
Review Board or Ethics Committee  
The Sponsor or designee is under obligation to report certain SAEs to regulatory authorities 
related to investigational drugs in clinical trials. The Sponsor or designee must be notified 
within 24 hours of an AE when the investigator determines that an AE meets the protocol 
definition of an SAE, regardless of the cause or relationship to study drug.  
An SAE related to study participation occurring before study drug administration and after 
informed consent should be promptly reported to the Sponsor. If the investigator learns of 
any SAE at any time after a participant has been discharged from the study, and the SAE is 
considered likely related to study drug, the SAE should be promptly reported to the Sponsor. 
Please see the SAE and Pregnancy Form Report Completion Guidelines for safety reporting 
instructions.  
The investigator must also comply with applicable requirements concerning reporting of 
SAEs to the Institutional Review Board (IRB) or Ethics Committee (EC). This may include 
initial or follow-up notification of an SAE or other safety information. 
7.5 
Reporting Serious Adverse Events to Regulatory Authorities and Study 
Investigators 
The Sponsor, or its designee, is responsible for submitting reports of serious, unexpected 
related AEs to regulatory authorities on an expedited basis, according to the ICH E2A 
Guideline and to other regulatory authorities according to national and local regulations as 
required. The Sponsor, or its designee, is responsible for prompt submission to the IRB or EC 
of any expedited SAE reports submitted to regulatory authorities. All investigators 
participating in ongoing clinical studies with serlopitant will receive copies of the SAE 
reports submitted on an expedited basis to regulatory authorities. 


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7.6 
Emergency Unblinding 
Emergency unblinding is available 24 hours per day/7 days per week and will be performed 
via IWRS. An Investigator may unblind a subject’s treatment assignment only when 
knowledge of the investigational product is essential for the welfare of a subject. There is no 
specific antidote for serlopitant and usual supportive medical management is recommended 
in the case of a medical emergency. 
8 
STATISTICAL METHODS  
Endpoints will be summarized with descriptive statistics by treatment group and visit. For 
continuous variables, the following information will be presented: n, mean, standard 
deviation, median, minimum and maximum. For categorical variables counts and percentages 
will be used. 
Baseline for all measures will be the last recorded value prior to the start of treatment. 
8.1 
Decision Rule and Sample Size  
The comparisons related to the primary and key secondary endpoints will be done in a 
hierarchical manner to control the familywise error rate. The testing procedure will start by 
testing the primary endpoint and then proceed to the key secondary endpoints by following 
the order as specified in Section 8.9.4.  
A total of 170 subjects (85/arm) in 1:1 ratio to serlopitant 5 mg or placebo will provide 90% 
power to detect a 25% relative reduction (placebo-adjusted ratio of 0.75) in 24-hour objective 
cough frequency or awake objective cough frequency using a two-sample t-test at a 
one-sided significance level of 0.05. This assumes that 24-hour cough frequency or awake 
cough frequency follows a log-normal distribution with a CV of 0.64. This sample size also 
considers an expected dropout rate of 15%. 
The sample size calculations have been performed in nQuery Advisor + nTerim.  
8.2 
Handling of Missing Data and Excluded Therapy Use 
For summary statistics results will generally be reported based upon observed data. Should a 
determination of treatment period (on treatment, pre-treatment) be required for AEs or 
concomitant medication but the corresponding date is missing, or is a partial date, the 
event/medication will be considered on treatment unless the portions of the date that are 
available indicate this is not possible. 
In case of missing data for the primary efficacy endpoint, two selected imputation approaches 
are specified for the sensitivity analyses (Section 8.9.2.1). All other efficacy endpoints, 
analysis will be conducted based on the observed data only. 
8.3 
Derivations of Efficacy Variables 
The 24-hour cough frequency (coughs per hour) for a specified visit is calculated as: 


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24-hour cough frequency = (total number of cough events during the monitoring period 
(24-hour interval))/24  
The awake cough frequency (coughs per hour) is defined as below: 
Awake cough frequency = (total number of cough events during the monitoring period 
(24-hour interval) the subject is awake)/(Total duration (in hours) for the monitoring period 
the subject is awake) 
Awake duration (hours) is time between waking up and sleep during the 24-hour monitoring 
period.  
The cough data will contain all cough events occurring during that 24-hour monitoring 
period as well as the information about “sleep time” and “awake time”. Any session with 
duration of recording < 4 hours will be considered as missing. 
In general, each 24-hour session is composed by an awake monitoring period and a sleep 
monitoring period. If a subject did not wake up before the end of the recording session, it will 
be assumed that the subject slept for the rest of the session. The session will have missing 
awake time, and the rest of session will be considered under the sleep monitoring period. For 
any session with both sleep time and awake time missing, the entire 24-hour session will be 
considered under the awake monitoring period, unless the session has early termination of 
recording.  
On each collection day, the cough count, the actual cough monitoring duration (in hours), 
and the coughs per hour will be derived for the total 24-hour period, the awake period, and 
the sleep period, respectively. 
The percent change in 24-hour coughs per hour is defined as below: 
Percent change in 24-hour cough frequency =  
[(Change from baseline in 24-hour cough frequency×100)/(Baseline 24-hour cough 
frequency)] 
The proportion of participants with ≥ 30% of reduction from baseline in 24-hour cough 
frequency is the number of participants with ≤-30% change in 24-hour cough frequency 
divided by the total number of participants with available data. 
8.4 
Analysis Populations  
The FAS will serve as the primary population for the analysis of efficacy data in this study. 
The FAS consists of all randomized subjects who have taken at least one dose of study 
medication and provided at least one baseline and at least one post-baseline primary endpoint 
observation during the treatment period. Subjects will be analyzed according to the treatment 
group to which they are randomized.  


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The safety analysis set will be used for the analysis of safety data in this study. The safety 
analysis set will consist of all subjects randomized who receive at least one dose of study 
medication. Subjects will be classified based upon the treatment received. For safety 
analyses, subjects will be classified based upon the treatment received.  
The PK analysis set will consist of all subjects who receive ≥ 1 dose of serlopitant and who 
have at least 1 post-dose PK blood sample available for analysis. 
8.5 
Subject Disposition  
An accounting of all randomized subjects by disposition will be presented. Subjects who 
discontinue study drug prematurely or withdraw from the study will be summarized and 
listed, with a description of the reason for early termination/withdrawal. 
8.6 
Subject Characteristics  
Demographic and other baseline characteristics will be summarized. Duration of chronic 
cough (years) will be derived as year of informed consent minus year of start date of the 
chronic cough medical history. 
8.7 
Concomitant Medications  
Concomitant medications will be coded by the World Health Organization (WHO) Drug 
Dictionary to Anatomical Therapeutic Classification (ATC) and preferred drug name. 
Concomitant medications will be summarized by ATC level and preferred drug name and 
listed. 
8.8 
Treatment Compliance and Extent of Exposure  
Percent compliance will be calculated for each subject as below: 
%
100
Therapy
on 
 
Be
 
Should
  
Days
 
of
Number 
Therapy
on 
 
Days
 
of
Number 
 
 
Compliance
Percent 
×
=
 
 
A day within the study will be considered an “On-Therapy” day if the participant takes all 
required medication. If a subject misses a daily dose, that day is not considered an 
On-Therapy day.  
The duration of exposure for each participant will be evaluated by calculating the number of 
days on therapy.  
Percent compliance and duration of exposure to study medication will be summarized using 
descriptive statistics (mean, SD, median, minimum, and maximum) for the safety analysis 
set. 


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8.9 
Efficacy Analyses  
8.9.1 
Statistical Hypotheses and Tests 
The study is designed to evaluate, the efficacy of serlopitant 5 mg relative to placebo. The 
primary hypothesis for this trial is that serlopitant is superior to placebo with respect to the 
mean change from baseline in 24-hour cough frequency (on the log scale).  
Symbolically, the hypotheses for serlopitant 5 mg compared to placebo can be written as: 
H0: µSP,Week 12 - µSP,Baseline = µPL,Week12 - µPL,Baseline 
HA: µSP,Week 12 - µSP,Baseline < µPL,Week 12 - µPL,Baseline 
where µSP and µPL represent the mean values at Week 12 for serlopitant 5 mg and placebo, 
respectively.  
As the primary endpoint, cough frequency, is to be analyzed on the log scale the null 
hypothesis relates to the ratio of Week 12/Baseline for serlopitant 5 mg being the same as 
that for placebo, and the alternative hypothesis being that the ratio of Week 12/Baseline for 
serlopitant 5 mg is smaller than the ratio for placebo. 
A family wise error rate will be controlled to adjust for multiplicity for the comparison of 
serlopitant 5 mg to placebo on the primary and key efficacy endpoints in a hierarchical 
manner (see details in Section 8.9.4). 
8.9.2 
Primary Endpoint 
The primary efficacy endpoint of this study is change from baseline in 24-hour objective 
cough frequency at each dose studied after 12 weeks of treatment. A negative result indicates 
a decrease in cough frequency, while a positive result indicates an increase in cough 
frequency. 
As the change in 24-hour cough frequency may have a skewed and wide distribution, the 
primary analysis for the primary endpoint will be on the natural log scale of the cough 
frequency data. The difference between serlopitant 5 mg and placebo will be estimated using 
a mixed effect repeated measures (MMRM) model. The model will include factors for 
treatment, visit, country, sex, the treatment-by-visit interaction; and the log-transformed 
baseline value as a covariate. The MMRM model will use all available 24-hour cough 
frequency data on Day 28, 56, and 84. An unstructured covariance structure will be applied 
for MMRM. In case the model will not converge with the unstructured covariance structure, 
the heterogeneous compound symmetry (CSH) will be used instead. Contrasts will be 
constructed to compare the serlopitant 5 mg group to the placebo group at each visit. 
The least-squares (LS) mean change from baseline (on the log scale) with the associated 
standard errors will be displayed for each treatment group. Estimated treatment differences 
(serlopitant vs. placebo) along with corresponding CIs will also be presented.  
In addition, the geometric mean of 24-hour cough frequency will be presented by treatment 
and by visit. The percent difference change between serlopitant and placebo will be estimated 


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by 100 (ediff - 1), where diff is the difference provided by the analysis of the log-transformed 
variable.  
An observation of zero coughs per hour will be replaced by a cough rate of 0.1/hr for the 
calculation of geometric means. If this rule is used the table will have a footnote detailing the 
participant and treatment. Further details of the model specification, assumptions, and SAS 
implementation codes will be provided in the SAP. 
Furthermore, the changes from baseline in 24-hour cough frequency on the original scale will 
be also analyzed using a the same MMRM model. 
8.9.2.1 
Sensitivity Analysis 
The primary analyses (MMRM) for assessing primary efficacy variable are valid if the 
missing data are missing at random (MAR), meaning that the probability of a value being 
missing, conditional on the observed data and factors in the statistical model, is random and 
not dependent on the unknown value of the missing data point. Therefore, two sensitivity 
analyses under missingness not at random (MNAR) will be conducted for the primary 
efficacy variable to evaluate the robustness of efficacy results and the effect of missing data.  
Sensitivity analysis using a copy-reference multiple-imputation method will be performed to 
assess the robustness of the primary analysis based on MMRM. In this sensitivity analysis, 
intermittent missing values will be imputed using the Markov Chain Monte Carlo (MCMC) 
methodology which assumes a multivariate normal distribution over all variables included in 
the imputation model. This imputation will be done by treatment group, using MI procedure 
in SAS 9.4. This imputation will be done by treatment group. Then all the monotone missing 
values will be multiply-imputed using the imputation model built from the control group, i.e., 
assuming the missing data in the treatment group will have a profile that equals the profile of 
the control group for all time points (i.e., a copy-reference imputation). The missing data 
imputation will be implemented using PROC MI in SAS 9.4 with the MNAR statement. The 
change from baseline values from each of the completed datasets will then be analyzed using 
MMRM to include terms for treatment and baseline. The results will be combined using SAS 
PROC MIANALYZE. It is known that this approach may produce an inflated variance 
estimate for the treatment comparison. To get a correct variance, a pattern mixture model 
approximation method will also be used. Results from both the MIANALYZE and the 
pattern mixture model approximation will be presented as sensitivity analyses.  
An additional sensitivity analysis using the tipping-point approach will be conducted. The 
Variant 3 of the tipping point will be applied (Ratitch 2013). The technical details for the 
sensitivity analyses will be provided in the SAP. 
8.9.3 
Secondary Endpoints 
Key Secondary 
• Change from baseline in awake objective cough frequency after 12 weeks (Day 84) of 
treatment 


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• Proportion of subjects with ≥ 30% reduction in 24-hour objective cough frequency per 
hour at Week 12 
• Proportion of subjects with ≥ 30% reduction in awake objective cough frequency per 
hour at Week 12 
• Change from baseline in Cough Severity Visual Analog Scale (VAS) at Week 12 
 
Other Secondary 
• Change from baseline in 24-hour objective cough frequency after 4 and 8 weeks (Day 28 
and 56) of treatment 
• Change from baseline in awake objective cough frequency after 4 and 8 weeks (Day 28 
and 56) of treatment 
• Change from baseline in 24-hour objective cough frequency at the Follow-Up visit 
(Day 112) 
• Change from baseline in sleep objective cough frequency after 4, 8 and 12 weeks 
(Day 28, 56 and 84) of treatment 
• Change from Baseline in Cough Severity Visual Analog Scale (VAS) at Weeks 4 and 8 
• Change from Baseline in Leicester Cough Questionnaire (LCQ) individual Domain and 
Total scores 
• Patient's Global Impression of Change (PGIC) 
• Clinician's Global Impression of Change (CGIC) 
 
Statistical approaches for analysis of the secondary endpoints will be detailed in the SAP. 
The continuous secondary efficacy endpoints will be analyzed using the same MMRM model 
as used for the primary efficacy analysis.  
The categorical secondary efficacy endpoints will be analyzed using the stratified Miettinen 
and Nurminen (M&N) method, adjusting for gender and country. 


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Table 2 
Analysis Strategy for Primary and Key Secondary Efficacy Endpoints 
Endpoint 
Statistical Method 
Analysis 
Population 
Missing Data 
Approach 
Primary Efficacy Endpoint 
Change from baseline in 24-hour 
objective cough frequency after 
12 weeks (Day 84) of treatment 
MMRM 
FAS 
Observed data 
only 
Reference-based 
imputation & 
Tipping-point 
approach 
Key Secondary Efficacy Endpoints 
Change from baseline in awake 
objective cough frequency after 
12 weeks (Day 84) of treatment 
MMRM  
FAS 
Observed data 
only 
Proportion of participants with ≥ 30% 
reduction in 24-hour objective cough 
frequency after 12 weeks (Day 84) of 
treatment 
Stratified Miettinen 
and Nurminen 
(M&N)  
FAS 
Observed data 
only 
Proportion of participants with ≥ 30% 
reduction in awake objective cough 
frequency after 12 weeks (Day 84) of 
treatment 
Stratified Miettinen 
and Nurminen 
(M&N)  
FAS 
Observed data 
only 
Change from baseline in VAS after 12 
weeks (Day 84) of treatment 
MMRM 
FAS 
Observed data 
only 
MMRM = Mixed Model Repeated Measures; GLMM= Generalized Linear Mixed Model; VAS = Visual 
Analogue Scales; FAS = Full Analysis set; 
 


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8.9.4 
Multiplicity Adjustment 
The study is designed to evaluate the efficacy profile of serlopitant 5 mg versus placebo. The 
sequential testing procedure will be employed to control the overall Type I error rate at 5% 
with respect to multiple comparisons for the primary and key secondary endpoints. The 
procedure will be done in a hierarchical manner. The order of the testing is outlined below.  
1. Primary endpoint: serlopitant 5 mg versus placebo 
2. Key secondary endpoint #1: serlopitant 5 mg versus placebo 
3. Key secondary endpoint #2: serlopitant 5 mg versus placebo 
4. Key secondary endpoint #3: serlopitant 5 mg versus placebo 
5. Key secondary endpoint #4: serlopitant 5 mg versus placebo 
 
First, the test ranked as first will be tested and the difference will be declared statistically 
significant if the one-sided p value is less than 0.05. Second, in case that the difference for 
the first comparison is statistically significant, the comparison ranked as second will be 
tested, and the difference will be declared statistically significant if the one-sided p-value is 
less than 0.05. The testing will continue as long as the previously ranked objective was 
statistically significant.  
All other efficacy variables will be tested at the 0.05 level of significance without 
multiplicity adjustment. 
8.10 
Safety Analyses  
8.10.1 
Adverse Events  
The incidence of all AEs and treatment-related AEs will be tabulated by treatment received. 
These AEs will be classified by system organ class and preferred term using the Medical 
Dictionary for Regulatory Activities (MedDRA). For incidence reporting, if a subject 
reported more than one AE that was coded to the same system organ class or preferred term, 
the subject will be counted only once for that specific system organ class or preferred term. 
An overview of AEs, which includes subject incidence of AEs, treatment-related AEs, AEs 
by severity, SAEs, deaths, and AEs leading to discontinuation, will be presented.  
SAEs will be listed and summarized in a similar manner to AEs. 
8.10.2 
Clinical Safety Laboratory Results  
Clinical safety laboratory values will be measured by a central laboratory. Summary statistics 
for actual values and for changes from baseline will be tabulated for laboratory results by 
scheduled visit. Graphs of laboratory values over time will also be produced.  


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Subjects with clinical laboratory values outside of the normal reference range at any 
post-baseline assessment will be summarized. Shifts from baseline laboratory values will be 
tabulated. 
8.10.3 
Vital Signs  
The observed data and change from baseline for each measurement day will be summarized 
with descriptive statistics.  
8.10.4 
Electrocardiograms  
The overall ECG assessment (abnormal or normal) will be summarized along with a 
summary of how many subjects developed a post treatment abnormal result. The study 
relevance of the finding will be provided in a listing. 
8.11 
Pharmacokinetics Analysis  
The PK data and analysis for serlopitant and metabolites will be reported in a PK report that 
will be a part of the clinical study report. 
9 
ADMINISTRATIVE ASPECTS 
9.1 
Changes to the Protocol 
Protocol amendments must be made only with the prior written approval of the Sponsor. 
An investigator signature will be obtained for the initial protocol and any amendments. 
Substantial amendments will be provided to the appropriate regulatory authorities. No 
protocol changes affecting the following will be made without the written approval of the 
Sponsor and the responsible IRB or EC: 
• Safety and/or eligibility of subjects 
• Data integrity 
• Study design or conduct 
• Willingness of a subject to participate in the study 
 
9.2 
Study Termination 
The Sponsor has the right to terminate this study at any time. Reasons may include, but are 
not limited to, evidence of a potential safety risk in this study or other serlopitant studies or 
poor enrollment. A written statement fully documenting the reasons for study termination 
will be provided to the IRB or EC. 


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9.3 
Monitoring and Auditing Procedures 
The Sponsor will designate study monitors who will be responsible for monitoring the 
conduct of this study. A separate study Monitoring Plan will include details regarding the 
responsibilities of the study monitors, investigator responsibilities in providing access to 
records and addressing issues identified, the frequency and structure of monitoring visits, and 
adherence to subject confidentiality as outlined in the Informed Consent Form (ICF). 
9.4 
Transfer of Obligations 
The Sponsor will delegate certain aspects of study oversight to Contract Research 
Organizations (CROs). The specific responsibilities will be detailed in Transfer of 
Obligations documents.  
9.5 
Informed Consent 
The purpose of the study, the procedures to be carried out, and any potential risks of study 
participation will be described in non-technical terms in the ICF. After having reviewed and 
understood the ICF, subjects will be required to read, sign, and date an IRB-approved or 
EC-approved consent form before any study-specific procedures are carried out. Subjects 
will be assured that they may withdraw from the study at any time without jeopardizing 
medical care related to or required as a result of study participation. The original signed 
consent form will be maintained in the investigator site file. Copies of signed consent form 
will be provided to the subject. 
9.6 
Communication with the Institutional Review Board or Ethics Committee 
The IRB or EC is constituted and operates in accordance with the principles and 
requirements described in the ICH E6 guideline. The protocol, informed consent, other 
written subject information, and any proposed study advertising material must be submitted 
to the IRB or EC for written approval. IRB or EC approval of these documents will be 
provided to the investigator. The study will not start until the IRB or EC has granted its 
approval of the study materials and procedures. 
Protocol amendments will be submitted to the IRB or EC as explained in Section 9.1. SAE 
information will be submitted to the IRB or EC as explained in Section 7.4.  
If the study is terminated by the Sponsor, a written statement fully documenting the reason(s) 
for study termination will be provided to the IRB or EC. 
9.7 
Disclosure and Confidentiality 
By signing this protocol, the investigator agrees to keep all information provided by the 
Sponsor in strict confidence and to require the same confidentiality from site staff and the 
IRB or EC. Study documents provided by the Sponsor (e.g. protocol, IB, eCRFs) will be 
stored appropriately to ensure their confidentiality. The information provided by the Sponsor 
to the investigator may not be disclosed to others without direct written authorization from 


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the Sponsor, except to the extent necessary to obtain informed consent from subjects who 
wish to participate in the study.  
The investigator must ensure that the subjects be identified by a unique subject study 
number. Other study-related documents that may contain confidential participant information 
(e.g. signed ICFs) will be kept in strict confidence by the investigator and be stored in a 
secure location with access restricted to the study staff. 
9.8 
Records and Electronic Case Report Forms 
All study data except central laboratory, PK, IWRS diary, cough counts, and ECG data will 
be recorded in an eCRF system. Data will be entered at the site by the appropriately 
designated and trained site personnel. All source documents from which eCRF entries are 
derived should be placed in the subject’s medical records. eCRFs will be completed for every 
subject screened in the study. 
The study monitor will review all eCRFs in detail and will have access to participant medical 
records, laboratory data, and other source documentation to allow required eCRF fields to be 
verified by source data. 
Data consistency and plausibility checks against data entered into the eCRF will be included 
in the eCRF system. Data corrections can be performed in the eCRFs by the site. For each 
instance of data modification, the system requires a reason for change. The system keeps a 
full audit trail of the data values, the date and time of modification, and the electronic 
signature of the user who performed the change. 
After a full review of the eCRFs by the study monitor and resolution of any data 
clarifications, the investigator will review, sign, and approve the subject’s eCRF. All 
essential documents, source data, clinical records, and laboratory data will be retained by the 
site in accordance with the ICH E6 guideline and the site’s data retention policies. These 
records must be available for inspection by the Sponsor, monitor, and regulatory authorities. 
Further detail regarding data management and eCRFs is included in the Data Management 
Plan. 
9.9 
Good Clinical Practices and Ethical Study Conduct 
The study procedures outlined in this protocol will be conducted in accordance with 
applicable ICH Guidelines, including ICH E6: Good Clinical Practices. As this study is 
conducted under a US IND, the investigator will also ensure that the basic principles of 
“Good Clinical Practice”, as outlined in 21 CFR 312, subpart D, “Responsibilities of 
Sponsors and Investigators”, 21 CFR, part 50 and 21 CFR, part 56 are adhered to. 
The study procedures outlined in this protocol will also be conducted in accordance with the 
principles of the Declaration of Helsinki, and other regulations applicable in the UK. 


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9.10 
End of Study Notification 
The Sponsor will notify appropriate regulatory authorities and the IRB or EC within 90 days 
from the end of the clinical study. The end of the clinical study is defined as the last study 
visit for the last subject globally. 
9.11 
Publication of Results 
All publications (e.g. manuscripts, abstracts, oral/slide presentations, book chapters) based on 
this study or relying on data from this study must be submitted to the Sponsor for review and 
release before submission for publication. The Sponsor is responsible for final approval of all 
publications. 
9.12 
Final Report 
A clinical trial summary report will be provided to the appropriate regulatory authorities 
within one year of the end of the clinical study. 


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10 
REFERENCES 
Abdulqawi R, Dockry R, Holt K, Layton G, McCarthy B, Ford A, Smith J. P2X3 Receptor 
Antagonist (AF-219) in Refractory Chronic Cough: A Randomised, Double-Blind, 
Placebo-Controlled Phase 2 Study. Lancet. 2015;28;385(9974):1198-205. 
Birring S, Prudon B, Carr A, et al. Development of a Symptom Specific Health Status 
Measure for Patients with Chronic Cough: Leicester Cough Questionnaire (LCQ). 
Thorax. 2003;58:339-343. 
Canning BJ. Central regulation of the cough reflex: therapeutic implications. 
Pulm Pharmacol Ther. 2009;22(2):75-81. 
Common Terminology Criteria for Adverse Events (CTCAE). 4.03 ed: National Institutes of 
Health; 2010. 
Dicpinigaitis P. Cough: An Unmet Clinical Need. Br J Pharmacol. 2011;163:116-124.  
Dicpinigaitis P, Morice A, Birring S, et al. Antitussive drugs—past, present and future. 
Pharmacol Rev. 2014;66(2):468-512.  
Examples of clinical inhibitors for P450-mediated metabolisms (for concomitant use clinical 
DDI studies and/or drug labeling) (9/26/2016). U.S. Food and Drug Administration; 
2016. 
Gibson P, Wang G, McGarvey L, et al. Treatment of Unexplained Chronic Cough: CHEST 
Guideline and Expert Panel Report. Chest. 2016;149(1):27-44. 
Grobman M, Reinero C. Investigation of Neurokinin-1 Receptor Antagonism as a Novel 
Treatment for Chronic Bronchitis in Dogs. J Vet Intern Med. 2016;30:847-852.  
Harle A. Aprepitant Decreases Cough in Patients with Lung Cancer. Palliative Care in 
Oncology Symposium (PCOS). 2015: Abstract 2.  
Irwin R, Baumann M, Bolser D, et al. Diagnosis and Management of Cough Executive 
Summary: ACCP Evidence-Based Clinical Practice Guidelines. Chest. 2006:129(1 
Suppl):1S-23S. 
Kelsall A, Decalmer S, Webster D, Brown N, McGuinness K, Woodcock A, Smith J. How to 
Quantify Coughing: Correlations with Quality of Life in Chronic Cough. Eur Respir 
J. 2008;32: 1–5. 
LaVinka P, Dong X. Molecular Signaling and Targets from Itch: Lessons for Cough. Cough. 
2013;9:8.  
Mazzone S, Mori N, Canning B. Synergistic Interactions Between Airway Afferent Nerve 
Subtypes Regulating the Cough Reflex in Guinea-Pigs. J Physiol. 569.2. 2005;559-
573.  


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Mazzone S, McGovern A. Sensory Neural Targets for the Treatment of Cough. Clin Exp 
Pharmacol Physiol. 2007;34:955-962.  
M3(R2) Nonclinical Safety Studies for the Conduct of Human Clinical Trials and Marketing 
Authorization for Pharmaceuticals. Food and Drug Administration; 2010. 
Ratitch B, O’Kelly M, Tosiello R. Missing Data in Clinical Trials: From Clinical 
Assumptions to Statistical Analysis Using Pattern Mixture Models. Pharm Stat. 
2013;12:337-347. 
Recommendations related to contraception and pregnancy testing in clinical trials. Clinical 
Trial Facilitation Group; 2014. 
Ryan N, Birring S, Gibson P. Gabapentin for Refractory Chronic Cough: A Randomised, 
Double-Blind, Placebo-Controlled Trial. Lancet. 2012;380:1583-89.  
Smith J, Allman D, Badri H, et al. The Neurokinin-1 Receptor Antagonist Orvepitant Is a 
Novel Anti-Tussive Therapy for Chronic Refractory Cough: Results from a Phase 2 
Study (VOLCANO-1). Am J Respir Crit Care Med. 2017;195:A2672.  
U.S. Medical Eligibility Criteria for Contraceptive Use, 2010. Vol 20172010. 


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APPENDIX A 
SCHEDULE OF ACTIVITIES AND ASSESSMENTS 
Table 3 
Schedule of Visit Activities 
Study Procedures 
Screening 
Baseline 
Treatment Period 
Follow-up 
 
Day –14 to Day –1a,b 
Day 0 
Day 1h 
Day 14k,o 
Day 28k 
Day 56k 
 Day 84h,k 
Day 85/ETD 
Day 112h,k 
Day 113 
Written Informed Consentn 
X 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
X 
 
 
 
 
 
 
 
 
Demographics; Medical & 
Medication History 
X 
X 
 
 
 
 
 
 
 
 
Chest Radiograph or CT Thoraxl 
X 
 
 
 
 
 
 
 
 
 
Physical Examination 
X 
 
 
 
 
 
 
X 
 
X 
Vital Signs 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
Height & Weight 
X 
 
 
 
Xm 
Xm 
 
Xm 
 
 
ECG (12-lead) 
X 
 
 
 
X 
X 
 
X 
 
X 
Spirometry 
X 
 
 
 
 
 
 
 
 
 
Clinical Laboratory Sampling 
X 
 
 
 
Xp 
Xp 
 
X 
 
X 
Urinalysis 
X 
 
 
 
X 
X 
 
X 
 
X 
Urine Drug Screen 
X 
 
 
 
X 
X 
 
X 
 
X 
Serum Pregnancy Test  
X 
 
 
 
 
 
 
 
 
 
Urine Pregnancy Test 
 
X 
 
 
X 
X 
 
X 
 
X 
PK Sample 
 
 
 
 
X 
X 
 
 
 
 
Attach Cough Monitor 
 
Xg 
 
 
Xg 
Xg 
Xf,g 
 
Xf,g 
 
Collect Cough Monitor 
 
 
Xf 
 
Xj 
Xj 
 
X 
 
X 
Adverse Event Monitoring 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
LCQ 
 
X 
 
 
X 
X 
 
X 
 
X 
Dosing Diary 
 
 
Daily during treatment period 
 
 
 
Cough Severity VAS 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
Study Drug Distribution and/or 
Accountability 
 
Xe 
Xc,i 
 
X 
X 
X 
Xq 
 
 
Review Dosing Diary Entries 
 
 
X 
X 
X 
X 
X 
X 
 
 
PGIC 
 
 
 
 
X 
X 
 
X 
 
 
CGIC 
 
 
 
 
 
 
 
X 
 
 
Abbreviations: CGIC – Clinician’s Global Impression of Change; ECG – electrocardiogram; ETD – early treatment discontinuation; 
LCQ – Leicester Cough Questionnaire; PGIC – Patient’s Global Impression of Change; VAS – visual analog scale. 
a 
Multiple clinic visits may be required to complete all screening assessments. 
b 
The Screening Period may be extended beyond 14 days if the Medical Monitor requires additional follow-up on findings from any of the Screening assessments.  


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c 
First dose of study drug administered on Study Day 1 after the cough monitor is removed and before 10am.  
d 
To be completed daily during Screening 
e 
Study drug is dispensed in a lockbox if subjects do not return to the clinic for Day 1.  
f 
May be managed by mobile research nurses. 
g 
Cough monitor should be attached before 10am and worn for 24 hours during each assessment. 
h 
Visits may be conducted at subject’s home (by mobile research nurses). 
i 
Mobile research nurses will retrieve the study drug from a lockbox on Day 1. 
j 
Cough monitor will be collected by a courier and delivered to the clinic on the following day. 
k 
Visit window is ± 3 days. 
l 
If not done within the past 5 years. 
m 
Weight only 
n 
 Informed consent must occur prior to any protocol-mandated procedures, including stopping of any excluded therapies. This may occur prior to Day -14.  
o 
Telephone visit. 
p 
Endocrine and reproductive endocrine tests are not done at Days 28 and 56. 
q 
ETD visit only at Day 85. 
 


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APPENDIX A (CONT’D) 
Table 4 
Schedule of Cough Monitoring and Patient Reported Outcomes (PROs) 
Cough monitoring devices (VitaloJAK) will be stored at each study center and attached to subjects at the visits shown below. The 
PROs will be completed within IVRS/IWRS or on paper as shown below. PROs are provided to subjects at the screening visit.  
Device 
Assessment 
Frequency and Duration of Assessment 
VitaloJAK 
Cough 
Monitoring 
Baseline, Day 28, Day 56, Day 84, Day 112 
IVRS/IWRS 
Daily dosing 
Daily during the 84-day treatment period 
Paper 
Cough Severity 
VAS 
Once at Screening, Baseline, Day 28, Day 56, Day 84, Day 85, Day 112, Day 113 
Paper 
LCQ 
Baseline, Day 28, Day 56, Day 84, Day 113 
Paper 
PGIC 
Day 28, Day 56, Day 84 
 


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APPENDIX B 
LIST OF STRONG CYP3A4 INHIBITORS 
The list of strong CYP3A4 inhibitors is based on the FDA list effective September 26, 2016, 
Examples of clinical inhibitors for P450-mediated metabolisms (for concomitant use clinical 
DDI studies and/or drug labeling) (“Examples of clinical inhibitors for P450-
mediatedmetabolisms (for concomitant use clinical DDI studies and/or drug labeling) 
(9/26/2016)”): 
1. boceprevir 
2. clarithromycin 
3. cobicistat 
4. conivaptan 
5. danoprevir and ritonavir 
6. diltiazem 
7. elvitegravir and ritonavir 
8. regular grapefruit juice consumption 
9. idelalisib 
10. indinavir and ritonavir 
11. itraconazolea 
12. ketoconazolea 
13. lopinavir and ritonavir 
14. nefazodone 
15. nelfinavir 
16. paritaprevir and ritonavir and (ombitasvir and/or dasabuvir) 
17. posaconazolea 
18. ritonavir 
19. saquinavir and ritonavir 
20. telaprevir 
21. tipranavir and ritonavir 
22. troleandomycin 
23. voriconazolea 
 
aTopical formulations of azoles are not considered strong CYP3A4 inhibitors due to limited systemic absorption.  
 
 


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APPENDIX C 
ACCP/BTS GUIDELINES 
 

SAP_001.pdf: 
Menlo Therapeutics Inc 
 
Statistical Analysis Plan Version 1.0 
Protocol No: MTI-110 
 
  
 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
A Randomized, Double-Blind, Placebo-Controlled Study of the Efficacy, 
Safety, and Tolerability of Serlopitant for the Treatment of Refractory 
Chronic Cough 
Protocol No: MTI-110 
Protocol Version / Date: Version 3.0 /08-MAR-2018 
 
Menlo Therapeutics Inc. 
200 Cardinal Way, 2nd Floor 
Redwood City, CA 94063 
 
 
 
 
 
 
Confidentiality Statement: 
This document is a confidential communication of Menlo Therapeutics Inc. As such, the 
recipients agree not to disclose or reproduce, without prior written approval, this document and 
any attachments, except to appropriate Institutional Review Boards, Ethics Committees, 
representatives of the US Food and Drug Administration, other regulatory agencies or as 
otherwise required by applicable laws or regulations. 




Menlo Therapeutics Inc 
 
Statistical Analysis Plan Version 1.0 
Protocol No: MTI-110 
 
 
 
 
 
 TABLE OF CONTENTS 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ............................................5 
1.0 
INTRODUCTION..............................................................................................................6 
2.0 
STUDY OBJECTIVE ........................................................................................................6 
 
Primary Objective: ...................................................................................................6 
 
Secondary Objectives...............................................................................................6 
3.0 
STUDY DESIGN AND PROCEDURES .........................................................................6 
 
Randomization .........................................................................................................8 
4.0 
INTERIM ANALYSES .....................................................................................................8 
5.0 
STUDY ENDPOINTS ........................................................................................................8 
 
Efficacy Endpoints ...................................................................................................8 
5.1.1 
Primary Endpoint ....................................................................................8 
5.1.2 
Key Secondary Endpoints .......................................................................8 
5.1.3 
Other Secondary Endpoints ....................................................................9 
 
Safety Endpoints ......................................................................................................9 
6.0 
ANALYSIS SETS.............................................................................................................10 
 
Full Analysis Set (FAS) .........................................................................................10 
 
Safety Analysis Set ................................................................................................10 
 
PK Analysis Set .....................................................................................................10 
7.0 
DEFINITION OF VARIABLES ....................................................................................10 
 
Baseline ..................................................................................................................10 
 
Study Day...............................................................................................................10 
 
Analysis Windows .................................................................................................11 
 
Age .........................................................................................................................11 
 
Duration of Chronic Cough ...................................................................................11 
 
Prior and Concomitant Medications ......................................................................11 
8.0 
GENERAL STATISTICAL CONSIDERATIONS ......................................................12 
 
General Analysis Considerations ...........................................................................12 
 
Determination of Sample Size ...............................................................................13 
 
Handling of Missing Data and Excluded Therapy Use .........................................13 
 
Data Handling Rules for Cough Analysis ..............................................................13 
 
Adjustments for Covariates....................................................................................14 
 
Examination of Subgroups .....................................................................................14 
 
Multiplicity Adjustments .......................................................................................15 


Menlo Therapeutics Inc 
 
Statistical Analysis Plan Version 1.0 
Protocol No: MTI-110 
 
 
 
 
 
9.0 
STATISTICAL ANALYSES ..........................................................................................15 
 
Subject Disposition ................................................................................................15 
 
Eligibility Assessments ..........................................................................................16 
 
Demographic and Baseline Information ................................................................16 
9.3.1 
Demographic and Baseline Characteristics ...........................................16 
9.3.2 
Medical History .....................................................................................16 
9.3.3 
Screening Laboratory Tests ..................................................................16 
 
Prior and Concomitant Medication ........................................................................16 
 
Study Treatment Exposure and Adherence ............................................................17 
 
Efficacy Analyses ..................................................................................................18 
9.6.1 
Statistical Hypotheses and Tests ...........................................................18 
9.6.2 
Primary Endpoint ..................................................................................18 
9.6.3 
Key Secondary Endpoints .....................................................................20 
9.6.4 
Other Secondary Endpoints ..................................................................22 
9.6.5 
Sensitivity Analysis ...............................................................................23 
 
Safety Analyses ......................................................................................................24 
9.7.1 
Adverse Events......................................................................................24 
9.7.2 
Laboratory Data ....................................................................................26 
9.7.3 
Physical Examination ............................................................................26 
9.7.4 
Vital Signs .............................................................................................27 
9.7.5 
12-Lead Electrocardiograms .................................................................27 
10.0 
REFERENCES .................................................................................................................28 
11.0 
APPENDICES ..................................................................................................................29 
Appendix A: SAS Sample codes .......................................................................................29 
Appendix B: Schedule of Assessments..............................................................................35 
Appendix C: Study Visit Map with Matched Interval ID ..................................................37 
Appendix D: Clinical Laboratory Tests .............................................................................38 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Term  
Definition 
AE 
adverse event 
ANCOVA 
Analysis of covariance 
BMI 
CGIC 
body mass index 
Clinician global impression change 
CMH 
Cochran Mantel Haenszel 
CRO 
contract research organization 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
eGFR 
electronic data capture 
estimated Glomerular Filtration Rate 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GLMM 
Generalized linear mixed model 
LCQ 
LS Mean 
Leicester cough questionnaire 
Least-squares mean 
M&N 
Stratified Miettinen and Nurminen 
MedDRA 
MMRM 
PCI 
PGIC 
Medical Dictionary for Regulatory Activities 
Mixed Model Repeated Measures 
Potentially Clinically Important 
Patient global impression change 
MI 
Multiple imputation 
PK 
pharmacokinetic (adjective) or pharmacokinetics (singular noun) 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SAS 
statistical analysis software 
TEAE 
VAS 
treatment-emergent adverse event 
Visual analogue scale 
WHO 
World Health Organization 
 
 
 


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1.0 
INTRODUCTION 
This statistical analysis plan (SAP) outlines the data and procedures used for assessing the 
efficacy, safety, and tolerability of serlopitant from Protocol MTI-110: A Randomized, Parallel, 
Double-Blind Study to Assess the Efficacy, Safety, and Tolerability of Serlopitant in Subjects 
with Treatment Refractory Chronic Cough.   
2.0 
STUDY OBJECTIVE 
 
Primary Objective: 
• To assess the effectiveness of serlopitant for the treatment of refractory chronic cough 
after 12 weeks of treatment in reducing 24-hour objective cough frequency 
 
Secondary Objectives 
• To evaluate the effectiveness of serlopitant as compared to placebo after 4 and 8 
weeks of treatment in reducing 24-hour objective cough frequency  
• To evaluate the effectiveness of serlopitant as compared to placebo after 4, 8 and 12 
weeks of treatment in reducing awake objective cough frequency 
• To evaluate the effectiveness of serlopitant as compared to placebo after 4, 8 and 12 
weeks of treatment in reducing sleep objective cough frequency 
• To evaluate the effectiveness of serlopitant in: 
o reducing the cough severity measured by a Visual Analog Scale (VAS) 
o improving cough-specific quality of life using Leicester Cough Questionnaire 
(LCQ) 
• To assess the safety and tolerability of repeated oral doses of serlopitant in subjects 
with treatment refractory chronic cough 
3.0 
STUDY DESIGN AND PROCEDURES 
This is a 12-week randomized, parallel, double-blind, placebo-controlled study of serlopitant in 
subjects with Treatment Refractory Chronic Cough. Approximately 170 subjects who meet entry 
criteria will be randomly assigned to serlopitant 5 mg or placebo. 
For all subjects, there will be a Screening Period of up to 2 weeks. At the Baseline visit (Study 
Day -1), eligible subjects will be randomly assigned to one of two treatment groups and will 
have baseline cough monitoring conducted. 


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After Baseline, subjects will be entered into a 12-week (84-day) treatment period and a 28-day 
follow-up period. Subjects who discontinue treatment early at any time during the treatment 
period will have an Early Treatment Discontinuation (ETD) visit within 7 days after their last 
dose of study drug in addition to a follow-up visit 28 days after the ETD visit.  
Study drug will be administered as follows (Table 1): 
Table 1: Treatment Schedule 
Study Days 
Study Drug Dose 
 
Days 1-84 
Serlopitant 5 mg  
Placebo 
 
One day after the Baseline visit, subjects will take a loading dose (3 tablets taken orally) in the 
morning on the first day of the treatment period (Study Day 1). Starting on Day 2, subjects will 
take one tablet per day orally in the morning. Subjects will be instructed to take all doses at 
approximately the same time each day. 
The following assessments will be conducted to evaluate the efficacy of serlopitant: 
• 
Objective Cough Frequency: 24-hour sound recordings at Baseline (Study Day -1) and on 
Days 28, 56, 84, and 112 using a 510(K) FDA approved and CE-marked digital recording 
device (VitaloJAK, Vitalograph, Ltd).  
• 
Cough Severity Visual Analogue Scale (VAS): scored on a 100 mm visual analogue scale 
at Screening, Baseline (Study Day -1), Days 28, 56, 84, 85/ETD, 112, and 113. 
• 
Leicester Cough Questionnaire (LCQ): completed at Baseline (Study Day -1), Days 28, 
56, 85/ETD, and Day 113. 
• 
Patient’s Global Impression of Change (PGIC): completed at Days 28, 56, 85/ETD 
• 
Clinician’s Global Impression of Change (CGIC): completed at Day 85/ETD 
Subjects will return 4 weeks after completing the 12-week Treatment Period and Day 
85/ETD Visit for Follow-Up Visits Day 112 and Day 113. The visit schedule and 
assessments are summarized in Appendix B. And, the study visit map is presented in 
Appendix C. 


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Randomization 
Subjects will be assigned to one of two treatment groups based on a randomization scheme.  The 
randomization schedule will be computer generated using a permuted block algorithm and will 
randomly allocate subjects to randomization numbers. Subjects who meet entry criteria will be 
randomly assigned to serlopitant 5 mg or placebo in a 1:1 ratio for up to 84 days. Treatment 
allocation/randomization will be stratified according to the following factors: 
• 
Gender (Male; Female) 
• 
Country (USA, UK) 
4.0 
INTERIM ANALYSES 
No interim analysis planned for this study. 
5.0 
STUDY ENDPOINTS  
 
Efficacy Endpoints 
5.1.1 
Primary Endpoint 
The primary efficacy endpoint of this study is:  
• Change from Baseline in 24-hour objective cough frequency after 12 weeks (Day 84) of 
treatment. 
The study is designed to evaluate the efficacy profile of serlopitant 5 mg versus placebo. The 
comparisons between serlopitant 5 mg and placebo related to the primary efficacy endpoint will 
be done in a hierarchical manner, see Section 8.5. 
5.1.2 
Key Secondary Endpoints 
Key secondary endpoints that will be assessed include:  
• Change from Baseline in awake objective cough frequency after 12 weeks (Day 84) of 
treatment 
• Proportion of subjects with ≥ 30% reduction in 24-hour objective cough frequency per 
hour at Week 12 (Day 84) 
• Proportion of subjects with ≥ 30% reduction in awake objective cough frequency per 
hour at Week 12 (Day 84) 


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• Change from Baseline in Cough Severity Visual Analog Scale (VAS) at Week 12 (Day 
84) 
5.1.3 
Other Secondary Endpoints 
• Change from Baseline in 24-hour objective cough frequency after 4 and 8 weeks (Days 
28 and 56) of treatment  
• Change from Baseline in awake objective cough frequency after 4 and 8 weeks (Days 28 
and 56) of treatment 
• Change from baseline and change from Day 84 in 24-hr objective cough frequency at the 
Follow-Up visit (Day 112) 
• Change from Baseline in sleep objective cough frequency after 4, 8 and 12 weeks (Day 
28, 56 and 84) of treatment 
• Change from Baseline in Leicester Cough Questionnaire (LCQ) individual Domain and 
Total scores 
• Patient's Global Impression of Change (PGIC) 
• Clinician's Global Impression of Change (CGIC) 
 
Safety Endpoints 
Safety will be assessed through monitoring of adverse events (AEs), physical examinations 
(including vital signs), electrocardiograms (ECGs), and laboratory tests. Safety assessment 
frequency is shown in the Schedule of Assessments and Procedures. 
The safety endpoints include:  
• Incidence of treatment-emergent adverse events (TEAEs) and serious adverse events 
(SAEs) 
• Change in clinical laboratory parameters following study drug exposure 
• Change in vital signs and ECG parameters following study drug exposure 
• Plasma concentrations of serlopitant and metabolites 


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6.0 
ANALYSIS SETS 
 
Full Analysis Set (FAS) 
All randomized subjects who have taken at least one dose of study medication and provided at 
least one baseline and at least one post-baseline primary endpoint observation during the 
treatment period. Participants will be analyzed according to the treatment group to which they 
are randomized.  
 
Safety Analysis Set 
The safety analysis set will consist of all subjects randomized who receive at least one dose of 
study medication. Subjects will be classified based upon the treatment received. 
 
PK Analysis Set 
The PK analysis set will consist of all subjects who receive ≥ 1 dose of serlopitant and who have 
at least 1 post-dose PK blood sample available for analysis.  
7.0 
DEFINITION OF VARIABLES 
 
Baseline 
For purposes of assessing changes in vital signs, physical examination results, 12-lead ECG 
results and clinical laboratory values, baseline refers to the study as a whole and is defined as the 
last observation prior to the first study treatment. For all efficacy variables, baseline refers to the 
observation collected at Baseline visit (Study Day -1).  
 
Study Day 
Study Day 1 is the date of first study medication.  Study Day relative to Study Day 1 will appear 
in the listings where applicable. 
If the date of event is on or after the 1st study medication date then  
Study Day = date of event – date of 1st study medication +1 
If the date of event is prior to the first study medication then: 
Study Day = date of event – date of 1st study medication  


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Analysis Windows 
The analysis windows used to report cough frequency endpoints are outlined in Table .  If more 
than one assessment is available within the range the assessment closest to the target day is 
reported for the analyses window. If two observations exist with the same distance to the target 
day, the first observation is used.   
Table 2:  Analysis Windows 
Analysis Visit 
Range 
Target Day 
Baseline 
Day ≤1  
Day 1 
Day 28 (Week 4) 
Day 2 to Day 42 
Day 28 
Day 56 (Week 8) 
Day 43 to Day 70 
Day 56 
Day 84 (Week 12) 
Day 71 to min (Day 91, TRTEDT+7) 
Day 84 
Day 112 (Follow-Up) 
> min (Day 91, TRTEDT+7) 
Day 112 
+TRTEDT – date of last study medication 
 
The Follow-Up assessment will be the last assessment available that is at least seven days after 
the end of treatment. Should no post treatment assessments be available the subject will not have 
a follow-up assessment. Any assessments reported after the date of last study medication will be 
considered as a follow-up assessment. 
 For other efficacy and safety endpoints, the study visits as specified in the protocol will be 
utilized as analysis visits.  
 
Age 
Age will be derived as date of informed consent minus date of birth then divided by 365.25 and 
presented in years. 
 
Duration of Chronic Cough 
Duration of chronic cough (years) will be derived as year of informed consent minus year of start 
date of the chronic cough medical history. 
 
Prior and Concomitant Medications 
Prior medications are all those medications that are not concomitant (for which there is enough 
information to determine that the medication was stopped prior to the first dose of study 
treatment).  Concomitant medications are those medications that begin after the first dose of 
study treatment or are present at baseline but continue after the first dose of study treatment. 
Medications missing both start and stop dates or having a start date prior to the start of study 
treatment and missing stop date will be counted as concomitant medication. 


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8.0 
GENERAL STATISTICAL CONSIDERATIONS 
The statistical software package SAS® Version 9.4 or higher (SAS Institute, Cary, NC, USA) 
will be used to perform all analyses and to summarize data.  
 
General Analysis Considerations 
For continuous variables, descriptive statistics will include the number of subjects 
reflected in the calculation (n), mean, standard deviation, median, minimum and 
maximum. Categorical variables will be summarized using frequency counts and 
percentages. Treatment differences in response rates (e.g., proportion of cough frequency 
responders) will be estimated using the stratified Miettinen and Nurminen (M&N) 
method (stratified by country and sex). Treatment differences in continuous data 
collected over multiple study visits (e.g., changes from baseline in awake cough 
frequency) will be assessed using the MMRM model with treatment, visit (nominal time 
point), country, sex, and the visit by treatment interaction as fixed effects, and baseline 
value as covariates. 
Individual subject data obtained from the electronic case report forms (eCRFs), central 
laboratory, cough monitoring data, diary data, and any derived data will be presented by 
subject in data listings to facilitate the investigation of tabulated values and to allow for 
the clinical review. In general, all tables will be presented by treatment group and listings 
will be displayed by sorted unique subject identifier and treatment group. A subject 
identification number is defined as a 3-digit site number followed by a 3-digit 
sequentially assigned subject id (xxx-xxx). The treatment group in the listings will be 
based on the planned treatment(s) as allocated by the randomization scheme.  
All p-values will be rounded to 4 decimal places. If a p-value is less than 0.0001 it will 
be displayed as “< 0.0001”, a p-value rounding to 1 will be displayed as “> 0.9999”. 
Unless otherwise specified all summaries will be performed by treatment group, all 
efficacy analyses will be based upon the FAS and all safety analyses will be based upon 
the Safety Analysis Set. Demographic and baseline characteristic analyses will be based 
upon the FAS, Safety All Randomized Subjects. The safety and demographic tables will 
include a total column along with the treatment columns. 
The analyses described in this plan are considered a priori, in that they have been defined 
prior to database lock. Any analyses not described herein performed subsequent to 
database lock will be considered post hoc and exploratory. 


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Determination of Sample Size 
The comparisons related to the primary and key secondary endpoints will be done in a 
hierarchical manner to control the familywise error rate. The testing procedure will start by 
testing the primary endpoint and then proceed to the key secondary endpoints by following the 
order as specified in Section 8.9.4.  
A total of 170 subjects (85/arm) in 1:1 ratio to serlopitant 5 mg or placebo will provide 90% 
power to detect a 25% relative reduction (placebo-adjusted ratio of 0.75) in 24-hour objective 
cough frequency or awake objective cough frequency using a two-sample t-test at a one-sided 
significance level of 0.05. This assumes that 24-hour cough frequency or awake cough frequency 
follows a log-normal distribution with a CV of 0.64. This sample size also considers an expected 
dropout rate of 15%. 
The sample size calculations have been performed in nQuery Advisor + nTerim.  
 
Handling of Missing Data and Excluded Therapy Use 
For summary statistics results will generally be reported based upon observed data. Should a 
determination of treatment period (on treatment, pre-treatment) be required for AEs or 
concomitant medication but the corresponding date is missing, or is a partial date, the 
event/medication will be considered on treatment unless the portions of the date that are 
available indicate this is not possible. 
In case of missing data for the 24-hr cough frequency and the awake cough frequency, two 
selected imputation approaches are specified for the sensitivity analyses (Section 9.6.5).  
 
Data Handling Rules for Cough Analysis 
The 24-hour cough frequency (coughs per hour) for a specified visit is calculated as: 
24-hour cough frequency = (total number of cough events over 24-hour monitoring period)/ 
Total duration (in hours) over 24-hour monitoring period  
The awake cough frequency (coughs per hour) is defined as below: 
Awake cough frequency = (total number of cough events during the monitoring period the 
subjects is awake)/(Total duration (in hours) for the monitoring period the subject is awake) 
Awake duration (hours) is time between waking up and sleep during the 24-hour monitoring 
period.  
The cough data will contain all cough events occurring during that 24-hour monitoring period as 
well as the information about “sleep time” and “awake time”. Any session with duration of 


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recording < 4 hours will be considered as missing. Repeated monitoring may be conducted when 
there is an equipment failure or an unacceptable evaluation from the initial monitoring. 
In general, each 24-hour session is composed by an awake monitoring period and a sleep 
monitoring period. If a subject did not wake up before the end of the recording session, it will be 
assumed that the subject slept for the rest of the session. The session will have missing awake 
time, and the rest of session will be considered under the sleep monitoring period. For any 
session with both sleep time and awake time missing, the entire 24-hour session will be 
considered under the awake monitoring period, unless the session has early termination of 
recording.  
On each collection day, the cough count, the actual cough monitoring duration (in hours), and the 
coughs per hour will be derived for the total 24-hour period, the awake period, and the sleep 
period, respectively. 
The percent change in 24-hour coughs per hour at each specific visit is defined as below: 
percent change in 24-hour cough frequency =  
[(change from baseline in 24-hour cough frequency×100)/(baseline 24-hour cough frequency)] 
 
Adjustments for Covariates 
The primary endpoint will be evaluated using a mixed effect repeated measures 
(MMRM) model which includes fixed effects for treatment group, visit, country, sex, the 
treatment-by-visit interaction, and the baseline value as a covariate. In addition, 
exploratory analysis of the primary endpoint will be conducted by adjusting additional 
covariates such as age and duration of cough in the MMRM model. 
 
Examination of Subgroups 
Analysis for the primary efficacy endpoint will be provided for the following subgroups of baseline 
factors: 
• Sex (Male, Female); 
• Country (USA, UK); 
• Age group (18 to 60 years, over 60 years); 
• Duration of cough (≥10, <10 in years); 
• Baseline 24-hr cough frequency (≥10, <10 in coughs/hour). 
For each subgroup, the similar mixed effect repeated measures (MMRM) model as the primary 
efficacy endpoint will be performed (Section 9.6.2.1) by subgroup variable. Descriptive summary 


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statistics including mean, SD, and 95% CIs will be also provided. Subsequently, subgroups may 
be identified on a data-driven basis, and such analyses will be considered exploratory and 
hypothesis generating only. 
 
Multiplicity Adjustments 
The study is designed to evaluate the efficacy profile of serlopitant 5 mg versus placebo. The 
sequential testing procedure will be employed to control the overall Type I error rate at 5% with 
respect to multiple comparisons for the primary and key secondary endpoints. The hypothesis 
testing procedure will be done in a hierarchical order as specified below:   
• H1: Change from baseline in 24-hour objective cough frequency after 12 weeks (Day 
84) of treatment. 
• H2: Change from baseline in awake objective cough frequency after 12 weeks (Day 
84) of treatment 
• H3: Proportion of subjects with ≥ 30% reduction in 24-hour objective cough 
frequency per hour at Week 12 (Day 84) 
• H4: Proportion of subjects with ≥ 30% reduction in awake objective cough frequency 
per hour at Week 12 (Day 84) 
• H5: Change from Baseline in cough severity visual analog scale (VAS) at Week 12 
(Day 84) 
First, the test ranked as first will be tested and the difference will be declared statistically 
significant if the one-sided p value is less than 0.05. Second, in case that the difference for the 
first comparison is statistically significant, the comparison ranked as second will be tested, and 
the difference will be declared statistically significant if the one-sided p-value is less than 0.05. 
The testing will continue as long as the previously ranked objective was statistically significant.  
All other efficacy variables will be tested at the 0.05 level of significance without multiplicity 
adjustment. 
 
 
9.0 
STATISTICAL ANALYSES  
 
Subject Disposition 
The disposition of subjects will be summarized by treatment group.  The number and percentage 
of subjects who completed the study and the number and percentage of subjects who were 
withdrawn will be presented.  Subjects who discontinued prematurely will be summarized by 
number and percentage by reason for discontinuation as specified in the eCRFs. 


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Protocol deviations will be listed. 
 
Eligibility Assessments 
Subject’s eligibility assessments will be listed. 
 
Demographic and Baseline Information 
9.3.1 
Demographic and Baseline Characteristics 
Demographic and baseline characteristics will be listed and summarized by treatment group and 
overall. Variables include sex, age, ethnicity, race, height, weight, body mass index (BMI), and 
duration of chronic cough (years). 
9.3.2 
Medical History 
Medical history will be listed and summarized. 
9.3.3 
Screening Laboratory Tests 
Serum pregnancy test and urine drug screen data will be listed. A list of urine drug screen tests is 
displayed in Appendix D. 
 
Prior and Concomitant Medication 
Prior and concomitant medications will be coded to anatomical therapeutic class and preferred 
name using the WHO drug dictionary. Listings and tabular summary of prior and concomitant 
medications will be presented. 
All medications will be classified using the Anatomical Therapeutic Chemical (ATC) 
classification codes and preferred drug names from the World Health Organization Drug 
Dictionary (WHO Drug B2 DDE  2017-09-01) 
For the medications recorded on CRF page “Prior and Concomitant Medications”, medications 
with a stop date before the first date of study drug dosing will be considered prior medications. 
Medications with start date or stop date on or after the first date of study drug dosing will be 
considered concomitant medications. 
Prior medications and concomitant medications will be presented in tabular form using the ATC 
Level 2 (pharmacological subgroup) and preferred term (PT). Frequencies and percentages will 
be presented by treatment group and overall. The tables will be sorted by overall descending 
frequency of ATC Level 2, and then, within an ATC Level, by overall descending frequency of 
PT.  


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Partial or Missing Medication Start and Stop Dates 
If the medication start date is incomplete, then it will be imputed as follows for the purpose of 
determining concomitance only:  
• If the start date is completely missing, the start date will be equal to the first dose date. 
However, if the stop date is not missing and is before the first dose date, then the stop 
date will be used instead.  
• If the start day is missing, the first day of the month will be used.  
• If the start day and month are missing, then the first day of the first month (January) will 
be used. 
If the medication stop date is partial, then it will be imputed as follows for the purpose of 
determining concomitance only:  
• If the stop date is completely missing and the medication is not ongoing, the stop date 
will be equal to the last dose date or date of completion/withdrawal, whichever is the 
latest.  
• If the stop day is missing, the last day of the month will be used.  
• If the stop day and month are missing, then the last day of the last month (December) will 
be used. 
The aforementioned missing or partial data handling rules will be applied to the summary tables.  
The recorded missing or partial date values will be presented in the listings. 
 
Study Treatment Exposure and Adherence 
Percent compliance will be calculated for each subject as below: 
%
100
Therapy
on 
 
Be
 
Should
  
Days
 
of
Number 
Therapy
on 
 
Days
 
of
Number 
 
 
Compliance
Percent 

=
 
 
A day within the study will be considered an “On-Therapy” day if the participant takes all 
required medication. If a subject misses a daily dose, that day is not considered an On-Therapy 
day.  
Overall treatment adherence (%) will be also calculated as below:  


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Overall treatment Adherence (%) = 100% * (Total number of tablets dispensed - Total number of 
tablets returned) / Total expected number of tablets taken during the treatment period 
The duration of exposure to study medication for each participant will be evaluated by 
calculating the number of days on therapy. Duration of exposure, percent compliance, and 
overall treatment adherence (%) will be summarized by treatment group using descriptive 
statistics (mean, SD, median, minimum, and maximum) for the safety analysis set. 
 
Efficacy Analyses  
For efficacy endpoints, the analysis on FAS will be considered as the primary analysis. 
9.6.1 
Statistical Hypotheses and Tests  
The study is designed to evaluate, the efficacy of serlopitant 5 mg relative to placebo. The 
primary hypothesis for this trial is that serlopitant is superior to placebo with respect to the mean 
change from baseline in 24-hour cough frequency (on the log scale).  
Symbolically, the hypotheses for serlopitant 5 mg compared to placebo can be written as: 
H0: SP,Week 12 - SP,Baseline = PL,Week12 - PL,Baseline 
HA: SP,Week 12 - SP,Baseline < PL,Week 12 - PL,Baseline 
where SP and PL represent the mean values at Week 12 for serlopitant 5 mg and placebo, 
respectively.  
As the primary endpoint, cough frequency, is to be analyzed on the log scale the null hypothesis 
relates to the ratio of Week 12/Baseline for serlopitant 5 mg being the same as that for placebo, 
and the alternative hypothesis being that the ratio of Week 12/Baseline for serlopitant 5 mg is 
smaller than the ratio for placebo. 
A family wise error rate will be controlled to adjust for multiplicity for the comparison of 
serlopitant 5 mg to placebo on the primary and key efficacy endpoints in a hierarchical manner 
(see details in Section 8.5). One-sided p-values at 0.05 significance level will be used. 
9.6.2 
Primary Endpoint  
The primary endpoint of the study is the change from baseline in 24-hour objective cough 
frequency after 12 weeks (Day 84) of treatment. 
Cough monitoring is conducted for Baseline (Study Day -1) and 24 hours after administration of 
the study drug on Days 28, 56, 84, and 112. An independent cough monitoring analysis center 


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will provide documentation of the time of each cough event over the 24-hour period, as well as 
the time when the subject goes to sleep and the time the subject awakens.   
A negative result indicates a decrease in cough frequency, while a positive result indicates an 
increase in cough frequency. The Baseline cough frequency is derived from the cough 
monitoring performed at Baseline Visit (Study Day -1), and the post-dose cough frequency is 
derived from the cough monitoring performed on Days 28, 56, 84, and 112. Change from 
baseline and percent change in 24-hour objective cough frequency will be calculated for each 
visit. For descriptive summary only, the percent change from baseline will be capped at 200% 
for any value > 200%. 
9.6.2.1 
Analyses of Primary Endpoint  
A. Primary Analysis - Mixed Model Repeated Measures Analysis of Log Transformed 
24-hour Cough Frequency:  
As the change in 24-hour cough frequency may have a skewed and wide distribution, the primary 
analysis for the primary endpoint will be on the natural log scale of the cough frequency data.  
The difference between serlopitant 5 mg and placebo will be estimated using a mixed effect 
repeated measures (MMRM) model. The model will include fixed effects for treatment group, 
visit, country, sex, the treatment-by-visit interaction, and the log-transformed baseline value as a 
covariate.  The MMRM model will use all available 24-hour cough frequency data on Day 28, 
56, and 84. An unstructured covariance structure will be applied for MMRM.  In case the model 
will not converge with the unstructured covariance structure, the heterogeneous compound 
symmetry (CSH) will be used instead. Furthermore, if the model fails to converge with CSH, the 
heterogeneous Toeplitz structure (TOEPH) will be used.  If the unstructured covariance structure 
will be used, the denominator degrees of freedom will be computed using the Kenward-Roger 
method. In case of other covariance structures, the BETWITHIN (SAS) option will be used for 
the denominator degrees of freedom.  Contrasts will be constructed to compare each of the three 
serlopitant treatment groups to the placebo group at each visit. The least-squares (LS) mean 
change from baseline (on the log scale) with the associated standard errors will be displayed for 
each treatment group.  Estimated treatment differences (serlopitant vs. placebo) along with 
corresponding one-sided 95% CIs and p-values will also be presented at each post-baseline 
timepoint.   
In addition, the geometric mean of 24-hour cough frequency will be presented by treatment and 
by visit.  The percent difference change between serlopitant and placebo will be estimated by 
100 (ediff - 1), where diff is the difference provided by the analysis of the log-transformed 
variable. A sample of SAS code for MMRM analysis is provided in Appendix A.  
An observation of zero coughs per hour will be replaced by a cough rate of 0.1 for the 
calculation of geometric means.  


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Missing data, in the assessment of the primary hypothesis, is assumed as missing at random 
(MAR). This assumption will be assessed with a missing data sensitivity analysis (see Section 
9.6.5 Sensitivity analysis of the primary endpoint). 
B. Secondary Analysis - Mixed Model Repeated Measures Analysis of 24-hour Cough 
Frequency on the Original Scale: 
The changes from baseline in 24-hour cough frequency on the original scale will be also 
analyzed using the same MMRM model, fitting terms for treatment group, visit, country, sex, the 
treatment-by-visit interaction, and the Baseline value as a covariate. The least-squares (LS) mean 
change from baseline (on the original scale) with the associated standard errors will be displayed 
for each treatment group. Estimated treatment differences (serlopitant 5 mg vs. placebo) along 
with corresponding one-sided 95% CIs and p-values will also be presented for each treatment 
group at each post-baseline timepoint. This analysis will be considered as secondary analysis for 
primary endpoint. 
C. Secondary Analysis - ANCOVA Analysis on Ranks of Log Transformed 24-hour 
Cough Frequency at Week 12:  
Additionally, the ranked scores of the primary endpoint (on the natural log scale) at Week 12 
(Day 84) will be analyzed using an analysis of covariance (ANCOVA) model with fixed effects 
for treatment group, visit, country, sex, and the log-transformed baseline value as a covariate. 
This analysis will be considered as secondary analysis for primary endpoint. A sample of SAS 
code for ANCOVA analysis for ranked data is provided in Appendix A. 
9.6.3 
Key Secondary Endpoints  
9.6.3.1 
Awake Objective Cough Frequency 
Analyses for awake objective cough frequency will proceed in the same manner as the analyses 
indicated in Section 9.6.2.1 above at for the Primary Efficacy endpoint. 
9.6.3.2 
Cough Frequency Responder Analysis 
Two key cough frequency responder endpoints are:  
• Proportion of subjects with ≥ 30% reduction in 24-hour objective cough frequency per 
hour at Week 12 (Day 84) 
• Proportion of subjects with ≥ 30% reduction in awake objective cough frequency per 
hour at Week 12 (Day 84) 


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The proportion of participants with ≥ 30% of reduction from baseline in 24-hour cough 
frequency at each specific visit is the number of participants with ≤-30% change in 24-hour 
cough frequency divided by the total number of participants with available data at the specific 
visit. Similar definition will be applied for awake cough frequency. 
In addition, the exploratory analyses of ≥ 50% of reduction and ≥ 70% of reduction will be 
conducted for both 24-hour and awake cough frequency.  
Moreover, for categorical analysis, three responder variables for 24-hour or awake objective 
cough frequency will be defined based on the magnitude of the percent change from baseline. 
≥ 70% Reduction = 1 if Percent Change from Baseline in cough frequency at each visit 
<= -70.0%; 0 Otherwise 
≥ 50% Reduction= 1 if Percent Change from Baseline in cough frequency at each visit <= 
-50.0%; 0 Otherwise 
≥ 30% Reduction= 1 if Percent Change from Baseline in cough frequency at each visit <= 
-30.0%; 0 Otherwise 
Note that these responder definitions are not mutually exclusive.  In particular, a subject who 
achieves a 1 for ≥ 70% Reduction, will, by definition, be classified as a 1 for ≥ 50% Reduction 
and ≥ 30% Reduction. The count and percentage of subjects who meet the responder criteria for 
≥70% Reduction, ≥50% Reduction, and ≥30% Reduction will be summarized by treatment group 
and by visit. 
For cough frequency responder endpoint, the primary analysis for the comparison of response 
rates between each of the serlopitant 5 mg and placebo will be conducted using the stratified 
Cochran Mantel Haenszel (CMH) test (stratified by country and sex, unless stated otherwise). 
Missing data will be categorized as discontinued or missing. Furthermore, the differences in 
proportions between two treatment groups will be estimated using the stratified Miettinen and 
Nurminen (M&N) method. A sample of SAS code for categorical analysis is provided in 
Appendix A. 
In addition, the responder endpoint will be analyzed by a generalized linear mixed model 
(GLMM) with treatment, visit, country, sex, and treatment by visit interaction as fixed effects.  
Visit ordering will be treated as a repeated measure within subjects. The GLMM model will use 
all available cough frequency data on Day 28, 56, and 84. The least-squares (LS) mean 
proportions with the associated standard errors will be displayed for each treatment group. 
Estimated odds ratio (serlopitant vs. placebo) along with corresponding one-sided 95% CIs and 
p-values will also be presented at each post-baseline timepoint.   


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9.6.3.3 
Cough Visual Analog Scale  
Cough Visual Analogue Scale (VAS) scored from 0 to 100 using a 100 mm visual analogue scale 
will be evaluated at Screening, Baseline (Study Day -1), Days 28, 56, 84, Day 85/ETD, Follow-
up (Day 112 and Day 113).  Baseline cough VAS is defined as the cough VAS at Baseline 
(Study Day -1). 
Change from baseline of cough VAS score will be analyzed in the same way as that for the 
primary endpoint as indicated in Section 9.6.2.1 above. To explore the correlation between VAS 
and 24-hour cough frequency, Scatter plots between VAS and 24-hour objective cough 
frequency counting will be generated. 
9.6.4 
Other Secondary Endpoints  
The following secondary endpoints are planned for analysis:  
9.6.4.1 
Sleep Objective Cough Frequency  
Analyses for sleep objective cough frequency will proceed in the same manner as the analyses 
indicated in Section 9.6.2.2 above at for the Primary Efficacy endpoint. 
9.6.4.2 
Cough Frequency at Follow-Up  
In order to assess whether 12 weeks of treatment with serlopitant can delay the return of chronic 
cough, the observed results, change from Day 84, and change from baseline for 24-hour cough 
frequency, awake cough frequency, and sleep cough frequency at Follow-up Visit (Day 112) will 
be also summarized.   
9.6.4.3 
Leicester Cough Questionnaire (LCQ)  
The Leicester cough questionnaire (LCQ) instrument will be assessed at Baseline (Study Day0), 
Day 28, Day 56, 85/Early Termination, and Follow-up (Day 113).  There are three domains in 
the LCQ instrument: Physical (items 1, 2, 3, 9, 10, 11, 14 and 15), Psychological (4, 5, 6, 12, 13, 
16, and 17), and Social (7, 8, 18, 19).  For each domain, the domain score (range 1-7) is the sum 
of individual item score within the domain divided by the number of items in the domain; total 
LCQ score (range 3-21) is the sum of the three domain scores. Baseline LCQ is defined as the 
LCQ collected at Baseline (Study Day -1). 
For each domain (physical, psychological, and social) and total LCQ score, change from baseline 
will be analyzed in similar manner as indicated for the primary endpoint in Section 9.6.2.1.  Line 
plots of individual subject baseline and post treatment scores will be generated by treatment 
group and serlopitant for each domain and total LCQ scores. 


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9.6.4.4 
Patient’s Global Impression of Change 
The self-report measure Patient’s Global Impression of Change (PGIC) reflects a patient's belief 
about the efficacy of treatment. PGIC is a 7-point scale depicting a patient's rating of overall 
improvement. Patients rate their change as “very much improved,” “much improved,” 
“minimally improved,” “no change,” “minimally worse,” “much worse,” or “very much worse.” 
The counts and proportions of ordered responses to the subject’s global perception of change will 
be computed for each treatment group on Day 28, Day 56, Day 85/ETD. Proportion of subjects 
with improvements (either "very much improved" or "much improved" on the PGIC scale) will 
also be presented. The distribution of responses will be compared between each of the serlopitant 
treatment groups and placebo using the stratified Cochran Mantel Haenszel (CMH) test 
(stratified by country and sex, unless stated otherwise). 
9.6.4.5 
Clinician’s Global Impression of Change 
The Clinician’s Global Impression of Change (CGIC) reflects a clinician's belief about the 
efficacy of treatment. CGIC has the same 7-point scale like PGIC.   
CGIC will be evaluated at Day 85/ETD.  Similar analysis for PGIC will be applied for CGIC.   
9.6.5 
Sensitivity Analysis  
The primary analyses (MMRM) for assessing 24-hr cough frequency and awake cough 
frequency are valid if the missing data are missing at random (MAR), meaning that the 
probability of a value being missing, conditional on the observed data and factors in the 
statistical model, is random and not dependent on the unknown value of the missing data point. 
Therefore, two sensitivity analyses under missingness not at random (MNAR) will be conducted 
for 24-hr cough frequency and awake cough frequency to evaluate the robustness of efficacy 
results and the effect of missing data.  
Sensitivity analysis using a copy-reference multiple-imputation method will be performed to 
assess the robustness of the primary analysis based on MMRM. In this sensitivity analysis, 
intermittent missing values will be imputed using the Markov Chain Monte Carlo (MCMC) 
methodology which assumes a multivariate normal distribution over all variables included in the 
imputation model. This imputation will be done by treatment group, using MI procedure in SAS 
9.4. The variables to be used in the imputation are treatment, corresponding baseline values, and 
values observed at all double-blind visits (Days 28, 56, and 84). Then all the monotone missing 
values will be multiply-imputed using the imputation model built from the control group, i.e., 
assuming the missing data in the treatment group will have a profile that equals the profile of the 
control group for all time points (i.e., a copy-reference imputation). The missing data imputation 
will be implemented using PROC MI in SAS 9.4 with the MNAR statement. Once the competed 


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data sets are formed, the same MMRM analysis model as specified for the primary analysis will 
be applied to each completed set and the inference drawn using Rubin’s combination rules (SAS 
proc MIANALYZE). While the results will be combined using SAS PROC MIANALYZE, it is 
known that this approach may produce an inflated variance estimate for the treatment 
comparison. To get a correct variance, a pattern mixture model approximation method will also 
be used. Results from both the MIANALYZE and the pattern mixture model approximation will 
be presented as sensitivity analyses. A sample of SAS code for sensitivity analysis using the 
copy-reference MI method is provided in Appendix A. 
An additional sensitivity analysis using the tipping-point approach will be conducted to assess 
the robustness of the primary analysis approach. If it is plausible that, for the active treatment 
group, the distribution of missing primary endpoint responses has a smaller expected reduction 
than that of the corresponding distribution of the observed primary endpoint responses, the 
conclusion under the MAR assumption should be examined. It is desired to impose a fixed and 
definite set of quantities to encapsulate the change in efficacy associated with withdrawal 
(missing) for the active treatment group, and the tipping point multiple imputation analysis as 
described in Ratitch et al. (2013) will be applied. Tipping point analysis is a means of exploring 
the influence of missingness on the overall conclusion from statistical inference by positing a 
wide spectrum of assumptions regarding the missingness mechanism (from less conservative to 
more conservative). The analysis finds a (tipping) point in this spectrum of assumptions, at 
which conclusions change from being favorable to the experimental treatment to being 
unfavorable. After such a tipping point is determined, clinical judgment can be applied as to the 
plausibility of the assumptions underlying this tipping point. The tipping point can be identified 
while the result is no longer statistically significant. This imputation analysis used a specified 
sequence of shift parameters, which adjust the imputed values for observations in the active 
treatment group. The tipping point can be identified while the result is no longer statistically 
significant. A sample of SAS code for sensitivity analysis using the tipping-point method is 
provided in Appendix A.  
For both sensitivity analyses, the multiple imputations will be completed before log-transforming 
data.  
 
Safety Analyses  
The safety analysis will utilize the Safety Analysis Set.  
9.7.1 
Adverse Events  
Adverse events will be mapped to system organ classes and preferred terms using the MedDRA 
dictionary version 20.1. All adverse event summaries will be restricted to treatment emergent 
adverse events (TEAE), which are defined as those AEs occurring on or after dosing and those 


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existing AEs worsening during the study. Only treatment-emergent adverse events will be 
included in the summary tables. 
For all AE tables, counting will be by subject and not by event. In other words, if a subject has 
more than one event with the same preferred term, the subject will be counted once for that 
preferred term in the treatment group. If a subject has more than one event in the same system 
organ class, the subject will be counted once for that system organ class in the treatment group.  
An overall summary of AEs will be presented. The overall summary will include the number and 
percentage of subjects experiencing any AEs, study drug related AEs, AEs by maximum severity 
(highest toxicity grade), SAEs, study drug related SAEs, discontinued due to AE, and deaths. 
The number and percentage of subjects experiencing each AE, study drug related AE, and SAEs 
will be summarized by treatment group according to system organ class and preferred term. 
Additional table including only preferred term summarized by treatment for the number and 
percentage of subjects experiencing each AE will be presented as well. 
Complete subject listings of all AE will be provided. For each AE the following will be 
specified: treatment group, start and stop dates, severity grade, MedDRA system organ class and 
preferred term, duration, relationship to study treatment, action taken, outcome of the adverse 
event and seriousness. 
Partial or Missing AE Start and Stop Dates 
If the AE start date is incomplete, then it will be imputed as follows for the purpose of 
determining the onset of AE only:  
In the event that the day portion (and only the day portion) of the AE onset date is missing: 
• If the start date is completely missing, the start date will be equal to the first dose date. 
However, if the stop date is not missing and is before the first dose date, then the stop 
date will be used instead.  
• If the start day is missing, the day of the first dose date will be used for the event 
occurring at the same month and year of the first dose date; otherwise, the first day of 
the month will be used.  
• If the start day and month are missing, then the first day of the first month (January) 
will be used. 
If the AE stop date is partial, then it will be imputed as follows for the purpose of determining 
the duration of AE only:  


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• If the stop date is completely missing and the event is not ongoing, the stop date will be 
equal to the last dose date or date of completion/withdrawal, whichever is the latest.  
• If the stop day is missing, the day of the last study day will be used for the event 
stopping at the same month and year of the last study day; otherwise, the last day of the 
month will be used.  
• If the stop day and month are missing, then the last day of the last month (December) 
will be used. 
The aforementioned missing or partial data handling rules will be applied to the summary tables.  
The recorded missing or partial date values will be presented in the listings. 
9.7.2 
Laboratory Data 
Laboratory evaluations will be collected at Screening, Day 28, Day 56, Day 85/ETD, and 
Follow-Up (Day 113). All laboratory results including hematology, chemistry, endocrinology, 
reproductive endocrinology, urinalysis, and urine microscopic parameters will be listed (see 
Appendix D for the list of parameters for each category). The observed results and change from 
baseline for hematology, chemistry, endocrinology, and reproductive endocrinology will be 
summarized descriptively by visit and by treatment group. Baseline for laboratory tests is defined 
as the last assessment performed prior to Day 1 dosing date. Most subjects have Screening visit 
as baseline. 
9.7.2.1 
Abnormal Laboratory Results 
For each quantitative hematology, chemistry, endocrinology, and reproductive endocrinology 
(AMH test only) laboratory parameter, observed values will be compared to normal laboratory 
reference ranges and classified as “Low”(where applicable), “Normal”, “High (if applicable). For 
each laboratory parameter, a 4x4 contingency table (shift table) will be displayed that 
summarizes the counts of subjects who were classified as “Low”, “Normal”, “High” or result 
missing at Baseline vs. “Low”, “Normal”, “High” or result missing at Post-baseline time points, 
where Post-baseline time points are Day 28, Day 56, Day 85/ETD, and Day 113. Separate shift 
tables will be generated for each treatment group at each visit. A listing of abnormal laboratory 
results will be provided. 
9.7.3 
Physical Examination 
Physical examination information will be listed. 


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9.7.4 
Vital Signs 
Vital signs will be collected at Screening, Baseline (Study Day -1), Day 1, Day 28, Day 56, Day 
84, Day 85/ETD, and at Follow-Up (Day 113). Vital signs will be summarized by visit and by 
treatment group. Variables summarized include, systolic blood pressure (mmHg), diastolic blood 
pressure (mmHg), pulse rate (bpm), respiratory rate (per minute), and temperature. Baseline for 
laboratory tests is defined as the last assessment performed prior to Day 1 dosing date. 
9.7.4.1 
Potentially Clinically Important (PCI) Findings in Vital Signs  
At each post-baseline vital signs assessment, observed vital signs results will be categorized into 
the categories according to the following criteria (Table 3) of potentially clinically important 
(PCI) findings. The count and percentage of subjects with vital signs parameters at each category 
of potentially clinically importance (PCI) will be summarized by treatment group for Day 1, Day 
28, Day 56, Day 84, Day 85/ETD, and Follow-Up (Day 113).  
Table 3:  Potentially Clinically Important (PCI) Criteria for Vital Signs 
Parameter 
Clinically significant value/change 
Pulse rate 
50 bpm and decrease from baseline 20 bpm  
110 bpm and increase from baseline 20 bpm  
Systolic BP 
90 mmHg and decrease from baseline 20 mm Hg  
160 mmHg and increase from baseline 20 mm Hg  
Diastolic BP 
50 mmHg and decrease from baseline 20 mm Hg  
105 mmHg and increase from baseline 20 mm Hg  
Respiration rate 
≤8 breaths/min and ≤-30% change from baseline  
≥25 breaths/min and≥30% change from baseline  
 
9.7.5 
12-Lead Electrocardiograms 
Electrocardiograms (12-lead) will be obtained at Screening, Day 28, Day 56, Day 85/ETD, and 
Follow-Up (Day 113). The observed results and change from baseline will be summarized 
descriptively by visit and by treatment group. ECG variables include heart rate, PR, QT, QTc, 
RR intervals and QRS duration. QTcB and QTcF are also calculated. Baseline for laboratory 
tests is defined as the last assessment performed prior to Day 1 dosing date.   
The overall ECG assessment will be summarized by visit and by treatment. The count and 
percentage of subjects with QTcF > 450, 480 and 500 msec and a change from baseline value > 
30 and 60 msec will be summarized by visit and by treatment group. 


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10.0 
REFERENCES 
[1] Yuan, Yang C. “Multiple Imputation for Missing Data: Concepts and New Development 
(Version 9.0)”, SAS Institute Inc., Rockville, MD 
[2] Rubin, D.B.  “Multiple Imputation for Nonresponse in Surveys.” New York:  John Wiley & 
Sons. (1987) 
[3] Ratitch B, O’Kelly M, Tosiello R. “Missing Data in Clinical Trials: From Clinical 
Assumptions to Statistical Analysis Using Pattern Mixture Models.” Pharm Stat. 2013;12:337-
347. 
[4] Carpenter J.R, Roger J, and Kenward M.G. “Analysis of Longitudinal Trials with Protocol 
Deviations: A Framework for Relevant, Accessible Assumptions, and Inference via Multiple 
Imputation.”  Journal of Biopharmaceutical Statistics (2013) 23:1352-1371 
[5] Birhanu T, Lipkovich I, Molenberghs G, Mallinckrodt CH. (2013). “A Multiple Imputation 
Based Approach to Sensitivity Analyses and Effectiveness Assessments in Longitudinal.” 
Clinical Trials, Journal of Biopharmaceutical Statistics.  
[6] Bornkamp, Björn, et al. "Innovative approaches for designing and analyzing adaptive dose-
ranging trials." Journal of biopharmaceutical statistics 17.6 (2007): 965-995. 
[7] SAS/STAT User’s Guide 
 
 


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11.0 
APPENDICES 
APPENDIX A: SAS SAMPLE CODES 
A sample of the SAS code for MMRM analysis is provided as below: 
 /*GENERATE LOG-TRANSFORMED COUGH FREQUENCY FIRST*/  
  
PROC MIXED DATA=LOGEFF METHOD=REML; 
CLASS TRT01PN USUBJID AVISITN COUNTRY SEX; 
MODEL LCHG = TRT01PN AVISITN COUNTRY SEX TRT01PN*AVISITN LBASE / DDFM=KR; 
/*LCHG AND LBASE ARE BASED ON THE LOG-TRANSFORMED COUGH FREQUENCY*/ 
REPEATED / SUBJECT=USUBJID (TRT01PN) TYPE=UN; 
LSMEANS TRT01PN*AVISITN / CL PDIFF; 
    ESTIMATE 'TRT S - P ON DAY 28' TRT01PN -1 1 
                   TRT01PN*AVISITN -1 0 0 1 / CL LOWER LOWERTAILED; 
    ESTIMATE 'TRT S - P ON DAY 56' TRT01PN -1 1 
                   TRT01PN*AVISITN 0 -1 0 0 1 / CL LOWER LOWERTAILED; 
    ESTIMATE 'TRT S - P ON DAY 84' TRT01PN -1 1 
                 TRT01PN*AVISITN 0 0 -1 0 0 1 / CL LOWER LOWERTAILED; 
RUN; 
Where TRT01PN = planned treatment group in numeric (1 = placebo, 2 = 
serlopitant 5 mg; AVISITN = time point (i.e. Day 28, Day 56, and Day 84); 
COUNTRY (USA, UK); SEX (Female, Male); TRT01PN*AVISITN = treatment by visit 
interaction; CHG = hourly cough frequency (on the log scale) – BASE (on the 
log scale); BASE = baseline hourly cough frequency (on the log scale); TYPE=UN 
specifies unstructured covariance matrix structure; METHOD=REML specifies the 
estimation method (REML is the default method); and DDFM=KR requests the 
Kenward-Roger method for the covariance matrix of the fixed-effect parameter 
estimates and denominator degrees of freedom for t and F tests. 
A sample of the SAS code for ANOVA analysis of ranked 24-hour cough frequency at Week 12 
(Day 84) is provided as below: 
 PROC RANK DATA= ADCF OUT=W12_RANK; 
  WHERE AVISIT=7; 
  RANKS CHG_RANK; 
  VAR CHG; /*CHG AND BASE ARE BASED ON THE LOG-TRANSFORMED COUGH FREQUENCY*/ 
 RUN;  
PROC MIXED DATA=W12_RANK METHOD=REML; 
CLASS TRT01PN USUBJID COUNTRY SEX; 
MODEL CHG_RANK = TRT01PN COUNTRY SEX BASE / DDFM=KR;  
/*CHG AND BASE ARE BASED ON THE LOG-TRANSFORMED COUGH FREQUENCY*/ 
LSMEANS TRT01PN / CL PDIFF; 
    ESTIMATE 'TRT S - P ON DAY 84' TRT01PN -1 1 
                   / CL LOWER LOWERTAILED; 
RUN; 


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A sample of the SAS code for CMH and M&H is provided as below: 
SAS PROC FREQ procedure will be used. CRIT1FN is the response variable = '1' 
(i.e. non-responder as the reference level).  
PROC SORT DATA=ADAMDATA.ADCF OUT=ADCF; 
BY USUBJID AVISITN; 
WHERE PARAMCD=' XXXXX' AND DTYPE='' AND AVISITN = x; 
RUN; 
 
/*Treatment comparison using stratified CMH*/  
PROC FREQ DATA=ADCF; 
   TABLES COUNTRY* SEX* TRT01PN* CRIT1FN/CMH  
                     alpha=0.1 ;  
   weight Count; 
run; 
 
/*Estimate difference in proportions (Serlopitant – Placebo) by Country*/ 
PROC FREQ DATA=ADCF; 
   TABLES COUNTRY* TRT01PN* CRIT1FN/ riskdiff (cl= MN CORRECT) 
                     alpha=0.1 ;  
   weight Count; 
run; 
 
/*Estimate difference in proportions (Serlopitant – Placebo) by Sex*/ 
PROC FREQ DATA=ADCF; 
   TABLES SEX* TRT01PN* CRIT1FN/ riskdiff (cl= MN CORRECT) 
                     alpha=0.1 ;  
   weight Count; 
run; 
 
/*Estimate difference in proportions (Serlopitant – Placebo) by Country and by 
Sex*/ 
PROC FREQ DATA=ADCF; 
   TABLES COUNTRY* SEX* TRT01PN* CRIT1FN/ riskdiff (cl= MN CORRECT) 
                     alpha=0.1 ;  
   weight Count; 
run; 
 
A sample of the SAS code for GLMM analysis is provided as below: 
 
PROC SORT DATA=ADAMDATA.ADCF OUT=ADCF; 
BY USUBJID AVISITN; 
WHERE PARAMCD=' XXXXX' AND DTYPE='' AND AVISITN>0; 
RUN; 
 
PROC GLIMMIX DATA=ADCF; 
CLASS TRT01PN USUBJID AVISITN COUNTRY SEX; 
MODEL CRIT1FN (EVENT='1') = TRT01PN AVISITN TRT01PN*AVISITN COUNTRY  
/ LINK=LOGIT DIST=BINARY ODDSRATIO (DIFF=FIRST); 


Menlo Therapeutics Inc. 
 
Statistical Analysis Plan Version 1.0 
Protocol No: MTI-110 
  
Page 31 of 39 
RANDOM _RESIDUAL_ / SUBJECT=USUBJID (TRT01PN) TYPE=UN; 
 
/*LS-mean estimates and SEs for proportions Serlopitant vs. placebo*/ 
LSMEANS TRT01PN*AVISITN / ILINK CL ;  
 
/*Estimates of odds ratio (Serlopitant vs. placebo) and CI at each post-
baseline visit*/ 
ESTIMATE 'TRT 5mg / P' TRT01PN -1 1,     
 
 
 'TRT 5mg / P ON DAY 28' TRT01PN -1 1  
 
               TRT01PN*AVISITN -1 0 0 1, 
 
 'TRT 5mg / P ON DAY 56' TRT01PN -1 1   
 
 
 
TRT01PN*AVISITN 0 -1 0 0 1,  
 
 'TRT 5mg / P ON DAY 84' TRT01PN -1 1  
 
 
 
TRT01PN*AVISITN 0 0 -1 0 0 1 / EXP CL UPPER UPPERTAILED; 
RUN; 
 
 
A sample of the SAS code for sensitivity analysis using the copy-reference MI method is 
provided as below:  
/*Generate transpose of adcf - wide format before Step 1*/ 
/*---- Generates 10 imputed data sets based on original (non-transformed) 
data----*/ 
 /*Step 1: Achieve Monotone Missing Data Pattern */ 
  PROC MI DATA=&DATA SEED=14823 NIMPUTE=10 OUT=MONO; 
       /* Use numeric TRT01PN */ 
     VAR BASE AVAL1 AVAL2 AVAL3; /*Refer to AVAL at Visits 5, 6, and 7*/  
     MCMC IMPUTE=MONOTONE NBITER=5000 NITER =5000; 
   BY TRT01PN; 
  run; 
   
 /*Step 2: Achieve Control-Based Copy-Reference Imputation */  
 
  PROC MI DATA=MONO SEED=14823 NIMPUTE=1 OUT=OUTM1; 
      CLASS TRT01PN; 
      By _IMPUTATION_; 
      VAR TRT01PN BASE AVAL1 AVAL2 AVAL3;  
      MONOTONE REG (AVAL2 AVAL3);  
      MNAR MODEL (AVAL1 AVAL2 AVAL3/ MODELOBS = (TRT01PN = ‘0’));    
        /*Control=Placebo*/ 
  RUN; 
  PROC SORT DATA =OUTM1; BY _IMPUTATION_ TRT01PN USUBJID LBASE; RUN; 
  /*Generate transpose of OUTM1 - skinny format before Step 3*/ 
   
/*Step 3: Run MMRM Analysis on Imputed Data */  
 
 PROC MIXED DATA=OUTM1 METHOD=REML; 
      BY _IMPUTATION_; 
CLASS TRT01PN USUBJID AVISITN COUNTRY SEX; 


Menlo Therapeutics Inc. 
 
Statistical Analysis Plan Version 1.0 
Protocol No: MTI-110 
  
Page 32 of 39 
MODEL LCHG = TRT01PN AVISITN COUNTRY SEX TRT01PN*AVISITN LBASE / DDFM=KR; 
/*LCHG AND LBASE ARE BASED ON THE LOG-TRANSFORMED COUGH FREQUENCY*/ 
REPEATED / SUBJECT=USUBJID (TRT01PN) TYPE=UN; 
LSMEANS TRT01PN*AVISITN / CL DIFF PDIFF; 
      ESTIMATE 'TRT S - P ON DAY 28' TRT01PN -1 1 
                   TRT01PN*AVISITN -1 0 0 1 / CL LOWER LOWERTAILED; 
      ESTIMATE 'TRT S - P ON DAY 56' TRT01PN -1 1 
                   TRT01PN*AVISITN 0 -1 0 0 1 / CL LOWER LOWERTAILED; 
      ESTIMATE 'TRT S - P ON DAY 84' TRT01PN -1 1 
                 TRT01PN*AVISITN 0 0 -1 0 0 1 / CL LOWER LOWERTAILED; 
     ODS OUTPUT PARAMETERESTIMATES=PESTIMATES; 
RUN; 
         
/*Step 4: Combining estimates from each imputed data set */ 
 /*First, sort the data of estimates by visit (variable “LABLE”) */ 
PROC MIANALYZE DATA=PESTIMATES;  
      MODELEFFECTS ESTIMATE; 
      STDERR STDERR; 
      BY LABEL;  
      ODS OUTPUT PARAMETERESTIMATES= MIPARM; 
RUN; 
 
A sample of the SAS code for sensitivity analysis using the tipping-point approach is provided as 
below:  
/*---------------------------------------------------------*/ 
/*--- Performs multiple imputation analysis             ---*/ 
/*--- for specified shift parameters:                   ---*/ 
/*--- data= input data set                              ---*/ 
/*--- smin= min shift parameter                         ---*/ 
/*--- smax= max shift parameter                         ---*/ 
/*--- sinc= increment of the shift parameter            ---*/ 
/*--- outparms= output parameters                       ---*/ 
/*---------------------------------------------------------*/ 
 
 
%MACRO MIPARMS( DATA=, SMIN=, SMAX=, SINC=, OUTPARMS=); 
 
DATA &OUTPARMS; 
   SET _NULL_; 
RUN; 
 
/*------------ # of shift values ------------*/ 
%LET NCASE= %SYSEVALF( (&SMAX-&SMIN)/&SINC, CEIL ); 
 
/*---- Multiple imputation analysis for each shift ----*/ 
%DO JC=0 %TO &NCASE; 
   %LET SJ= %SYSEVALF( &SMIN + &JC * &SINC); 
 
  /*---- Generates 10 imputed data sets ----*/ 


Menlo Therapeutics Inc. 
 
Statistical Analysis Plan Version 1.0 
Protocol No: MTI-110 
  
Page 33 of 39 
    
  /*Step 1: Achieve Monotone Missing Data Pattern */ 
  PROC MI DATA=&DATA SEED=14823 NIMPUTE=10 OUT=MONO; 
       ** Use numeric TRT01PN ; 
     VAR BASE AVAL1 AVAL2 AVAL3; /*Refer to AVAL at Visits 5, 6, and 7*/   
     MCMC IMPUTE=MONOTONE NBITER=5000 NITER =5000; 
     BY TRT01PN; 
  run; 
   
/*Step 2: Impute all visits under MAR first, then apply delta adjustments at 
each visit*/ 
  PROC MI DATA= OUTM1 SEED=14823 NIMPUTE=1 OUT=OUTM2; 
      CLASS TRT01PN; 
      BY _IMPUTATION_;  
      VAR TRT01PN BASE AVAL1 AVAL2 AVAL3;  
      MONOTONE REG (AVAL2 AVAL3); 
      MNAR ADJUST( AVAL1 / SHIFT=&SJ  ADJUSTOBS=(TRT01PN ='1') ); 
      MNAR ADJUST( AVAL2 / SHIFT=&SJ  ADJUSTOBS=(TRT01PN ='1') ); 
      MNAR ADJUST( AVAL3 / SHIFT=&SJ  ADJUSTOBS=(TRT01PN ='1') ); 
      RUN; 
      PROC SORT DATA =OUTM1; BY _IMPUTATION_ TRT01PN USUBJID BASE; RUN; 
/*Generate transpose of OUTM2 - skinny format before Step 3*/ 
   
/*Step 3: Run MMRM Analysis on Imputed Data */  
 
 PROC MIXED DATA=OUTM2 METHOD=REML; 
      BY _IMPUTATION_; 
CLASS TRT01PN USUBJID AVISITN COUNTRY SEX; 
MODEL LCHG = TRT01PN AVISITN COUNTRY SEX TRT01PN*AVISITN LBASE / 
DDFM=KR; /*CHG AND BASE ARE BASED ON THE LOG-TRANSFORMED COUGH 
FREQUENCY*/ 
REPEATED / SUBJECT=USUBJID (TRT01PN) TYPE=UN; 
LSMEANS TRT01PN*AVISITN / CL DIFF PDIFF; 
       ESTIMATE 'TRT S - P ON DAY 28' TRT01PN -1 1 
                   TRT01PN*AVISITN -1 0 0 1 / CL LOWER LOWERTAILED; 
       ESTIMATE 'TRT S - P ON DAY 56' TRT01PN -1 1 
                   TRT01PN*AVISITN 0 -1 0 0 1 / CL LOWER LOWERTAILED; 
       ESTIMATE 'TRT S - P ON DAY 84' TRT01PN -1 1 
                 TRT01PN*AVISITN 0 0 -1 0 0 1 / CL LOWER LOWERTAILED; 
      ODS OUTPUT PARAMETERESTIMATES=PESTIMATES; 
      RUN; 
      /*First, sort the data of estimates by visit (variable “LABLE”) */       
       PROC SORT DATA=PESTIMATES; BY LABEL; RUN: 
    /*Step 4: Combining estimates from each imputed data set */ 
PROC MIANALYZE DATA=PESTIMATES;  
      MODELEFFECTS ESTIMATE; 
      STDERR STDERR; 
      BY LABEL; 
      ODS OUTPUT PARAMETERESTIMATES=MIPARM; 


Menlo Therapeutics Inc. 
 
Statistical Analysis Plan Version 1.0 
Protocol No: MTI-110 
  
Page 34 of 39 
RUN; 
 
DATA MIPARM; 
SET MIPARM; 
     SHIFT= &SJ; 
RUN; 
 
 /*----- Output multiple imputation results ----*/ 
DATA &OUTPARMS; 
  SET &OUTPARMS MIPARM; 
RUN; 
 
%END; 
%MEND MIPARMS; 
 
/*Assume that the tipping point for the shift parameter that reverses the 
study conclusion is between 0 and 100. The following statement performs 
multiple imputation analysis for each of the shift parameters 0,10,20,30,…, 
100.*/ 
 
ODS LISTING CLOSE; 
%MIPARMS(DATA=XXXX, SMIN=0, SMAX=100, SINC=10, OUTPARMS=PARMS1); 
 
 
/* Step 5: Finding Tipping Point for Shift Parameter between 0 and 100 such 
that p-value is less than 0.05, below is an example for a tipping point for 
the shift parameter between 40 and 50. 
 
For a two-sided Type I error level of 0.05, the tipping point for the shift 
parameter is greater than 40. The following statement performs multiple 
imputation analysis for shift parameters 40, 41, …, 50*/ 
 
%MIPARMS(DATA=XXXX, SMIN=40, SMAX=50, SINC=1, OUTPARMS=PARM2); 
/*The following statements display the p-values that are associated with the 
shift parameters.*/ 
 
PROC PRINT LABEL DATA=PARM2; 
   VAR SHIFT PROBT; 
   TITLE 'P-VALUES FOR SHIFT PARAMETERS'; 
   LABEL PROBT='PR > |T|'; 
   FORMAT PROBT 8.4; 
RUN; 


Menlo Therapeutics Inc. 
 
Protocol Number MTI-110 
  
Page 35 of 39 
 
APPENDIX B: SCHEDULE OF ASSESSMENTS 
MTI-110 Schedule of Visit Activities 
Study Procedures 
Screening 
Baseline 
Treatment Period 
Follow-up 
 
Day –14 to Day –1a,b 
Day 0 
Day 1h 
Day 14k,o 
Day 28k 
Day 56k 
 Day 84h,k 
Day 85/ETD 
Day 112h,k,r 
Day 113 
Written Informed Consentn 
X 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
X 
 
 
 
 
 
 
 
 
Demographics; Medical & 
Medication History 
X 
Xd 
 
 
 
 
 
 
 
 
Chest Radiograph or CT Thoraxl 
X 
 
 
 
 
 
 
 
 
 
Physical Examination 
X 
 
 
 
 
 
 
X 
 
X 
Vital Signs 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
Height & Weight 
X 
 
 
 
Xm 
Xm 
 
Xm 
 
 
ECG (12-lead) 
X 
 
 
 
X 
X 
 
X 
 
X 
Spirometry 
X 
 
 
 
 
 
 
 
 
 
Clinical Laboratory Sampling 
X 
 
 
 
Xp 
Xp 
 
X 
 
X 
Urinalysis 
X 
 
 
 
X 
X 
 
X 
 
X 
Urine Drug Screen 
X 
 
 
 
X 
X 
 
X 
 
X 
Serum Pregnancy Test  
X 
 
 
 
 
 
 
 
 
 
Urine Pregnancy Test 
 
X 
 
 
X 
X 
 
X 
 
X 
PK Sample 
 
 
 
 
X 
X 
 
 
 
 
Attach Cough Monitor 
 
Xg 
 
 
Xg 
Xg 
Xf,g 
 
Xf,g 
 
Collect Cough Monitor 
 
 
Xf 
 
Xj 
Xj 
 
X 
 
X 
Adverse Event Monitoring 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
LCQ 
 
X 
 
 
X 
X 
 
X 
 
X 
Dosing Diary 
 
 
Daily during treatment period 
 
 
 
Cough Severity VAS 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
Study Drug Distribution and/or 
Accountability 
 
Xe 
Xc,i 
 
X 
X 
X 
Xq 
 
 
Review Dosing Diary Entries 
 
 
X 
X 
X 
X 
X 
X 
 
 
PGIC 
 
 
 
 
X 
X 
 
X 
 
 
CGIC 
 
 
 
 
 
 
 
X 
 
 
Abbreviations: CGIC – Clinician’s Global Impression of Change; ECG – electrocardiogram; ETD – early treatment discontinuation; 
LCQ – Leicester Cough Questionnaire; PGIC – Patient’s Global Impression of Change; VAS – visual analog scale. 


Menlo Therapeutics Inc. 
 
Protocol Number MTI-110 
  
Page 36 of 39 
 
a 
Multiple clinic visits may be required to complete all screening assessments. 
b 
The Screening Period may be fewer than 14 days.  Additionally, the Screening Period may be extended beyond 14 days if the Menlo Therapeutics Medical Monitor requires additional follow-up on 
findings from any of the Screening assessments.  
c 
First dose of study drug administered on Study Day 1 after the cough monitor is removed and before 10am.  
d 
Medical and medication history only. 
e 
Study drug is dispensed in a lockbox if subjects do not return to the clinic for Day 1.  
f 
May be managed by mobile research nurses. 
g 
Cough monitor should be attached before 10am and worn for 24 hours during each assessment. 
h 
Visits may be conducted at subject’s home (by mobile research nurses). 
i 
Mobile research nurses will retrieve the study drug from a lockbox on Day 1. 
j 
Cough monitor will be collected by a courier and delivered to the clinic on the following day. 
k 
Visit window is ± 3 days. 
l 
If not done within the past 5 years (considered to be part of standard of care in the UK). 
m 
Weight only 
n 
 Informed consent must occur prior to any protocol-mandated procedures, including stopping of any excluded therapies. This may occur prior to Day -14.  
o 
Telephone visit. 
p 
Endocrine and reproductive endocrine tests are not done at Days 28 and 56. 
q 
ETD visit only at Day 85. 
r 
Day 112 not required if subject has discontinued treatment early. 
 
 
 
 
 


Menlo Therapeutics Inc. 
 
Protocol Number MTI-110 
  
Page 37 of 39 
APPENDIX C: STUDY VISIT MAP WITH MATCHED INTERVAL ID 
 
Study Visits and Matched Interval IDs in Datasets 
Study 
Procedures 
Screening 
 
Baseline 
 
Treatment Period 
Follow-up 
VISIT 
Screening 
Day 0 
Study Day -1 
Day 1 
Day 14 
Day 28 
 
Day 56 
Day 84 
Day 85 
/ETD 
Day 112 
 
Day 113 
VISITNUM 
1 
2 
3 
4 
5 
6 
7 
8 
9 
 
10 
Interval ID 
148 
149 
150 
151 
155 
156 
157 
158 
159 
 
  160 
Study Visit 
Window 
 
 
1ST DAY 
DOSING 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
Vital Sign Dataa 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
Cough Severity 
VAS Monitoring 
Dataa 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
Telephone 
Contact Dataa 
 
 
 
X 
 
 
 
 
 
 
Cough 
Monitoring 
Datab 
 
X 
 
 
X 
X 
X 
 
X 
 
a Data collected at visits marked as X. Visit dates will be derived based on the following three datasets: vital sign, cough severity VAS monitoring, 
and telephone contact. If there is any discrepancy in a visit date, the date recorded in vital sign dataset will be considered as the primary date. 
bThe cough monitoring data has regular visits labeled as Baseline, Day28, Day56, Day84, and Day112, and the repeated visits labeled as Baseline-
R, Day28-R, Day56-R, Day84-R and Day112-R. Both regular and repeated records at the specific visit will be included in analysis data. Repeated 
evaluations are usually due to equipment failures or unacceptable initial evaluations.  
 
 


Menlo Therapeutics Inc. 
 
Protocol Number MTI-110 
  
Page 38 of 39 
APPENDIX D: CLINICAL LABORATORY TESTS 
For all lab outputs order parameters as indicated in each category as below:  
Hematology  
Chemistry  
Urinalysis 
 
HGB 
Hemoglobin (g/dL) 
ALP 
Alkaline Phosphatase (U/L) 
APPEAR 
Appearance 
HCT 
Hematocrit (%) 
ALT 
Alanine Aminotransferase (U/L) 
COLOR 
Color 
RBC 
Erythrocytes (10^6/uL) 
AST 
Aspartate Aminotransferase (U/L) 
KETONES 
Ketones 
WBC 
Leukocytes (10^3/uL) 
BILI 
Bilirubin (mg/dL) 
LEUKASE 
Leukocyte Esterase 
NEUT 
Neutrophils (10^3/uL) 
ALB 
Albumin (g/dL) 
NITRITE 
Nitrites 
NEUTLE 
Neutrophils/Leukocytes (%) 
CA 
Calcium (mg/dL) 
OCCBLD 
Occult Blood 
LYM 
Lymphocytes (10^3/uL) 
K 
Potassium (mmol/L) 
PH 
pH 
LYMLE 
Lymphocytes/Leukocytes (%) 
URATE 
Urate (mg/dL) 
SPGRAV 
Specific Gravity 
MONO 
Monocytes (10^3/uL) 
CREAT 
Creatinine (mg/dL) 
BILI 
Bilirubin 
MONOLE 
Monocytes/Leukocytes (%) 
GLUC 
Glucose (mg/dL) 
GLUC 
Glucose 
EOS 
Eosinophils (10^3/uL) 
SODIUM 
Sodium (mmol/L) 
PROT 
Protein 
EOSLE 
Eosinophils/Leukocytes (%) 
MG 
Magnesium (mg/dL) 
UROBIL 
Urobilinogen 
BASO 
Basophils (10^3/uL) 
CL 
Chloride (mg/dL) 
 
 
BASOLE 
Basophils/Leukocytes (%) 
LDH 
Lactate Dehydrogenase (U/L) 
 
 
PLAT 
Platelets (10^3/uL) 
CHOL 
Cholesterol (mg/dL) 
 
 
MCH 
Ery. Mean Corpuscular 
Hemoglobin (pg) 
HDL 
HDL Cholesterol (mg/dL) 
 
 
MCHC 
Ery. Mean Corpuscular HGB 
Concentration (g/dL) 
LDL 
LDL Cholesterol (mg/dL) 
 
 
MCV 
Ery. Mean Corpuscular 
Volume (fL) 
TRIG 
Triglycerides (mg/dL) 
 
 
 
 
UREAN 
Urea Nitrogen (mg/dL) 
 
 
Endocrinology 
PHOS 
Phosphate (mg/dL) 
 
 
TSH 
TSH ULTRASENSITIVE 
(uIU/mL) 
CPROT 
Protein (g/dL) 
 
 
CORTISOL 
CORTISOL, SERUM 
RANDOM (ug/dL) 
BICARB 
Bicarbonate (mmol/L) 
 
 
ACTH 
ACTH, PLASMA (pg/mL) 
 
 
 
 
T4FR 
Thyroxine, Free (ng/dL) 
 
 
 
 
 
 
Reproductive endocrinology (females under 55)    
 
 
 
ESTRDIOL 
Estradiol (pg/mL) 
 
 
 
 
FSH 
FSH (mIU/mL) 
 
 
 
 
LH 
Luteinizing Hormone (mIU/mL) 
 
 
 
 
PROGEST 
Progesterone (ng/mL) 
 
 
 
 
AMH 
ANTI-MULLERIAN HORMONE 
(ng/mL) 
 
 


Menlo Therapeutics Inc. 
 
Protocol Number MTI-110 
  
Page 39 of 39 
Urine Microscopic 
7BAC 
BACTERIA(/HPF)   
V7OXC 
CA OXALASTE CRYSTALS (/HPF) 
7EPIR 
EPITHELIAL RENAL (/HPF) 
7EPIS 
EPITHELIAL SQUAMOUS (/HPF) 
7EPIT 
EPITHELIAL TRANSITIONAL (/HPF) 
V7GRC 
GRANULAR CAST (/LPF) 
7UHC2 
HYALINE CAST (/LPF) 
V7RCS 
RBC CAST (/LPF) 
7URBC 
RBCS (/HPF) 
V7TPC 
TRI PHOSPHATE CRYSTALS (/HPF) 
V7UAC 
URIC ACID CRYSTALS 
V7WAC 
WAXY CAST (/LPF) 
V7WCS 
WBC CAST (/LPF) 
7UWBC 
WBCS (/HPF) 
V7YST 
YEAST (/HPF) 
 
 
 
 
 
 
Urine Drug Screen  
OPIATE 
OPIATES 
OXYCDN 
OXYCODONE 
HYDCDN 
HYDROCODONE 
HYDMRPHN 
HYDROMORPHONE 
OXMCC 
OXYMORPHONE 
MORPHINE 
MORPHINE 
CODEINE 
CODEINE 
 
 
 
 
Pregnancy, Qualitative  
HCG 
Choriogonadotropin Beta (ng/mL) 
 
 
Urine Pregnancy (reported on eCRF) 
 
 
Other Tests (Manual Diff W/CALC ABS) 
PK (Primary and Secondary)