Clinical trial NCT02975206
Conditions: Pruritus Atopic Dermatitis
Sponsor: Vyne Therapeutics Inc.
Start date: 2016-11-01; Completion date: 2018-02-23
Enrollment: 484 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Study of the Efficacy, Safety, and Tolerability of Serlopitant for Pruritus (Itch) in Atopic Dermatitis

Detailed description:
This is a double-blind, randomized, placebo-controlled study. Approximately 450 subjects will be randomized in a 1:1:1 ratio to receive daily oral doses of serlopitant 1 mg, 5 mg, or placebo for 6 weeks. During the screening period, subjects will be provided with an electronic device for recording electronic diary (eDiary) assessments throughout the study. This eDiary will be used to capture efficacy endpoint data and treatment information. At the Baseline visit, eligible subjects will be randomized, and study drug dispensed beginning with a loading dose of 3 tablets to be taken at bedtime that same day. Starting on Study Day 2, subjects will take one tablet per day at bedtime. Treatment will continue for 6 weeks. The primary efficacy endpoint will be assessed during Week 6. After completion of the 6-week treatment period, all subjects will enter a 4-week follow-up period.

Arms: arm 1: serlopitant tablets - high dose arm 2: serlopitant tablets - low dose arm 3: matching placebo tablets
Interventions: intervention 1: Serlopitant High Dose intervention 2: Placebo Oral Tablet intervention 3: Serlopitant Low Dose
Intervention descriptions: intervention 1: serlopitant tablets - high dose intervention 2: placebo tablet intervention 3: serlopitant tablets - low dose

Protocol documents:
Prot_000.pdf: 
Menlo Therapeutics Inc. 
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Protocol MTI-103 
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CLINICAL STUDY PROTOCOL 
TITLE: 
A RANDOMIZED, DOUBLE-BLIND, PLACEBO-
CONTROLLED STUDY OF THE EFFICACY, SAFETY, 
AND TOLERABILITY OF SERLOPITANT FOR THE 
TREATMENT OF PRURITUS IN ADULTS AND 
ADOLESCENTS WITH A HISTORY OF ATOPIC 
DERMATITIS (ATOMIK) 
IND No.: 
117780 
ClinicalTrials.gov ID: 
NCT02975206 
Protocol No.:  
MTI-103 
Protocol Version / Date: 
Version 3.0 / 21-NOV-2017 
Development Phase:  
Phase 2 
Sponsor: 
Menlo Therapeutics Inc. 
200 Cardinal Way, 2nd Floor 
Redwood City, CA 94063  
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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Version 3.0 
 
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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 PRURITUS IN ADULTS AND 
ADOLESCENTS WITH A HISTORY OF ATOPIC 
DERMATITIS (ATOMIK) 
 
IND No.: 
 
 
117780 
 
ClinicalTrials.gov ID: 
NCT02975206 
 
Protocol No.:  
 
MTI-103 
 
Protocol Version / Date: 
Version 3.0 / 21-NOV-2017 
 
Development Phase:  
Phase 2 
 
Sponsor: 
 
 
Menlo Therapeutics Inc. 
200 Cardinal Way, 2nd Floor 
Redwood City, CA 94063  
 
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) 


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SPONSOR PROTOCOL APPROVAL SIGNATURE(S) 
TITLE: 
IND No.: 
ClinicalTrials.gov ID: 
Protocol No.: 
Protocol Version: 
Development Phase: 
Sponsor: 
Approved by: 
 
Senior Vice President, 
Clinical Development 
Version 3.0 
A RANDOMIZED, DOUBLE-BLIND, PLACEBO-
CONTROLLED STUDY OF THE EFFICACY, SAFETY, 
AND TOLERABILITY OF SERLOPIT ANT FOR THE 
TREATMENT OF PRURITUS IN ADULTS AND 
ADOLESCENTS WITH A HISTORY OF ATOPIC 
DERMATITIS (A TOMIK) 
117780 
NCT02975206 
MTI-103 
3.0 
Phase 2 
Menlo Therapeutics Inc. 
200 Cardinal Way, 2nd Floor 
Redwood City, CA 94063 
USA 
;? I -;Vov - ;2-Vl7--
Date (DD-MMM-YYYY) 
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 Pruritus in Adults 
and Adolescents with a History of Atopic Dermatitis (ATOMIK) 
Protocol Number: 
MTI-103 
Sponsor: 
Menlo Therapeutics Inc. 
Development Phase: 
Phase 2 
Study Objectives: 
Primary objective: To assess the efficacy of serlopitant for the treatment of 
pruritus in adults and adolescents with a history of atopic dermatitis. 
Secondary objectives: 
• 
To assess the safety and tolerability of repeated oral doses of 
serlopitant in adults and adolescents with a history of atopic dermatitis. 
• 
To assess the psychometric properties of Worst-Itch Numeric Rating 
Scale (WI-NRS). 
Study Design: 
This is a double-blind, randomized, placebo-controlled study to assess the 
efficacy, safety, and tolerability of serlopitant for the treatment of pruritus in 
adults and adolescents with a history of atopic dermatitis. Subjects who meet the 
study entry criteria will be randomized in a 1:1:1 ratio to receive daily oral doses 
of serlopitant 1 mg, 5 mg, or placebo for 6 weeks. The study will be conducted 
at approximately 40 study sites. 
The study will consist of three periods, for a total study period of approximately 
12 weeks: 
• 
Screening period: 2 weeks 
• 
Treatment period: 6 weeks 
• 
Follow-up period: 4 weeks 
During the screening period, subjects will undergo eligibility evaluation and will 
have their baseline symptom scores established. Subjects must be willing and 
able to complete an electronic diary (eDiary) within a consistent timeframe on a 
daily basis, to wear actigraphy devices during sleep, and 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 1 mg, serlopitant 5 mg, or placebo. Subjects will take a loading dose 
(3 tablets taken orally) at bedtime 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 at bedtime. 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 during Week 6 of treatment.  
After completion of the 6-week treatment period, all subjects will enter a 4-week 
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. 


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Safety Review: 
An independent Data Monitoring Committee (iDMC) will be established to 
monitor unblinded safety data on a regular basis throughout the study. The 
iDMC may make recommendations to the Sponsor to continue or terminate the 
study based upon the outcomes of the data reviews. 
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. 
Planned Sample Size: 
Approximately 450 subjects will be randomized. 
Study Population: 
The study will consist of adults and adolescents with a history of atopic 
dermatitis who have pruritus despite treatment with standard of care anti-pruritic 
therapies.  
Inclusion Criteria: 
1. Male or female, age 13 years or older at consent/assent. 
a. 
For subjects below the legal age of consent, the subject must 
be willing and able to provide assent and to comply with study 
visits and study-related requirements and his/her 
parent(s)/guardian(s) must be willing and able to provide 
written informed consent. 
2. Pruritus of at least 4 weeks duration prior to the initial Screening visit 
and during the 2-week screening period, despite treatment with 
standard of care anti-pruritic therapies such as H1 antihistamines or 
emollients. 
a. 
Subjects using stable doses of oral H1 antihistamines at the 
initial Screening visit must be willing to continue these at the 
same doses and frequencies throughout the study inclusive of 
the follow-up period. 
3. WI-NRS score ≥ 7 in the 24-hour period prior to the initial Screening 
visit.  
4. Average weekly WI-NRS score ≥ 6 for each week of the Screening 
period, as recorded in the eDiary. 
5. Diagnosis of atopic dermatitis, as defined by the 2014 American 
Academy of Dermatology (AAD) Guidelines of Care for the 
Management of Atopic Dermatitis.1 
a. 
Subjects with active atopic dermatitis skin involvement must 
have had stable skin disease, defined as experiencing no 
disease flares, for at least 4 weeks immediately prior to 
randomization. Subjects using stable doses of bland 
emollients, topical calcineurin inhibitors, and/or low- to 
mid-potency topical corticosteroids at the initial Screening 
visit must be willing to continue these at the same doses and 
frequencies throughout the study. 
b. Subjects without active atopic dermatitis skin involvement 
must have had a past diagnosis of atopic dermatitis, supported 
by written records documenting the presence of features 
consistent with the 2014 AAD Guidelines. 
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. All fertile male 
subjects, with partners who are females of childbearing potential, must 
use condoms from randomization until 4 weeks after last dose of study 


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drug. All subjects who are fertile males or females of childbearing 
potential must also refrain from sperm/egg donation starting from first 
dose of study drug and until 4 weeks after last dose of study drug. 
Please refer to Section 7.1.5 for acceptable methods of contraception. 
7. Weight ≥ 32 kg at the baseline visit. 
8. Willing and able to complete once-daily eDiary entries within a 
consistent timeframe for the duration of the study. 
a. 
Subjects must have ≥ 80% eDiary completion rate during the 
screening period. 
9. Judged to be in good health in the investigator’s opinion. 
Exclusion Criteria: 
1. Prior treatment with serlopitant or other neurokinin-1 receptor (NK1-R) 
antagonists (e.g. aprepitant). 
2. Clearly defined etiology for pruritus other than atopic dermatitis. These 
include but are not limited to urticaria, psoriasis or other non-atopic 
dermatologic conditions, hepatic or renal disease, psychogenic pruritus, 
drug reaction, untreated hyperthyroidism, and infection. 
3. Presence of any acute condition which may risk inducing an atopic 
dermatitis flare during the course of the study, such as impetigo or 
active herpes simplex infection. 
4. Treatment with systemic corticosteroids within 4 weeks prior to 
randomization. 
a. 
Treatment with non-systemic corticosteroids that do not 
involve skin application (e.g. inhaled, intranasal, or intra-
articular corticosteroids) will be permitted. 
5. Treatment with Class III or higher potency topical corticosteroids2 or 
any topical anti-pruritic therapies (other than stable doses low- or 
mid-potency topical corticosteroids, topical calcineurin inhibitors, or 
bland emollients) within 2 weeks prior to randomization. 
6. Treatment with systemic therapies with recognized anti-pruritic 
(e.g. tricyclic antidepressants, sedatives, tranquilizers, gabapentin, 
marijuana or other cannabinoids, opioid receptor agonists/antagonists) 
or pruritic (e.g. opioids, angiotensin-converting enzyme inhibitors, 
cocaine, antimalarials) properties within 4 weeks prior to 
randomization. 
a. 
Stable doses of H1 antihistamines will be permitted (see 
Inclusion Criterion 2a). 
7. For subjects using bland emollients, low- or mid-potency topical 
corticosteroids, topical calcineurin inhibitors, and/or oral H1 
antihistamines, any clinically significant changes in dose or frequency 
during the screening period. 
8. Treatment with systemic immunosuppressive/ immunomodulatory 
therapies within 4 weeks prior to randomization (including but not 
limited to phosphodiesterase-4 inhibitors, cyclosporine, 
mycophenolate-mofetil, methotrexate, azathioprine, interferon-gamma, 
or phototherapy). 
9. Treatment with biologic therapies within 8 weeks or 5 half-lives prior 
to randomization, whichever is longer. 
10. Treatment with strong CYP3A4 inhibitors within 4 weeks prior to 
randomization (see Appendix B). 


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11. Use of an indoor tanning facility within 4 weeks prior to 
randomization. 
12. Treatment with any investigational therapy within 4 weeks prior to 
randomization. 
13. Allergen immunotherapy within 6 months prior to randomization. 
14. Serum creatinine, total bilirubin, alanine aminotransferase (ALT) or 
aspartate aminotransferase (AST) > 2x the upper limit of normal 
(ULN) during screening. 
15. History of malignancy within 5 years prior to randomization, with the 
exception of completely treated and non-metastatic basal cell 
carcinoma or squamous cell carcinoma of the skin. 
16. History of a major psychiatric condition (including major depressive 
disorder, bipolar disorder, or schizophrenia), suicidal ideation, or 
suicide attempt. 
17. Known active hepatitis infection. 
18. Known history of human immunodeficiency virus (HIV) infection. 
19. Documented history of parasitic infection, including skin parasites such 
as scabies, within 12 months prior to randomization. 
20. Known active parasitic infection. 
21. Regular long-distance running (e.g. 10Ks, marathons) or long-distance 
bicycling (e.g. 30 + miles) and/or strenuous physical activity 
(e.g. bodybuilding) within 2 weeks prior to randomization. 
22. 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. 
23. History of hypersensitivity to serlopitant or any of its components. 
24. Currently pregnant or breastfeeding, or male subject with a pregnant or 
breastfeeding partner. 
25. Females of childbearing potential who are unable or unwilling to 
practice highly effective contraception (pregnancy prevention); fertile 
males who are unable or unwilling to use condoms with female 
partners of childbearing potential. 
Study Drug: 
Serlopitant 1 mg and 5 mg oral tablets and matching placebo. 
Dosage:  
Serlopitant: 1 mg or 5 mg once daily by mouth for 6 weeks, following a 3-tablet 
loading dose on the first day of the treatment period. 
Matching placebo: Once daily by mouth for 6 weeks, following a 3-tablet 
loading dose on the first day of the treatment period. 
Primary Efficacy 
Endpoint: 
The primary efficacy endpoint is the change in WI-NRS from baseline to Week 
6. 
Secondary Efficacy 
Endpoints: 
The key secondary efficacy endpoints are as follows: 
• 
WI-NRS 4-point responder rate at Week 6 
• 
Change in ItchyQoL from baseline to Week 6 
Additional secondary efficacy endpoints include the following: 
• 
WI-NRS 3-point responder rates 
• 
Change in Average-Itch NRS (AI-NRS) and AI-NRS responder rates 
• 
Change in 5-D Pruritus Scale 


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• 
Change in Static Patient Global Assessment of Itch Severity (sPGA) 
• 
Change in Patient Global Impression of Change in Itch Severity 
(PGIC) 
• 
Change in number of night-time scratching events per hour from 
baseline to Week 6 
Safety Endpoints: 
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 electrocardiogram (ECG) parameters 
following study drug exposure 
• 
Plasma concentrations of serlopitant and metabolites 
Exploratory Endpoints: 
Exploratory endpoints include the following: 
• 
Change in Investigators’ Global Assessment of atopic dermatitis 
severity (IGA-AD) 
• 
Change in sleep efficiency  
• 
Change in mean activity during the sleep period 
Decision Rule and 
Sample Size 
A stepdown procedure will be used to control for multiplicity of dose groups 
with testing starting with the 5 mg group and then proceeding to the 1 mg group. 
A gatekeeper procedure within dosing group will be used for the key secondary 
endpoints. 
The sample size of 150 per group has been selected to achieve 90% power for 
the pairwise tests with a 5% one-sided alpha level assuming a treatment effect 
(placebo change from baseline - serlopitant change from baseline) of -1 and a 
standard deviation of 2.9. 
Statistical Methods: 
Efficacy analyses will be based upon an intent-to-treat philosophy. The primary 
efficacy population will be the Full Analysis Set (FAS) that will include all 
randomized and treated subjects. Subjects will be analyzed within the treatment 
group to which they are randomized. 
Efficacy Analyses: 
The primary efficacy endpoint will be tested using an analysis of variance 
(ANOVA) model controlling for the stratification factors. A main effects model 
with an interaction term (treatment by stratification factors) and a Type II 
hypothesis will be used. Missing data imputation will be used for subjects who 
fail to complete the eDiary at Week 6 or receive excluded therapy. The primary 
endpoint will be summarized with descriptive statistics by treatment group and 
study week. These summary statistics will include estimates of the treatment 
differences and associated confidence interval.  
Testing, using an analysis of variance (ANOVA) model or Cochran Mantel 
Haenszel (CMH) test of the key secondary endpoints will also be employed. 
Safety Analyses: 
The incidence of all adverse events (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 


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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. Graphs of laboratory values 
over time will also be produced.  
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. 
Study Sites: 
Approximately 40 study sites 
Planned Dates of Study: 
Oct 2016-Dec 2017 
Expected Duration of 
Subject’s Participation 
Approximately 12 weeks: 2 weeks of screening, 6 weeks of treatment, and a 
follow-up period of 4 weeks. 
 
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 .........................................................................................................10 
LIST OF APPENDICES ..........................................................................................................13 
LIST OF FIGURES .................................................................................................................13 
LIST OF TABLES ...................................................................................................................13 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..........................................14 
1 
INTRODUCTION .................................................................................................15 
1.1 
Atopic Dermatitis and Pruritus ........................................................................15 
1.2 
Substance P and the Neurokinin-1 Receptor ...................................................15 
1.3 
Serlopitant ........................................................................................................16 
1.3.1 
Serlopitant Background .......................................................................16 
1.3.2 
Serlopitant in Chronic Pruritus ............................................................16 
2 
STUDY OBJECTIVES ..........................................................................................18 
3 
STUDY DESIGN...................................................................................................18 
3.1 
Overall Study Design .......................................................................................18 
3.2 
Rationale for Study Design and Dose Selection ..............................................19 
3.3 
Study Endpoints ...............................................................................................20 
3.3.1 
Primary Efficacy Endpoint ..................................................................20 
3.3.2 
Key Secondary Efficacy Endpoints .....................................................20 
3.3.3 
Additional Secondary Efficacy Endpoints ...........................................20 
3.3.4 
Safety Endpoints ..................................................................................20 
3.3.5 
Exploratory Endpoints .........................................................................21 
3.4 
Safety Review ..................................................................................................21 
3.4.1 
Independent Data Monitoring Committee ...........................................21 
3.4.2 
Safety Monitoring Team ......................................................................21 
4 
SELECTION OF STUDY POPULATION ...........................................................21 
4.1 
Study Population ..............................................................................................21 
4.2 
Inclusion Criteria .............................................................................................21 
4.3 
Exclusion Criteria ............................................................................................22 
5 
STUDY DRUG ......................................................................................................24 
5.1 
Study Drug Supply, Route of Administration, and Storage.............................24 
5.2 
Labeling and Study Drug Accountability ........................................................24 
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 ............................................................................25 
5.6.1 
Early Termination ................................................................................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 ...................27 
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 ......................................................28 
6.1 
Efficacy Parameters .........................................................................................28 
6.1.1 
Itch Numeric Rating Scale ...................................................................28 
6.1.2 
Static Patient Global Assessment of Itch Severity ...............................29 
6.1.3 
Patient Global Impression of Change in Itch Severity .........................29 
6.1.4 
ItchyQoL ..............................................................................................29 
6.1.5 
5-D Pruritus Scale ................................................................................29 
6.1.6 
Actigraphy............................................................................................29 
6.1.7 
Investigators’ Global Assessment of Atopic Dermatitis Severity .......30 
6.2 
Safety Parameters.............................................................................................30 
6.2.1 
Vital Signs ............................................................................................30 
6.2.2 
Physical Examination...........................................................................30 
6.2.3 
Clinical Laboratory Assessments .........................................................31 
6.2.4 
Electrocardiogram ................................................................................31 
6.3 
Pharmacokinetics Measurements .....................................................................31 
6.4 
Subject Flow Diagram .....................................................................................31 
6.5 
Study Visits ......................................................................................................32 
6.5.1 
Informed Consent/Assent.....................................................................32 
6.5.2 
Screening Visit/Period .........................................................................33 
6.5.3 
Baseline Visit .......................................................................................33 
6.5.4 
Week 1 Visit ........................................................................................34 
6.5.5 
Week 2 Visit ........................................................................................34 
6.5.6 
Week 4 Visit ........................................................................................35 
6.5.7 
Week 6 Visit ........................................................................................35 
6.5.8 
Early Treatment Discontinuation Visit ................................................36 
6.5.9 
Follow-up Visit ....................................................................................37 
7 
ASSESSMENT OF SAFETY ................................................................................37 


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7.1 
Definitions........................................................................................................37 
7.1.1 
Adverse Event ......................................................................................37 
7.1.2 
Serious Adverse Event .........................................................................38 
7.1.3 
Abnormal Physical Exam, Laboratory, Vital Sign, and 
Electrocardiogram Findings .................................................................38 
7.1.4 
Deaths ..................................................................................................39 
7.1.5 
Pregnancies and Contraception Requirements for Males and 
Females ................................................................................................39 
7.1.6 
Worsening of Pruritus or Atopic Dermatitis ........................................40 
7.2 
Methods and Timing for Recording and Reporting Adverse Events ...............41 
7.2.1 
Adverse Event Reporting Period .........................................................41 
7.2.2 
Eliciting Adverse Events......................................................................41 
7.2.3 
Assessment of Severity ........................................................................41 
7.2.4 
Assessment of Causality ......................................................................42 
7.3 
Follow-up of Adverse Events and Serious Adverse Events ............................43 
7.4 
Reporting Serious Adverse Events to the Sponsor and Institutional Review 
Board or Ethics Committee ..............................................................................43 
7.5 
Reporting Serious Adverse Events to Regulatory Authorities and Study 
Investigators .....................................................................................................43 
7.6 
Emergency Unblinding ....................................................................................43 
8 
STATISTICAL METHODS ..................................................................................43 
8.1 
Decision Rule and Sample Size .......................................................................44 
8.2 
Handling of Missing Data and Excluded Therapy Use ...................................44 
8.3 
Analysis Populations ........................................................................................45 
8.4 
Subject Disposition ..........................................................................................45 
8.5 
Subject Characteristics .....................................................................................45 
8.6 
Concomitant Medications ................................................................................45 
8.7 
Treatment Compliance and Extent of Exposure ..............................................46 
8.8 
Efficacy Analyses ............................................................................................46 
8.9 
Psychometric Analyses ....................................................................................47 
8.10 
Safety Analyses ................................................................................................47 
8.10.1 
Adverse Events ....................................................................................47 
8.10.2 
Clinical Safety Laboratory Results ......................................................47 
8.10.3 
Vital Signs ............................................................................................47 
8.10.4 
Electrocardiograms ..............................................................................48 
8.11 
Interim Analyses ..............................................................................................48 
8.12 
Pharmacokinetics Data.....................................................................................48 
9 
ADMINISTRATIVE ASPECTS ...........................................................................48 
9.1 
Changes to the Protocol ...................................................................................48 


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9.2 
Study Termination ...........................................................................................48 
9.3 
Monitoring and Auditing Procedures...............................................................48 
9.4 
Transfer of Obligations ....................................................................................49 
9.5 
Informed Consent.............................................................................................49 
9.6 
Communication with the Institutional Review Board or Ethics Committee ...49 
9.7 
Disclosure and Confidentiality ........................................................................49 
9.8 
Records and Electronic Case Report Forms ....................................................50 
9.9 
Good Clinical Practices and Ethical Study Conduct........................................50 
9.10 
End of Study Notification ................................................................................50 
9.11 
Publication of Results ......................................................................................51 
9.12 
Final Report .....................................................................................................51 
10 
REFERENCES ......................................................................................................52 
 
LIST OF APPENDICES 
Appendix A 
Schedule of Activities and Assessments ....................................................55 
Appendix B 
List of Strong CYP3A4 Inhibitors .............................................................57 
 
LIST OF FIGURES 
Figure 1 
Subject Flow Diagram ...............................................................................32 
 
LIST OF TABLES 
Table 1 
Adverse Event Grading ..............................................................................42 
Table 2 
Schedule of Visit Activities .......................................................................55 
Table 3 
Schedule of eDiary and Actigraphy Assessments .....................................56 
 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
AAD 
American Academy of Dermatology 
AD 
Atopic dermatitis  
ADL 
Activities of daily living 
AE 
Adverse event 
AI-NRS 
Average-Itch Numeric Rating Scale 
ALT 
Alanine aminotransferase  
ANOVA 
Analysis of variance 
AST 
Aspartate aminotransferase 
ATC 
Anatomical Therapeutic Classification 
BOCF 
Baseline Observation Carried Forward 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
eDiary 
Electronic diary 
ETD 
Early treatment discontinuation 
FAS 
Full Analysis Set 
iDMC 
Independent Data Monitoring Committee 
ICF 
Informed Consent Form 
IGA-AD 
Investigators’ Global Assessment of atopic dermatitis severity 
IRB 
Institutional Review Board 
IWRS 
Interactive Web Response System  
LOCF 
Last Observation Carried Forward 
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 
SAE 
Serious adverse event 
SOC 
System organ class 
SP 
Substance P 
sPGA 
Static Patient Global Assessment 
TEAE 
Treatment-emergent adverse event 
VAS 
Visual Analog Scale 
WI-NRS 
Worst-Itch Numeric Rating Scale 
 


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1 
INTRODUCTION 
1.1 
Atopic Dermatitis and Pruritus 
Atopic dermatitis (AD, atopic eczema, eczema) is an inflammatory, chronically relapsing and 
intensely pruritic skin disease occurring often in families with atopic diseases (AD, asthma, 
and/or allergic rhinoconjunctivitis).3 It is frequently referred to as “the itch that rashes,”4 
highlighting the central role that pruritus plays in AD pathology. Pruritus is the “cardinal 
symptom” in AD5 and it has been characterized as the “most distressing” symptom of AD.6 
Mollanazar et al7 describe a prevalence of 58%-91% of chronic pruritus in patients with AD. 
Overall, pruritus is responsible for much of the disease burden borne by patients and their 
families.1 
1.2 
Substance P and the Neurokinin-1 Receptor 
The itch/scratch cycle is a hallmark of atopic dermatitis and is a major factor in perpetuating 
the disease.6 The itch in atopic dermatitis often begins without visible lesions8,9  and has been 
shown to involve altered sensory responses to exogenous and endogenous stimuli10,11 as well 
as modifications in sensory innervation of involved skin, including increased density of 
substance P-positive nerve fibers.12  
Substance P (SP) is an undecapeptide that belongs to the tachykinin family of neuropeptides, 
a group that also includes neurokinin A and neurokinin B.13 SP has been implicated in a 
number of biological functions, both physiological and pathophysiological, including pruritus 
perception, vomiting reflex, pain perception, and immunomodulatory responses.14,15,16 The 
role of SP in pruritic conditions has been supported by evidence of increased serum levels in 
atopic dermatitis,17 as well as other pruritic diseases such as cholestatic pruritus,18 and 
prurigo nodularis.19 
The biological actions of SP are mediated by tachykinin receptors, which consist of seven 
hydrophobic transmembrane domains coupled to G-proteins. Three tachykinin receptors have 
been identified: the neurokinin-1, neurokinin-2, and neurokinin-3 receptors.20 The 
neurokinin-1 receptor (NK1-R) in particular has been studied in great detail. NK1-R is the 
primary receptor for SP in the human body, and is found on multiple cell types, include 
central and peripheral neurons, keratinocytes, and mast cells.  
NK1-R stimulation has been shown to be an important pathway for pruritus perception.21 
Inhibition of this pathway results in decreased pruritus and scratching reflexes in animal 
models.22 More importantly, a commercially available NK1-R antagonist (aprepitant, 
Emend) has been used as a therapy to decrease pruritus in patients with chronic pruritus due 
to etiologies such as cutaneous T-cell lymphoma23,24,25 and erlotinib-induced pruritus.26,27 
Additionally, in a study of 20 patients with chronic pruritus of various etiologies treated with 
aprepitant, 16/20 patients (80%) experienced a considerable reduction of itch intensity.28  


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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 70-80 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 humans, serlopitant has been evaluated in over 850 subjects across thirteen Phase 1 studies 
and three completed Phase 2 studies. Escalating single doses up to 400 mg have been well 
tolerated in healthy young males. Multiple doses of up to 50 mg a 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 (bioequivalent 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 the Phase 1 studies, no drug-related serious adverse events (SAEs) were observed. The 
most commonly reported adverse events (AEs) in subjects who received serlopitant in the 
Phase 1 studies were headache (15%), diarrhea (5%), dizziness (5%), drowsiness (4%), 
nausea (4%), somnolence (3%), abdominal discomfort (3%), loose stools (3%), cough (3%), 
cold (3%) sore throat (3%) and tiredness (2%). Laboratory abnormalities noted were transient 
microscopic hematuria (4%) and mild transient elevation of liver function tests (2 to < 3 fold 
increase in alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) (2%). 
In a Phase 2 study examining treatment of overactive bladder (Study P003), the most 
common clinical AEs 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%). 
1.3.2 
Serlopitant in Chronic Pruritus 
Serlopitant has been evaluated in a Phase 2 study of subjects with chronic pruritus 
(TCP-101). A Phase 2 study in subjects with prurigo nodularis (TCP-102) has been 
conducted in Germany; the clinical study report is under preparation. 
TCP-101 
Study design: a total of 257 adult subjects 18-65 years of age with chronic pruritus were 
randomized to receive one of 4 dose groups: placebo (64 subjects), serlopitant 0.25 mg 


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(64 subjects), serlopitant 1 mg (65 subjects), and serlopitant 5 mg (64 subjects). Subjects 
received a loading dose of 3 tablets on Day 1 and thereafter received 1 tablet per day for 
6 weeks. The primary efficacy endpoint was itch severity as measured on a visual analog 
scale (VAS), summarized as a percentage change from baseline. 
Efficacy results: The mean percent decreases from baseline VAS scores were larger in the 
active-treatment groups versus placebo at every scheduled post-baseline study visit. The 
largest pairwise differences of least squares means versus placebo occurred in the serlopitant 
1 mg group (p-value < 0.05 at study Weeks 1, 3, 4, 5, 6, and 10). Similar results were seen in 
the serlopitant 5 mg group for the least squares mean differences versus placebo 
(p-value < 0.05 at study Weeks 3, 4, 5, 6, and 10).  
Safety results: Treatment-emergent adverse events (TEAEs) were reported in 25.4% of 
subjects in the placebo group and in 31.3%, 36.9%, and 37.5% of subjects in the serlopitant 
0.25 mg, 1 mg, and 5 mg groups, respectively. “Infections and Infestations” was the system 
organ class (SOC) with the highest incidence of TEAEs.  
Overall, headache was the most commonly-reported TEAE, reported in 6.3% of subjects in 
the placebo group and in 1.6%, 4.6%, and 1.6% of subjects in the serlopitant 0.25 mg, 1 mg, 
and 5 mg groups, respectively. Somnolence and diarrhea were the TEAEs with the highest 
overall incidence in the active-treatment groups. Somnolence was reported in 1.6% of 
subjects in the placebo group and in 1.6%, 4.6%, and 4.7% of subjects in the serlopitant 
0.25 mg, 1 mg, and 5 mg groups, respectively. Diarrhea occurred in 1.6% of subjects in the 
placebo group and in 0%, 6.2%, and 3.1% of subjects in the serlopitant 0.25 mg, 1 mg, and 
5 mg groups, respectively. 
Most of the TEAEs were mild or moderate in severity. Two severe TEAEs were reported: 
hypothyroidism in 1 subject in the serlopitant 0.25 mg group and peripheral neuropathy in 
1 subject in the serlopitant 5 mg group. Both of these events were considered not related to 
study treatment.  
Treatment-related TEAEs were reported in 7.9% of subjects in the placebo group and in 
10.9%, 13.8%, and 12.5% of subjects in the serlopitant 0.25 mg, 1 mg, and 5 mg groups, 
respectively. “Nervous systems disorders” was the SOC with the highest incidence of 
treatment-related events.  
One SAE (spontaneous abortion) occurred in a subject in the serlopitant group. This event 
was considered not related to study treatment. Six subjects (3 in the placebo group, 1 in the 
serlopitant 1 mg group, and 2 in the serlopitant 5 mg group) discontinued the study as a result 
of a TEAE. Two of these subjects had events considered not related to study treatment 
(pruritus in 2 subjects) and 3 subjects had events considered to be treatment related 
(headache in 1 subject; diarrhea in 1 subject; and symptoms of a panic attack in 1 subject).  
There was no evidence of meaningful trends in laboratory abnormalities or changes in vital 
signs. Two subjects had a clinically significant change in an electrocardiogram (ECG). One 
subject in the serlopitant 0.25 mg group had a normal ECG at screening and Visit 4 but at 
Visit 6 was noted to have supraventricular extrasystoles and ectopic atrial rhythm. These 


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changes were considered mild and possibly due to study drug but required no treatment. One 
subject in the serlopitant 5 mg group had first degree AV block at screening, Visit 4 and Visit 
6. Although the ECG interpretation was the same at each time point, the investigator 
considered the on-study findings clinically significant. No treatment was required.  
These results, together with the extensive safety experience with serlopitant to date, the 
scientific rationale for neurokinin-1 receptor (NK1-R) inhibition in the treatment of pruritus, 
and the previously published human data with aprepitant, serve to support the evaluation of 
serlopitant for the treatment of pruritus in patients with atopic dermatitis. 
2 
STUDY OBJECTIVES  
The primary objective of this study is to assess the efficacy of serlopitant for the treatment of 
pruritus in adults and adolescents with a history of atopic dermatitis. 
The secondary objectives of this study are as follows: 
• To assess the safety and tolerability of repeated oral doses of serlopitant in adults and 
adolescents with a history of atopic dermatitis 
• To assess the psychometric properties of the Worst-Itch Numeric Rating Scale (WI-NRS) 
 
3 
STUDY DESIGN 
3.1 
Overall Study Design 
This is a double-blind, randomized, placebo-controlled study to assess the efficacy, safety, 
and tolerability of serlopitant for the treatment of pruritus in adults and adolescents with a 
history of atopic dermatitis. Approximately 450 subjects who meet the study entry criteria 
will be randomized in a 1:1:1 ratio to receive daily oral doses of serlopitant 1 mg, 5 mg, or 
placebo for 6 weeks. The study will be conducted at approximately 40 study sites. 
The study will consist of three periods, for a total study period of approximately 12 weeks: 
• Screening period: 2 weeks 
• Treatment period: 6 weeks 
• Follow-up period: 4 weeks 
 
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 their baseline 
symptom scores established. Subjects must be willing and able to complete an electronic 
diary (eDiary) within a consistent timeframe on a daily basis, to wear actigraphy devices 


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during sleep, and to comply with restrictions on allowable therapies for the duration of the 
study. Subjects who meet initial screening requirements will be provided with an electronic 
device for recording eDiary assessments throughout the study. 
At the baseline visit, eligible subjects will be randomly assigned to receive study drug 
(serlopitant 1 mg, serlopitant 5 mg, or placebo). Subjects will take a loading dose (3 tablets 
taken orally) at bedtime 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 at bedtime. 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 during Week 6 
of treatment.  
After completion of the 6-week treatment period, all subjects will enter a 4-week 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 
In the TCP-101 study, 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. 
The current MTI-103 study is designed to confirm the efficacy, safety, and tolerability of 
serlopitant for the treatment of pruritus, specifically in patients with a history of atopic 
dermatitis. Although the TCP-101 study included subjects with a history of atopic dermatitis, 
the greater number of subjects in the MTI-103 study will allow for a more in-depth 
evaluation of the efficacy and safety profile of serlopitant in this population. 
As a post-hoc analysis of the TCP-101 study suggested possible variability in baseline levels 
of pruritus and change over time based on gender and race, in MTI-103 randomization will 
be stratified by gender (male, female) and race (white, non-white).  
The serlopitant 1 mg and 5 mg doses were selected for this study based on their comparable 
safety and efficacy profiles in the TCP-101 study. The clinical outcomes seen in TCP-101 
support the previously completed human CNS PET receptor occupancy studies with 
serlopitant, which demonstrated higher CNS NK1-R occupancy levels with once daily doses 
of 1 mg and 5 mg compared to lower doses. Analyses of dosing relative to body weight 
suggest that the doses selected for this study are suitable for body weights 32 kg and up.  
In the completed serlopitant Phase 2 studies, over 250 subjects were exposed to serlopitant at 
doses and durations similar to those planned for the MTI-103 study. 41 subjects were 
exposed for one year. Overall, serlopitant was well tolerated. The results from MTI-103 are 


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expected to provide additional data regarding any potential differences in either efficacy or 
safety between the 1 mg and 5 mg doses. 
3.3 
Study Endpoints 
3.3.1 
Primary Efficacy Endpoint 
The primary efficacy endpoint is the change in WI-NRS from baseline to Week 6. 
3.3.2 
Key Secondary Efficacy Endpoints 
The key secondary efficacy endpoints are as follows: 
• WI-NRS 4-point responder rate at Week 6 
• Change in ItchyQoL from baseline to Week 6 
 
3.3.3 
Additional Secondary Efficacy Endpoints 
Additional secondary efficacy endpoints include the following: 
• WI-NRS 3-point responder rates 
• Change in Average-Itch NRS (AI-NRS) and AI-NRS responder rates 
• Change in 5-D Pruritus Scale 
• Change in Static Patient Global Assessment of Itch Severity (sPGA) 
• Change in Patient Global Impression of Change in Itch Severity (PGIC) 
• Change in number of night-time scratching events per hour from baseline to Week 6 
 
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  
 


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3.3.5 
Exploratory Endpoints 
Exploratory endpoints include the following: 
• Change in Investigators’ Global Assessment of atopic dermatitis severity (IGA-AD) 
• Change in sleep efficiency 
• Change in mean activity during the sleep period 
 
3.4 
Safety Review 
3.4.1 
Independent Data Monitoring Committee 
An independent Data Monitoring Committee (iDMC) will be established to monitor 
unblinded safety data on a regular basis throughout the study. The iDMC may make 
recommendations to the Sponsor to continue or terminate the study based upon the outcomes 
of the data reviews. The iDMC is not tasked with stopping the study early for success 
(i.e. early stopping for efficacy) or for stopping for futility. The iDMC member list and its 
responsibilities and processes will be described in the iDMC charter. 
3.4.2 
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 450 adult and adolescent subjects with pruritus and a history of atopic 
dermatitis will be randomized into this study. 
4.2 
Inclusion Criteria 
Subjects must meet the following criteria to be randomized into the study: 
1. Male or female, age 13 years or older at consent/assent. 
a. For subjects below the legal age of consent, the subject must be willing and able to 
provide assent and to comply with study visits and study-related requirements and 
his/her parent(s)/guardian(s) must be willing and able to provide written informed 
consent. 
2. Pruritus of at least 4 weeks duration prior to the initial Screening visit and during the 2-
week screening period, despite treatment with standard of care anti-pruritic therapies such 
as H1 antihistamines or emollients. 


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a. Subjects using stable doses of oral H1 antihistamines at the initial Screening visit 
must be willing to continue these at the same doses and frequencies throughout the 
study inclusive of the follow-up period. 
3. WI-NRS score ≥ 7 in the 24-hour period prior to the initial Screening visit. 
4. Average weekly WI-NRS score ≥ 6 for each week of the screening period, as recorded in 
the eDiary. 
5. Diagnosis of atopic dermatitis, as defined by the 2014 American Academy of 
Dermatology (AAD) Guidelines of Care for the Management of Atopic Dermatitis.1  
a. Subjects with active atopic dermatitis skin involvement must have had stable skin 
disease, defined as experiencing no disease flares, for at least 4 weeks immediately 
prior to randomization. Subjects using stable doses of bland emollients, topical 
calcineurin inhibitors, and/or low- to mid-potency topical corticosteroids at the initial 
Screening visit must be willing to continue these at the same doses and frequencies 
throughout the study. 
b. Subjects without active atopic dermatitis skin involvement must have had a past 
diagnosis of atopic dermatitis, supported by written records documenting the presence 
of features consistent with the 2014 AAD Guidelines. 
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.  All 
fertile male subjects, with partners who are females of childbearing potential, must use 
condoms from randomization until 4 weeks after last dose of study drug. All subjects 
who are fertile males or females of childbearing potential must also refrain from 
sperm/egg donation starting from first dose of study drug and until 4 weeks after last dose 
of study drug. Please refer to Section 7.1.5 for acceptable methods of contraception. 
7. Weight ≥ 32 kg at the baseline visit. 
8. Willing and able to complete once-daily eDiary entries within a consistent timeframe for 
the duration of the study. 
a. Subjects must have ≥ 80% eDiary completion rate during the screening period. 
9. Judged to be in good health in the investigator’s opinion.  
 
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 NK1-R antagonists (e.g. aprepitant). 
2. Clearly defined etiology for pruritus other than atopic dermatitis. These include but are 
not limited to urticaria, psoriasis or other non-atopic dermatologic conditions, hepatic or 
renal disease, psychogenic pruritus, drug reaction, untreated hyperthyroidism, and 
infection. 


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3. Presence of any acute condition which may risk inducing an atopic dermatitis flare during 
the course of the study, such as impetigo or active herpes simplex infection. 
4. Treatment with systemic corticosteroids within 4 weeks prior to randomization. 
a. Treatment with non-systemic corticosteroids that do not involve skin application (e.g. 
inhaled, intranasal, or intra-articular corticosteroids) will be permitted. 
5. Treatment with Class III or higher potency topical corticosteroids2 or any topical 
anti-pruritic therapies (other than stable doses of low- or mid-potency topical 
corticosteroids, topical calcineurin inhibitors, or bland emollients) within 2 weeks prior to 
randomization. 
6. Treatment with systemic therapies with recognized anti-pruritic (e.g. tricyclic 
antidepressants, sedatives, tranquilizers, gabapentin, marijuana or other cannabinoids, 
opioid receptor agonists/antagonists) or pruritic (e.g. opioids, angiotensin-converting 
enzyme inhibitors, cocaine, antimalarials) properties within 4 weeks prior to 
randomization. 
a. Stables doses of H1 antihistamines will be permitted (see Inclusion Criterion 2a) 
7. For subjects using bland emollients, low- or mid-potency topical corticosteroids, topical 
calcineurin inhibitors, and/or oral H1 antihistamines, any clinically significant changes in 
dose or frequency during the screening period. 
8. Treatment with systemic immunosuppressive/immunomodulatory therapies (including 
but not limited to phosphodiesterase-4 inhibitors, cyclosporine, mycophenolate-mofetil, 
methotrexate, azathioprine, interferon-gamma, or phototherapy) within 4 weeks prior to 
randomization. 
9. Treatment with biologic therapies within 8 weeks or 5 half-lives prior to randomization, 
whichever is longer. 
10. Treatment with strong CYP3A4 inhibitors within 4 weeks prior to randomization (see 
Appendix B). 
11. Use of an indoor tanning facility within 4 weeks prior to randomization. 
12. Treatment with any investigational therapy within 4 weeks prior to randomization. 
13. Allergen immunotherapy within 6 months prior to randomization. 
14. Serum creatinine, total bilirubin, ALT or AST > 2x the upper limit of normal (ULN) 
during screening. 
15. History of malignancy within 5 years prior to randomization, with the exception of 
completely treated and non-metastatic basal cell carcinoma or squamous cell carcinoma 
of the skin. 
16. History of a major psychiatric condition (including major depressive disorder, bipolar 
disorder, or schizophrenia), suicidal ideation, or suicide attempt. 
17. Known active hepatitis infection. 
18. Known history of human immunodeficiency virus (HIV) infection. 


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19. Documented history of parasitic infection, including skin parasites such as scabies, within 
12 months prior to randomization. 
20. Known active parasitic infection. 
21. Regular long-distance running (e.g. 10Ks, marathons) or long-distance bicycling (e.g. 
30 + miles) and/or strenuous physical activity (e.g. bodybuilding) within 2 weeks prior to 
randomization  
22. 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. 
23. History of hypersensitivity to serlopitant or any of its components. 
24. Currently pregnant or breastfeeding, or male subject with a pregnant or breastfeeding 
partner 
25. Females of childbearing potential who are unable or unwilling to practice highly effective 
contraception (pregnancy prevention); fertile male subjects who are unable or unwilling 
to use condoms with female partners of childbearing potential. 
 
5 
STUDY DRUG 
5.1 
Study Drug Supply, Route of Administration, and Storage 
The study drug in this study is serlopitant 1 mg, 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. One bottle will be issued via 
Interactive Web Response System (IWRS) at baseline and at the Week 2 and Week 4 visits, 
for a total of 3 bottles dispensed for subjects completing 6 weeks 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. 


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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) at bedtime 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 at bedtime. 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 at bedtime, no 
sooner than 2 hours before or after a meal. If the bedtime dose is missed, that dose should be 
skipped, and the following dose should be taken at bedtime of the following day. The 
skipped dose will be considered and documented as a missed dose.  
5.6 
Study Drug Discontinuation 
Subjects will be discontinued from study drug treatment in the following events: 
• The subject experiences a NCI CTCAE Grade 2 or higher treatment emergent AE that is 
assessed as likely related to study drug.  
• The subject receives treatment with an excluded therapy or has a clinically significant 
change in dose or frequency of allowed adjunctive therapies (see Section 5.7.3 for 
additional details regarding exceptions) 
• The female subject becomes pregnant or female partner of a male subject becomes 
pregnant or is breastfeeding 
Discontinuation from study drug treatment may also occur for any of the following reasons: 
• Subject decision to discontinue study drug treatment, or subject decision to withdraw 
consent/assent from the study 
• 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 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.   


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Subjects who discontinue treatment with study drug prior to completing the treatment period 
will have an ETD visit within 7 days after their last dose of study drug in addition to a 
follow-up visit. 
5.6.1 
Early Termination 
Early termination from the study may occur due to loss to follow-up or withdrawal of 
consent/assent 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). 
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.  
Stable doses of the following therapies for pruritus and/or atopic dermatitis will be allowed 
as adjunctive therapies during the study: 
• Low- or mid-potency topical corticosteroids 
• Topical calcineurin inhibitors 
• Oral H1 antihistamines 
• Bland emollients 
- 
Per AAD recommendations, for subjects with active AD the regular application of 
emollients is an integral part of treatment of AD. Regular emollient use at stable 
doses is highly recommended for these subjects. 
 
Subjects using any of these adjunctive therapies should maintain their regimen without 
clinically significant changes in dose or frequency throughout the screening, treatment, and 
follow-up periods. 
A record of all concomitant therapies will be maintained for each subject. 


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5.7.2 
Excluded Therapies 
The following therapies and activities are excluded from the initial Screening visit through 
the follow-up period: 
• NK1-R antagonists (other than study drug) 
• Systemic corticosteroids 
- 
Treatment with non-systemic corticosteroids that do not involve skin application (e.g. 
inhaled, intranasal, or intra-articular corticosteroids) will be permitted.  
• Class III or higher topical corticosteroids or any topical anti-pruritic therapies (other than 
the allowed adjunctive therapies in Section 5.7.1)  
• Systemic therapies with recognized anti-pruritic (e.g. tricyclic antidepressants, sedatives, 
tranquilizers, gabapentin, marijuana or other cannabinoids, opioid receptor 
agonists/antagonists) or pruritic (e.g. opioids, angiotensin-converting enzyme inhibitors, 
cocaine, antimalarials) properties  
- 
Stable doses of oral H1 antihistamines will be permitted 
• Systemic immunosuppressive/immunomodulatory therapies (including but not limited to 
PDE4 inhibitors, cyclosporine, mycophenolate-mofetil, methotrexate, azathioprine, 
interferon-gamma, or phototherapy) 
• Biologic therapies 
• Strong CYP3A4 inhibitors (See Appendix B) 
• Use of an indoor tanning facility 
• Allergen immunotherapy 
• Long-distance running (e.g. 10Ks, marathons) or long-distance bicycling 
(e.g. 100 + miles) and/or strenuous physical activity (e.g. bodybuilding) 
• Any investigational therapy 
 
5.7.3 
Use of Excluded Therapies During the Treatment Period  
Subjects who use an excluded therapy during the treatment period for treatment of atopic 
dermatitis or pruritus will be discontinued from study drug treatment, with the following 
exception: 
• Subjects who require short treatment for indications other than atopic dermatitis or 
pruritus (up to a total of 3 days over the treatment period) with sedatives, tranquilizers, 
opioids, and/or topical therapies will not be required to discontinue from study drug 
treatment.   


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Similarly, subjects with clinically significant changes in the dose or frequency of allowed 
adjunctive therapies (low- or mid-potency topical corticosteroids, topical calcineurin 
inhibitors, oral H1 antihistamines, bland emollients) during the treatment period will also be 
discontinued from study drug treatment.  
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 1 mg, 5 mg, or placebo in a 1:1:1 
ratio. Stratified permuted block randomization will be used. Randomization will be stratified 
by gender (male, female) and race (white, non-white). 
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 eDiary (available in the eDiary 
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. 
6 
STUDY SCHEDULE AND ASSESSMENTS  
6.1 
Efficacy Parameters 
6.1.1 
Itch Numeric Rating Scale 
The Itch NRS is a validated, self-reported instrument for measurement of itch intensity. It 
uses a 24-hour recall period and asks subjects to rate the intensity of their itch on an 11-point 


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scale ranging from 0 (no itch) to 10 (worst itch imaginable). Higher scores indicate greater 
itch intensity. In this study, both worst itch intensity (WI-NRS) and average itch intensity 
(AI-NRS) during a 24-hour recall period will be captured. Subjects will record their Itch 
NRS scores once daily via eDiary throughout the screening, treatment, and follow-up 
periods, as outlined in Appendix A. 
6.1.2 
Static Patient Global Assessment of Itch Severity  
The sPGA is designed to assess overall itch severity. Each subject is asked to rate the 
severity of his/her itchiness in the past 7 days on a 5-point scale as none, mild, moderate, 
severe, and very severe. Higher scores indicate greater itch severity. The sPGA scores will be 
captured via eDiary as outlined in Appendix A. 
6.1.3 
Patient Global Impression of Change in Itch Severity 
The PGIC in Itch Severity is a single item used to assess the change in overall itch severity 
since the baseline visit. Each subject will rate the change in his/her itch severity on a 7-point 
scale from (very much better) to (very much worse). PGIC scores will be captured via eDiary 
as outlined in Appendix A. 
6.1.4 
ItchyQoL 
ItchyQoL is a validated, pruritus-specific instrument that measures the degree to which 
pruritus affects quality of life (QoL).29 This impact is quantified into 3 subscores (symptom, 
function, emotion) and an overall score. A higher score corresponds to a more adverse impact 
on QoL. Subjects will complete ItchyQoL as outlined in Appendix A. 
6.1.5 
5-D Pruritus Scale 
The 5-D Pruritus Scale is a validated, multi-dimensional measure of itching that assesses the 
five domains of degree, duration, direction, disability and distribution. Subjects rate their 
symptoms over the preceding 2-week period on a 1 to 5 scale, with 5 being the most affected. 
Subjects will complete the 5-D Pruritus Scale during study visits as outlined in Appendix A. 
6.1.6 
Actigraphy 
High-resolution actigraphy is an objective method for quantifying nocturnal scratching 
events and sleep-related parameters using high resolution actigraphy devices on each wrist. 
The device weighs 16g (0.56oz) without the strap, and is made of medical device grade 
housing material. The device is water resistant up to 10 meters, dust-tight, and drop-resistant 
to 0.5m. It is functional for operation between 41 and 104 degrees Fahrenheit (5 and 
40 degrees Celsius). 
The assessment requires each subject to wear the actigraphy devices, which are the size of a 
medium size wrist watch, on each wrist during sleep, with the option to wear them during 
waking hours as well. The devices will be programmed and activated prior to being provided 
to subjects. Once received, the subjects can simply put the devices on their wrists and they 
will record automatically. The devices are returned to the study site where the data are 


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downloaded and sent for analysis. Subjects will be permitted to not wear the devices up to 
three sleep sessions over any seven-day period throughout the study, to allow for cases of 
temporary irritation or discomfort. 
The 3-D acceleration data (m/sec2) from the actigraphy device is analyzed with a neural 
network that was developed to discriminate scratching from other nighttime events. The 
algorithm was developed and tested in a study of 24 subjects (6 healthy, 18 with atopic 
dermatitis) who were video recorded for one night in a sleep lab while wearing actigraphy 
devices on each wrist. The video recordings were scored to quantify the time and duration of 
each scratching event. A strong correlation was shown (r = 0.98) between the number of 
scratching events per hour measured with the actigraphy analysis versus the video scoring. In 
contrast, subjective questionnaires completed by the subjects the following morning had a 
poor correlation with the true number of scratching events. For example, the best correlation 
was 0.6 with a VAS. The full description of the algorithm and the study has been submitted 
to IEEE Journal of Biomedical and Health Informatics.30  
Actigraphy measurements will be assessed as outlined in Appendix A. 
6.1.7 
Investigators’ Global Assessment of Atopic Dermatitis Severity  
The IGA-AD is an instrument used to assess the overall severity of atopic dermatitis at a 
given time point, as determined by the investigator. It consists of a 6-point scale ranging 
from 0 (clear) to 5 (very severe). The IGA-AD uses clinical characteristics of erythema, 
infiltration, papulation, oozing and crusting as guidelines for the overall severity 
assessment.31 IGA-AD scores will be assessed as 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. A complete physical examination will be performed at 
the initial Screening visit, while subsequent examinations may be abbreviated and targeted to 
changes in disease activity and/or subjects’ symptoms. 


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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 
(BUN), 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 
• Urinalysis: color, clarity, pH, specific gravity, bilirubin, glucose, ketones, leukocytes, 
nitrite, blood, protein, urobilinogen, microscopic analysis 
• Endocrine and cardiac: TSH, free T4, cortisol, corticotropin, troponin 
• Reproductive endocrine (for all female subjects): serum FSH, LH, estradiol, progesterone  
 
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 
Sparse PK sampling will collect one PK sample at each of the Week 2, Week 4, and Week 6 
visits as well as the ETD visit as 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 
eDiary and actigraphy assessments are performed throughout the study and are 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 eDiary and actigraphy assessments are performed throughout the study and are not 
confined to scheduled visits. Refer to Appendix A for frequency and duration of these 
assessments. 
6.5.1 
Informed Consent/Assent 
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. 


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6.5.2 
Screening Visit/Period 
An initial Screening visit should be scheduled to occur 14 days (-2 days, +3 days) prior to the 
Baseline visit. The following screening procedures are to be performed at the initial 
Screening visit: 
• Inclusion/exclusion criteria review 
• Medical history 
• Complete physical examination 
• Vital signs (including height and weight) 
• IGA-AD 
• 5-D Pruritus Scale 
• ECG 
• Schedule the baseline visit 
• Provide actigraphy device with instructions 
• Provide eDiary with instructions 
 
During the screening period (after consent/assent and prior to the baseline visit), the 
following screening procedure is to be performed: 
• Laboratory 
- 
Reproductive endocrine labs for females  
- 
Urine pregnancy test for females of childbearing potential (with positive or equivocal 
results confirmed by a serum pregnancy test) 
- 
Endocrine and cardiac 
- 
Hematology 
- 
Chemistry 
- 
Urinalysis 
 
6.5.3 
Baseline Visit 
The Baseline visit occurs 14 days (-2 days, +3 days) after the Screening visit. At the Baseline 
visit, the following procedures and assessments are to be performed: 
• Inclusion/exclusion criteria review  
• Vital signs 


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• IGA-AD 
• 5-D Pruritus Scale 
• Concomitant medications 
• AEs 
• Randomization if eligible 
• Dispense study drug 
• Schedule future visits 
 
Randomized subjects will begin treatment with study drug in the evening of the Baseline visit 
(Study Day 1). 
6.5.4 
Week 1 Visit 
The Week 1 visit is a telephone visit that occurs 7 days (±3 days) after the Baseline visit 
(Study Day 5-11). At the Week 1 visit, the following procedures and assessments are to be 
performed:  
• Concomitant medications 
• AEs 
 
6.5.5 
Week 2 Visit 
The Week 2 visit occurs 14 days (±2 days) after the Baseline visit (Study Day 13-17). At the 
Week 2 visit, the following procedures and assessments are to be performed:  
• Vital signs (including weight) 
• IGA-AD 
• 5-D Pruritus Scale 
• Targeted physical examination 
• ECG 
• Laboratory 
- 
Urine pregnancy test for females of childbearing potential (with positive or equivocal 
results confirmed by a serum pregnancy test) 
- 
Hematology 


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- 
Chemistry 
- 
Urinalysis 
• PK blood sample collection 
• Concomitant medications 
• AEs 
• Collect returned study drug 
• Dispense study drug 
 
6.5.6 
Week 4 Visit 
The Week 4 visit occurs 28 days (± 3 days) after the Baseline visit (Study Day 26-32). At the 
Week 4 visit, the following procedures and assessments are to be performed: 
• Vital signs 
• IGA-AD 
• 5-D Pruritus Scale 
• PK blood sample collection 
• Concomitant medications 
• AEs 
• Collect returned study drug 
• Dispense study drug 
 
6.5.7 
Week 6 Visit 
The Week 6 visit occurs 42 days (± 3 days) after the Baseline visit (Study Day 40-46). At 
this visit, the following procedures and assessments are to be performed: 
• Vital signs (including weight) 
• Targeted physical examination 
• Laboratory 
- 
Reproductive endocrine labs for females  
- 
Urine pregnancy test for females of childbearing potential (with positive or equivocal 
results confirmed by a serum pregnancy test) 


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- 
Endocrine and cardiac 
- 
Hematology 
- 
Chemistry 
- 
Urinalysis 
• IGA-AD 
• 5-D Pruritus Scale 
• PK blood sample collection 
• Concomitant medications 
• AEs 
• Collect returned study drug 
6.5.8 
Early Treatment Discontinuation Visit 
The ETD visit occurs 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:  
• Vital signs (including weight) 
• Targeted physical examination 
• Laboratory 
- 
Reproductive endocrine labs for females  
- 
Urine pregnancy test for females of childbearing potential (with positive or equivocal 
results confirmed by a serum pregnancy test) 
- 
Endocrine and cardiac 
- 
Hematology 
- 
Chemistry 
- 
Urinalysis 
• IGA-AD 
• 5-D Pruritus Scale 
• PK blood sample collection 
• Concomitant medications 
• AEs 
• Collect returned study drug 


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6.5.9 
Follow-up Visit 
The Follow-up visit occurs 28 days (± 3 days) after the Week 6 visit (Study Day 68-74) or 
the ETD visit (for subjects who discontinue study drug early). Subjects who discontinue 
study drug prior to Study Day 15 should have a follow-up visit 6 weeks (± 3 days) after 
randomization (Study Day 40-46) so that all randomized subjects will have a Week 6 
evaluation. At the Follow-up visit, the following procedures and assessments are to be 
performed: 
• Vital signs (including weight) 
• Targeted physical examination 
• ECG 
• Laboratory 
- 
Reproductive endocrine labs for females  
- 
Urine pregnancy test for females of childbearing potential (with positive or equivocal 
results confirmed by a serum pregnancy test) 
- 
Endocrine and cardiac 
- 
Hematology 
- 
Chemistry 
- 
Urinalysis 
• IGA-AD 
• 5-D Pruritus Scale 
• Concomitant medications 
• AEs 
 
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 that are temporally associated with the 
use of study drug and AEs that occur as a result of protocol-mandated interventions. 


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7.1.2 
Serious Adverse Event  
An SAE is considered “serious” if it results in any of the following outcomes: 
• Death 
• 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 hospitalizations 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/assent, 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.   


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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 
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 unless their 
severity, seriousness, or etiology changes. 
7.1.4 
Deaths  
Any deaths that occur from the time of informed consent/assent to the follow-up visit, 
regardless of attribution, must be reported within 24 hours of investigator’s awareness of the 
death. See MTI-103 SAE and Pregnancy Form Completion Instructions 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 Males and Females 
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.  A fertile male is defined as any male who is post-pubertal and not castrated 
(e.g. history of bilateral orchiectomy) or sterilized (i.e. history or vasectomy).  
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 
guidelines32,33,34:  
1. For female subjects: All female subjects of childbearing potential must use highly 
effective contraception, which includes the use of one or more of the following 
acceptable methods:  
a. Surgical sterilization (e.g., bilateral tubal occlusion or ligation, hysterectomy, bilateral 
salpingectomy, bilateral oophorectomy) 
b. Total (as opposed to periodic or cyclic) abstinence 


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c. 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. 
d. Intrauterine device/system  
e. Exclusive monogamous heterosexual intercourse with a sterilized (i.e., vasectomized) 
or otherwise non-fertile (e.g., castrated) male partner  
2. For male subjects: All fertile male subjects, with sexual partners who are females of 
childbearing potential, must use condoms with or without spermicide.  
3. All subjects who are fertile males or females of childbearing potential must also refrain 
from sperm/egg donation starting from first dose of study drug and until 4 weeks after 
last dose of study drug. 
 
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 MTI-103 SAE and 
Pregnancy Form Completion Instructions 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 
MTI-103 SAE and Pregnancy Form Completion Instructions for complete instructions.  
7.1.6 
Worsening of Pruritus or Atopic Dermatitis  
Pruritus or atopic dermatitis should be recorded as an AE or SAE only if considered by the 
investigator to have unexpectedly worsened in severity or worsened beyond the subject’s 
normal fluctuations during the study. It is important to include a description of the nature of 
the unexpected worsening when recording the AE or SAE (e.g. significant atopic dermatitis 
flare in previously uninvolved skin). 


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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/assent, 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) v4.0335 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. 


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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 
 
a 
Use 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. 
b 
Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, 
managing money, etc. 
c 
Self 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) v4.0335 
 
Regardless of severity, some AEs may meet the criteria for seriousness. See Section 7.1.2 for 
the definition of an SAE. 
The Sponsor or designee should be notified within 24 hours of investigator’s awareness of 
any Grade 3 or higher AE whenever possible. 
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: 
• 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. 


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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/assent 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 MTI-103 SAE and Pregnancy Form Report Completion Instructions 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. 
7.6 
Emergency Unblinding 
The investigator will immediately notify the Sponsor or the medical monitor to discuss the 
need for unblinding any subject via IWRS. 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 


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deviation, median, minimum and maximum. For categorical variables counts and percentages 
will be used. 
Baseline for measures other than the eDiary and actigraphy based measures, will be the last 
recorded value prior to the start of treatment. For Itch NRS measures, baseline will be the 
average result measured over 7 days prior to treatment. Additionally, the Itch NRS measures 
will be summarized in one week intervals by taking the average result recorded within the 
associated week. 
8.1 
Decision Rule and Sample Size  
This study contains two active dosing arms. A stepdown procedure will be used to control for 
multiplicity. This procedure will start by testing the primary endpoint for the 5 mg treatment 
group and then proceed to the 1 mg group should statistical significance (one-sided p-values 
< 0.05) be reached for the 5 mg vs placebo comparison.  
Statistical significance for the key secondary endpoints will be dependent upon statistical 
significance being reached for the primary endpoint at the given dose level (i.e. a gatekeeper 
within dose arm will be used for the secondary endpoints). As there are multiple secondary 
endpoints a stepdown procedure will be used starting with the WI-NRS endpoint and then the 
ItchyQoL. 
If the one-sided p-values are additionally less than 2.5%, then the serlopitant-based regimen 
will have met the generally accepted level of evidence required to demonstrate efficacy.   
The target sample size of 450 randomized and dosed subjects (150 per group) has been 
determine based upon a 1:1:1 allocation of subjects to treatment groups, an assumed common 
treatment effect for the 1 mg and 5 mg arms, and a 5% one-sided alpha level. One-hundred 
and fifty subjects per group results in 90% power for each test individually assuming a 
treatment effect (placebo change from baseline - serlopitant change from baseline) of -1 and 
a standard deviation of 2.9.  
The sample size calculations have been performed in PASS 1336 and use a t-test. The primary 
analysis will control for the stratification factors. It is expected that this unstratified power 
estimate will under-estimate the true power as it does not take the variance reduction 
resulting from stratification into account.37 
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. 
If a subject fails to complete their eDiary for a week or more, the Itch NRS endpoints, 
including the primary endpoint, will be missing for that week. In this case, their Itch NRS 
change from baseline value will be imputed. This approach uses the subject’s last week with 


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data. From that point forward their trajectory will be imputed based upon the trajectory of 
their treatment group. 
The imputation approach first determines the average change for each week for each 
treatment group. The difference in the weekly measures between weeks n-1 and n will be 
considered the change for Week n. These weekly change measure will be used to ‘fill in’ the 
missing weeks between the last completed week and Week 6.  
For subjects who receive excluded therapy or with clinically significant changes in allowed 
adjunctive therapies as outlined in Section 5.7.3, their Itch NRS results after the use of this 
therapy will be imputed using the same algorithm as indicated above. Hence, a placebo 
subject who receives excluded therapy in Week 4 will have their Week 6 WI-NRS change 
from baseline imputed as ∆4+∆P(4-6), where ∆4 is the observed change from baseline result for 
the subject up to Week 4 and ∆P(4-6) is the placebo change from Week 4 to 6 (i.e. the average 
placebo decrease from Week 4 to 6). 
As a sensitivity analysis, a similar approach will be used where the imputation step uses 
multiple imputation methodology. 
8.3 
Analysis Populations  
The primary efficacy population will be the Full Analysis Set (FAS) that will include all 
randomized and treated subjects. Following the intent-to-treat philosophy, subjects will be 
analyzed within the treatment group to which they are randomized.  
The primary safety population will be all treated subjects. For safety analyses, subjects will 
be classified based upon the treatment received.  
8.4 
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. 
8.5 
Subject Characteristics  
Demographic and other baseline characteristics will be summarized. 
8.6 
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. 


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8.7 
Treatment Compliance and Extent of Exposure  
Compliance with study drug dosing will be recorded within the eDiary. From these entries, 
summaries of treatment compliance and exposure will be produced. 
8.8 
Efficacy Analyses  
The efficacy endpoints will be summarized within the FAS using descriptive statistics by 
time point and treatment. For the WI-NRS and AI-NRS endpoints (change from baseline, 
3-point and 4-point responders) results will be summarized at the primary time point, 
Week 6, as well as at Week 2 and 4. The WI-NRS and AI-NRS results will be summarized at 
baseline and Weeks 2, 4 and 6. For each of these measures the result at a time point are based 
upon the average of the results leading up to that time point. The night-time scratching 
events, ItchyQoL, 5-D Pruritus Scale and sPGA will also be summarized at baseline and 
Weeks 2, 4 and 6 with change from baseline summarized at Weeks 2, 4 and 6. Week 6 is the 
primary time point for the ItchyQoL. The PGIC will be summarized at Weeks 2, 4 and 6. 
For the primary and key secondary endpoints these statistics will include 95% confidence 
intervals for the treatment difference. Testing will also be used for the primary and key 
secondary endpoints.  
For the responder rate endpoints subjects will be considered a responder if they have at least 
a 3 or 4 point reduction in WI-NRS / AI-NRS between baseline and the corresponding week. 
The difference in the primary efficacy outcome measure (WI-NRS change from baseline to 
Week 6) between treatment groups will be tested using an analysis of variance (ANOVA) 
model controlling for the stratification factors. A main effects model with an interaction term 
(treatment by stratification factors) and a Type II hypothesis will be used. More precisely this 
ANOVA model uses the following as a stratified adjusted measure of the change from 
baseline for a given treatment group: 
∆= ∑
𝑛𝑛1𝑗𝑗𝑛𝑛2𝑗𝑗
𝑛𝑛1𝑗𝑗+𝑛𝑛2𝑗𝑗
4
𝑗𝑗=1
∆𝑗𝑗 , 
where j represents the stratification cells, n is the sample size for treatment 1 and 2 and ∆j is 
the change measures for stratum j.  
Conceptually the hypotheses being tested are: 
H0:∆Placebo ≥  ∆Serlopitant 
 
Ha: ∆Placebo < ∆Serlopitant 
 
where ∆Placebo is the placebo change from baseline and ∆Serlopitant is the similar measure for 
serlopitant. Each serlopitant treatment group (1 mg and 5 mg) will be compared to placebo 
separately.  
The primary endpoint will utilize the imputation methods as outlined in Section 8.2. 
Sensitivity analyses in which Last Observation Carried Forward, LOCF, and Baseline 
Observation Carried Forward, BOCF, are used will be performed. The LOCF approach 
assumes subject’s final assessment is reflective of their future assessment and can be useful if 


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subjects are withdrawing due to lack of efficacy, as this lack of efficacy is carried forward. 
The BOCF approach for responder rate endpoints is equivalent to a missing equals failure 
imputation. 
The differences between treatment groups for the ItchyQoL key secondary endpoint will be 
tested using the same analysis of variance (ANOVA) model used for the primary endpoint.   
A Cochran Mantel Haenszel (CMH) test controlling for the ‘as randomized’ stratification 
factors will be used for the responder rate key secondary endpoint. 
8.9 
Psychometric Analyses  
A psychometric assessment of the WI-NRS will be conducted to assess test-retest reliability, 
construct validity and responsiveness. These will be conducted outside of the statistical 
analysis plan for this study and will include analyses of: intra-class correlation coefficients 
(ICC), Pearson’s correlations, and change scores for test-retest reliability; Pearson Product 
Moment or Spearman Correlations for concurrent validity; t-test analyses or ANOVA for 
known groups validity; and correlations of change scores for WI-NRS and other measures for 
responsiveness. In addition, a responder definition will be explored using anchor- and 
distribution-based methods. 
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.  
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.  


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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 
Interim Analyses  
This study includes an iDMC that will review study results to identify potential safety 
concerns. The iDMC is not tasked with stopping the study early for efficacy or for futility 
determinations.  
8.12 
Pharmacokinetics Data  
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, or the recommendation of the iDMC. A written statement fully 
documenting the reasons for study termination will be provided to the IRB or EC. 
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). 


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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 
below the legal age of consent will be required to read, sign, and date an IRB-approved or 
EC-approved assent form, and his/her parent(s)/guardian(s) will be required to read, sign, and 
date an IRB-approved or EC-approved consent form. 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 and assent forms will be 
maintained in the investigator site file. Copies of signed consent/assent forms 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/assent form, 
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 
the Sponsor, except to the extent necessary to obtain informed consent/assent 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 


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(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, eDiary, actigraphy, 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. 
9.10 
End of Study Notification 
The Sponsor will notify appropriate regulatory authorities and the IRB 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. 


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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 
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Stander S, Luger TA. NK-1 antagonists and itch. Handb Exp Pharmacol. 
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APPENDIX A 
SCHEDULE OF ACTIVITIES AND ASSESSMENTS 
Table 2 
Schedule of Visit Activities 
Examination 
Consent 
Screening 
Baseline 
Week 1 
Week 2 
Week 4 
Week 6 
ETD* 
F/U** 
Comments & Clarifications 
Study Days (D) 
 
 
D 1 
D 8 
D 15 
D 29 
D 43 
* 
** 
 
Visit Window in Days (d) 
 
 
-2d, +3 d 
±3 d 
±2 d 
±3 d 
±3 d 
* 
±3 d 
 
Informed consent/assent 
X 
 
 
 
 
 
 
 
 
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. 
Medical history 
 
X 
 
 
 
 
 
 
 
 
I/E criteria 
 
X 
X 
 
 
 
 
 
 
 
Randomization 
 
 
X 
 
 
 
 
 
 
 
Physical exam 
 
X 
 
 
X 
 
X 
X 
X 
Screening physical exam is complete; other 
exams are targeted 
Vital signs 
 
X 
X 
 
X 
X 
X 
X 
X 
Height will be assessed at screening; Weight 
will be assessed at screening, baseline, Week 2, 
Week 6, ETD, and F/U 
ECG 
 
X 
 
 
X 
 
 
 
X 
 
Labs 
 
X 
 
 
X 
 
X 
X 
X 
Screening labs, including urine pregnancy test, 
may be collected during the screening period 
(after Screening visit but prior to the Baseline 
visit); Endocrine and cardiac, and reproductive 
endocrine labs will be collected at screening, 
Week 6, ETD, and F/U 
PK 
 
 
 
 
X 
X 
X 
X 
 
 
IGA-AD 
 
X 
X 
 
X 
X 
X 
X 
X 
 
5-D Pruritus Scale 
 
X 
X 
 
X 
X 
X 
X 
X 
 
Dispense study drug 
 
 
X 
 
X 
X 
 
 
 
 
Collect study drug 
 
 
 
 
X 
X 
X 
X 
 
 
Concomitant medications 
 
 
X 
X 
X 
X 
X 
X 
X 
 
AEs 
 
 
X 
X 
X 
X 
X 
X 
X 
After informed consent/assent, but prior to study 
drug administration, only SAEs caused by a 
protocol-mandated intervention will be collected 
* Early Treatment Discontinuation (ETD) visit occurs within 7 days of last dose for subjects who discontinue study drug treatment prior to the Week 6 visit 
**The Follow-up (F/U) visit occurs 28 days (± 3 days) after the Week 6 visit (Study Day 68-74) or the ETD visit (for subjects who discontinue study drug early). Subjects 
who discontinue study drug prior to Study Day 15 should have a follow-up visit 6 weeks (± 3 days) after randomization (Study Day 40-46) so that all randomized subjects 
will have a Week 6 evaluation. 


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APPENDIX A (CONT’D) 
Table 3 
Schedule of eDiary and Actigraphy Assessments 
eDiary and actigraphy devices are provided to subjects at the screening visit. eDiary devices are collected at the Follow-up Visit. 
Actigraphy watches will be returned to site and new watches dispensed to subject as needed during the study period.  
Device 
Assessment 
Frequency and Duration of Assessment 
eDiary 
WI-NRS 
Once daily from Screening visit through the Follow-up visit 
eDiary 
AI-NRS 
Once daily from Screening visit through the Follow-up visit 
eDiary 
ItchyQOL 
Once at screening, baseline*, Week 2, Week 4, Week 6, ETD, and Follow-up visit 
eDiary 
sPGA 
Once at screening, baseline*, Week 2, Week 4, Week 6, ETD, and Follow-up visit 
eDiary 
PGIC 
Once at Week 2, Week 4, Week 6, ETD, and Follow-up visit 
Actigraphy watch 
Scratching 
Continuous nighttime monitoring from Screening visit through the Follow-up visit 
Actigraphy watch 
Sleep 
Continuous nighttime monitoring from Screening visit through the Follow-up visit 
*Baseline assessments need to be done prior to initial study drug administration. 
 
 
 


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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)38: 
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 
 
a 
Topical formulations of azoles are not considered strong CYP3A4 inhibitors due to limited systemic absorption.  
 

SAP_001.pdf: 
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Version 2.0, Date: 07 February 2018 
 
STATISTICAL ANALYSIS PLAN 
 
A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY OF 
THE EFFICACY, SAFETY, AND TOLERABILITY OF SERLOPITANT FOR 
THE TREATMENT OF PRURITUS IN ADULTS AND ADOLESCENTS WITH 
A HISTORY OF ATOPIC DERMATITIS (ATOMIK) 
 
MTI-103 
 
Sponsored by: 
Menlo Therapeutics Inc. 
200 Cardinal Way, 2nd Floor 
Redwood City, CA 94063 
 
Version: 2.0 
Date Approved: 07 February 2018 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ....................................................................................................4 
1 
STUDY DESCRIPTION .........................................................................................5 
1.1 
Introduction ........................................................................................................5 
1.2 
Objectives ..........................................................................................................5 
1.3 
Study Design ......................................................................................................5 
1.4 
Method of Assigning Subjects to Treatment Groups .........................................7 
1.5 
Treatment Blinding ............................................................................................7 
1.6 
Decision Rule and Sample Size .........................................................................7 
2 
STATISTICAL METHODS ....................................................................................8 
2.1 
Populations Analyzed ........................................................................................8 
2.2 
Study Drug Dosing and Compliance .................................................................8 
2.3 
Study Endpoints .................................................................................................9 
2.3.1 
Endpoint Data Capture .........................................................................10 
2.3.2 
Itch Numeric Rating Scale ...................................................................10 
2.3.3 
Static Patient Global Assessment of Itch Severity ...............................10 
2.3.4 
Patient Global Impression of Change in Itch Severity .........................10 
2.3.5 
ItchyQoL ..............................................................................................10 
2.3.6 
5-D Pruritus Scale ................................................................................11 
2.3.7 
Actigraphy............................................................................................12 
2.3.8 
Investigators’ Global Assessment of Atopic Dermatitis Severity .......12 
2.3.9 
Safety Parameters.................................................................................13 
2.3.10 
Pharmacokinetic Measurements ..........................................................13 
2.4 
Study Day and Visit Windows .........................................................................13 
2.5 
Statistical Assessment of the Study Objectives ...............................................14 
2.5.1 
Primary Analysis ..................................................................................14 
2.5.2 
Secondary Analyses .............................................................................15 
2.6 
Confounding Event ..........................................................................................15 
2.7 
Handling of Missing Data ................................................................................15 
2.8 
Sensitivity Analyses, Subgroups and Covariates .............................................16 
2.9 
Safety Analyses ................................................................................................17 
2.10 
Interim Analysis ...............................................................................................17 
3 
SUMMARY TABLES, LISTINGS, AND FIGURES ...........................................18 
3.1 
General Conventions ........................................................................................18 
3.2 
Definition of Baseline ......................................................................................18 
3.3 
Clinical Study Subjects ....................................................................................18 
3.3.1 
Subject Disposition and Analysis Populations. ...................................18 
3.3.2 
Demographics and Baseline Characteristics ........................................19 


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3.3.3 
Concomitant Medications and Procedures...........................................19 
3.3.4 
Medical History ...................................................................................20 
3.3.5 
Clinical Study Treatment .....................................................................20 
3.4 
Analysis of Efficacy Endpoints .......................................................................20 
3.4.1 
Calculation Examples for Daily Measures ..........................................20 
3.4.2 
WI-NRS ...............................................................................................21 
3.4.3 
ItchyQol ...............................................................................................22 
3.4.4 
Additional and Exploratory Endpoints ................................................22 
3.5 
Analysis of Safety Endpoints ...........................................................................23 
3.5.1 
Adverse Events ....................................................................................23 
3.5.2 
Clinical Laboratory Evaluations ..........................................................23 
3.5.3 
Vital Signs ............................................................................................23 
3.5.4 
Electrocardiogram Results ...................................................................23 
3.6 
Pregnancy .........................................................................................................23 
3.7 
Psychometric Analyses ....................................................................................24 
3.8 
Pharmacokinetic Analyses ...............................................................................24 
4 
REFERENCES ......................................................................................................25 
 
LIST OF TABLES 
Table 1 
Schedule of eDiary and Actigraphy Assessments .......................................6 
Table 2 
Schedule of Visit Activities .........................................................................6 
Table 3 
Analysis Windows .....................................................................................13 
Table 4 
Daily Windows ..........................................................................................14 
 
 
 
 


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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
AD 
Atopic dermatitis  
AE 
Adverse Event 
AI-NRS 
Average-Itch Numeric Rating Scale 
ANOVA 
Analysis of Variance 
BOCF 
Baseline Observation Carried Forward 
CMH 
Cochran Mantel Haenszel  
CRF 
Case report form 
ECG 
Electrocardiogram 
eDC 
Electronic data capture 
eDiary 
Electronic diary 
ETD 
Early Treatment Discontinuation 
FAS 
Full Analysis Set 
iDMC 
Independent data monitoring committee 
ICF 
Informed Consent Form 
IGA-AD 
Investigators’ Global Assessment of atopic dermatitis severity 
Itch NRS 
Itch Numeric Rating Scale 
LOCF 
Last Observation Carried Forward 
NK1-R 
Neurokinin-1 receptor 
PGIC 
Patient Global Impression of Change 
PK 
Pharmacokinetics 
SAE 
Serious Adverse Event 
sPGA 
Static Patient Global Assessment 
TEAE 
Treatment-Emergent Adverse Events 
WI-NRS 
Worst-Itch Numeric Rating Scale 


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1 
STUDY DESCRIPTION 
1.1 
Introduction 
In this study serlopitant is being studied for the treatment of pruritus (itching) in adults and 
adolescents with a history of atopic dermatitis. Atopic dermatitis (AD) is an inflammatory, 
chronically relapsing and intensely pruritic skin disease referred to as “the itch that rashes.” 
Pruritus is the “cardinal symptom” in AD (Lewis-Jones 2006).   
Serlopitant is a small molecule, highly selective neurokinin-1 receptor (NK1-R) antagonist 
that is administered orally. NK1-R stimulation has been shown to be an important pathway 
for pruritus perception (Ständer 2015). Evidence suggests that inhibition of this pathway 
results in decreased pruritus, see protocol for details. Prior to initiation of this study, 
serlopitant was evaluated in over 1,000 subjects across thirteen Phase 1 studies and four 
Phase 2 studies.   
1.2 
Objectives 
Study MTI-103 contains primary and secondary objectives.   
The primary objective is to assess the efficacy of serlopitant for the treatment of pruritus in 
adults and adolescents with a history of atopic dermatitis. 
The secondary objectives of this study are as follows: 
• To assess the safety and tolerability of repeated oral doses of serlopitant in adults and 
adolescents with a history of atopic dermatitis 
• To assess the psychometric properties of Worst-Itch Numeric Rating Scale (WI-NRS) 
 
1.3 
Study Design 
This is a double-blind, randomized, placebo-controlled study. Approximately 450 subjects 
will be randomized in a 1:1:1 ratio to receive daily oral doses of serlopitant 1 mg, 5 mg, or 
placebo for 6 weeks. The study will consist of three periods (screening, treatment, 
follow-up), for a total study period of approximately 12 weeks. 
During the screening period, subjects will be provided with an electronic device for recording 
electronic diary (eDiary) assessments throughout the study. This eDiary will be used to 
capture efficacy endpoint data and treatment information (see Table 1). At the Baseline visit, 
eligible subjects will be randomized, and study drug dispensed beginning with a loading dose 
of 3 tablets to be taken at bedtime that same day (Study Day 1). Starting on Study Day 2, 
subjects will take one tablet per day at bedtime. Treatment will continue for 6 weeks. The 
primary efficacy endpoint will be assessed during Week 6.  
After completion of the 6-week treatment period, all subjects will enter a 4-week follow-up 
period. Subjects who discontinue treatment early at any time during the treatment period will 


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have an Early Treatment Discontinuation (ETD) visit within 7 days after their last dose of 
study drug in addition to a follow-up visit 4 weeks after the end of treatment or at Week 6, 
whichever is later. 
An abbreviated schedule of activities for the study can be found in Table 2 with greater 
details available in the protocol. 
Table 1 
Schedule of eDiary and Actigraphy Assessments 
Device 
Assessment 
Timing of Assessments 
eDiary 
WI-NRS /  
AI-NRS 
Once daily for duration of the study 
ItchyQoL / 
sPGA 
At Screening, Baseline visit, Days 15 (±2), 29 (±3), 43 
(±3) and 28 days (±3) after the ETD visit 
PGIC 
Days 15 (±2), 29 (±3), 43 (±3) and 28 days (±3) after ETD 
visit 
Actigraphy 
watch 
Scratching / 
Sleep 
Nighttime monitor for duration of the study 
 
Table 2 
Schedule of Visit Activities 
Examination 
Screening 
Baseline 
Day 1 
Week 1 
Day 8 
Week 2 
Day 15 
Week 4 
Day 29 
Week 6 
Day 43 / 
ETD 
Follow-up 
ETD + 28 
Informed 
consent 
X 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
I/E criteria 
X 
X 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
Physical exam 
X 
 
 
X 
 
X 
X 
Vital signs 
X 
X 
 
X 
X 
X 
X 
ECG 
X 
 
 
X 
 
 
X 
Labs 
X 
 
 
X 
 
X 
X 
PK 
 
 
 
X 
X 
X 
 
IGA-AD 
X 
X 
 
X 
X 
X 
X 
5-D Pruritus 
Scale 
X 
X 
 
X 
X 
X 
X 
Concomitant 
medications 
Procedures/ 
Non-Medication 
Therapy 
 
X 
X 
X 
X 
X 
X 
Adverse events 
 
X 
X 
X 
X 
X 
X 
 


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1.4 
Method of Assigning Subjects to Treatment Groups 
Subjects will be randomized to serlopitant 1 mg, 5 mg, or placebo in a 1:1:1 ratio. Stratified 
permuted block randomization will be used. Randomization will be stratified by sex (male, 
female) and race (white, non-white).  An Interactive Web Response System will be used to 
perform the randomization.  
1.5 
Treatment Blinding 
This is a double-blind study. The sponsor will not have access to unblinded data during the 
study and there is no expectation that the study data (e.g. adverse events, dosing, or lab 
results) will unblind the sponsor, investigator or subjects.  Greater details concerning study 
blinding can be found in a separate blinding plan. 
1.6 
Decision Rule and Sample Size 
The significance level for this study is 5% (one-sided).  If the one-sided p-values are less 
than 5% then the null hypothesis of no treatment effect is rejected.   If the one-sided p-values 
are additionally less than 2.5%, then the serlopitant-based regimen will have met the 
generally accepted level of evidence required to demonstrate efficacy. 
This study contains two active dosing arms. A stepdown procedure will be used to control for 
multiplicity. This procedure will start by testing the primary endpoint for the 5 mg treatment 
group and then proceed to the 1 mg group should statistical significance (one-sided p-values 
< 0.05) be reached for the 5 mg vs placebo comparison.  
Statistical significance for the key secondary endpoints will be dependent upon statistical 
significance being reached for the primary endpoint at the given dose level (i.e. a gatekeeper 
within dose arm will be used for the secondary endpoints). As there are multiple secondary 
endpoints a stepdown procedure will be used starting with the WI-NRS 4 point responder 
rate endpoint, then the ItchyQoL. 
The target sample size of 450 randomized and dosed subjects (150 per group) has been 
determined based upon a 1:1:1 allocation of subjects to treatment groups, an assumed 
common treatment effect for the 1 mg and 5 mg arms, and a 5% one-sided alpha level. One-
hundred and fifty subjects per group results in 90% power for each test individually assuming 
a treatment effect (placebo change from baseline - serlopitant change from baseline) of -1 
and a standard deviation of 2.9. 
The sample size calculations have been performed in PASS 13 using a t-test. The primary 
analysis will control for the stratification factors. It is expected that this unstratified power 
estimate will under-estimate the true power as it does not take the variance reduction 
resulting from stratification into account (Matts and Lachin 1988). 


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2 
STATISTICAL METHODS 
2.1 
Populations Analyzed 
Four analysis populations will be defined.  These populations are: 
• Screened Population – All subjects who provide informed consent and attend the 
screening visit. 
• Randomized Population – All subjects who are randomized.  Subjects will be analyzed 
within the treatment group to which they are randomized. 
• Full Analysis Set (FAS) – Subset of subjects in the randomized population who received 
at least one dose of study medication.  Subjects will be analyzed within the treatment 
group to which they are randomized. 
• Safety Population – Subset of subjects who received at least one dose of study 
medication. This population will be analyzed based upon the actual treatment received. If 
a dosing error occurs and the subjects received treatment at more than one dose level, 
where placebo is considered a dose level, they will be summarized in the dose group 
which represents the highest dose received.  
 
2.2 
Study Drug Dosing and Compliance 
Study drug usage (medication taken yes/no) on each study day will be recorded within the 
eDiary. Tablet counts will also be recorded in the case report form.  Each data source will be 
independently used to summarize tablets used and compliance.  In this way two measures of 
dosing and compliance will be available.  The calculation of these two measures will be 
identical and hence any difference between them will be reflective of the extent the subject 
reported dosing data in the eDiary and tablet counts disagree. 
The total number of tablets used will be summarized along with the duration of treatment and 
compliance.  The duration of treatment (last dose date – first dose date + 1) will be based on 
dosing information provided within the CRF. Compliance will be calculated as, 
𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶(%) =
𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇 𝑈𝑈𝑈𝑈𝑈𝑈𝑈𝑈
𝐿𝐿𝐿𝐿𝐿𝐿𝐿𝐿 𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷 𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷−𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹 𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷 𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷+ 3  . 
 
The number of tablets used will be based upon the results provided within the eDiary and the 
recorded tablet counts within eDC.  Should a subject not return a bottle, for compliance 
calculations it will be assumed they returned the average number of tablets that were returned 
in their other bottles.  Subjects with no returned bottles will have missing tablet count 
compliance. The denominator for the compliance calculation includes a + 3 to account for the 
loading dose received on Study Day 1.  This compliance calculation implies a subject who 
takes treatment for one week but takes all expected tablets for that week will be 100% 
compliant with treatment. 


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2.3 
Study Endpoints 
The study endpoints are listed below, with greater detail concerning these endpoints provided 
in Sections 2.3.2 to 2.3.10. 
Primary Efficacy Endpoint 
The primary efficacy endpoint is the change in WI-NRS from baseline to  Week 6. 
Key Secondary Efficacy Endpoints 
The key secondary efficacy endpoints are as follows: 
• WI-NRS 4-point responder rate at Week 6 
• Change in ItchyQoL from baseline to Week 6 
Additional Endpoints 
Additional secondary efficacy endpoints include the following: 
• WI-NRS 3-point responder rates 
• Change in Average-Itch NRS (AI-NRS) and AI-NRS responder rates 
• Change in 5-D Pruritus Scale 
• Change in Static Patient Global Assessment of Itch Severity (sPGA) 
• Change in Patient Global Impression of Change in Itch Severity (PGIC) 
• Change in number of night-time scratching events per hour from baseline to Week 6 
Safety endpoints include the following: 
• Incidence of treatment-emergent adverse events (TEAEs) and serious adverse events 
(SAEs) 
• Changes in clinical laboratory parameters following study drug exposure 
• Changes in vital sign and electrocardiogram (ECG) parameters following study drug 
exposure 
• Plasma concentrations of serlopitant and metabolites 
Exploratory endpoints include the following: 
• Change in Investigators’ Global Assessment of atopic dermatitis severity (IGA-AD) 
• Change in sleep efficiency 
• Change in mean activity during the sleep period   
 


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2.3.1 
Endpoint Data Capture  
The study endpoints will be captured within five electronic systems, the electronic data 
capture (eDC system) , subject eDiary, subject actigraphy devices, central laboratories (ACM 
Global) and centralized ECG assessments. The adverse events, vital signs, and IGA-AD will 
be captured in the CRF. The eDiary will capture the WI-NRS, ItchyQoL, AI-NRS, sPGA, 
and PGIC. The actigraphy devices will record night-time scratching, sleep efficiency, and 
mean activity during the sleep period during each night the subjects is on study. 
2.3.2 
Itch Numeric Rating Scale 
The Itch NRS is an instrument for measurement of itch intensity that asks subjects to rate the 
intensity of their itch on an 11-point scale ranging from 0 (no itch) to 10 (worst itch 
imaginable) during a 24-hour recall period. Both WI-NRS and AI-NRS during a 24-hour 
recall period will be captured. The daily NRS results will be summarized at Weeks 2, 4, 6 
and follow-up as outlined in Section 2.4. A 4-point responder is a subject who had at least a 
4-point reduction in score between the visit and baseline. A 3-point responder is similarly 
defined.  
2.3.3 
Static Patient Global Assessment of Itch Severity  
The sPGA assesses overall itch severity by asking the severity of itchiness in the past 7 days 
on a 5-point scale as none (0), mild (1), moderate (2), severe (3), and very severe (4).  
2.3.4 
Patient Global Impression of Change in Itch Severity 
The PGIC in Itch Severity is a single item measure that assesses the change in overall itch 
severity since the Baseline visit on a 7-point scale from (very much better) to (very much 
worse).  
2.3.5 
ItchyQoL 
ItchyQoL is a 22-item pruritus-specific instrument that measures the degree to which pruritus 
affects quality-of-life. The responses to the items are Never (1), Rarely (2), Sometimes (3), 
Often (4) and All the Time (5). This impact is quantified into 3 subscales (symptom, 
function, emotion) and an overall score. A higher score corresponds to a more adverse 
impact. The overall score is the average of the 22 items. If an item is missing the total score 
will be missing. The score for each subscale is the average score for the items that make up 
the subscale. The items that make up the subscales are, 
• Symptom subscale score (items 1-6):  
- 
My itchy skin condition bleeds,  
- 
My skin hurts because of my itchy skin condition,  
- 
My itchy skin condition burns or stings,  
- 
I get scars from my itchy skin condition,  


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- 
I need to scratch my itchy skin condition,  
- 
Temperature/seasonal changes aggravate my itchy skin condition  
• Function subscale score (items 7-13):  
- 
I spend a lot of money treating my itchy skin condition,  
- 
My itchy skin condition makes it hard to work or do what I enjoy,  
- 
My itchy skin condition affects my interaction with others,  
- 
My itchy skin condition affects how well I sleep,  
- 
My itchy skin often makes it difficult to concentrate,  
- 
My itchy skin condition limits the types of clothes I can wear,  
- 
My itchy skin condition forces me to buy special soaps, detergents, and lotions.  
• Emotion subscale score (items 14-22):  
- 
I am frustrated by my itchy skin condition,  
- 
I am embarrassed by my itchy skin condition,  
- 
My itchy skin condition drives me crazy/nuts,  
- 
My itchy skin condition makes me feel angry or irritable,  
- 
My itchy skin condition makes me feel depressed or sad,  
- 
I worry about what other people think about me because of my itchy skin condition,  
- 
I worry that the itching will last forever,  
- 
I feel self-conscious because of my itchy skin condition,  
- 
My personality has changed because of my itchy skin condition. 
 
2.3.6 
5-D Pruritus Scale 
The 5-D Pruritus Scale assesses the five domains of degree, duration, direction, disability and 
distribution of pruritus. Subjects rate their symptoms over the preceding 2-week period. The 
scores of each of the five domains are achieved separately and then summed together to 
obtain a total 5-D score (Elman 2010) resulting in a range of scores from 5 to 25 (no to most 
severe pruritus). If any one item is missing the total score will be missing. 
The single-item domains, duration, degree and direction, are captured on a likert scale. The 
score for these domains is equal to the value recorded for the domain (i.e. 1 to 5). The 
disability domain includes four items that assess the impact of itching on: sleep, leisure 
⁄social activities, housework ⁄errands and work ⁄school. The score for the disability domain is 
achieved by taking the highest score on any of the four items. For the distribution domain, 
the number of affected body parts is given a point total (0–2 = 1, 3–5 = 2, 6–10 = 3, 11–13 = 
4, 14–16 = 5). 


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2.3.7 
Actigraphy 
The actigraphy assessments requires each subject to wear the actigraphy devices, which are 
the size of a medium size wrist watch, on each wrist at night (during sleep), with the option 
to wear them during the waking hours as well. The waking hours data will be captured but 
not directly analyzed. The devices are returned to the study site where the data are 
downloaded and sent for analysis. Subjects will be permitted to not wear the devices up to 
three nights over any seven-day period (i.e. up to three nights per week). 
The 3-dimensional acceleration data (m/sec2) from the actigraphy device is analyzed to 
discriminate scratching from other nighttime events. These scratching results will include  
1. Scratching Endpoints 
a. scratching time per sleep period (the time of the first and last itching event),  
b. number of scratching events per sleep period 
c. the itching events per hour (secondary endpoints) and  
d. the intensity of itching per hours (seconds of itching per hour). 
2. Sleep Endpoints 
a. sleep duration (end of sleep – start of sleep),  
b. total sleep time (time subject was asleep during sleep period, does not include 
wake time during sleep period),  
c. sleep efficiency (exploratory endpoint: sleep time/sleep duration),  
d. Wake After Sleep Onset (WASO) and  
e. the mean activity during the sleep period (exploratory endpoint). 
For the actigraphy endpoints to mirror the techniques used in development of the actigraphy 
tool as outlined in Moreau et al. (2017), the analysis will be limited to sleep periods between 
30 minutes and 18 hours in length.   
2.3.8 
Investigators’ Global Assessment of Atopic Dermatitis Severity 
The IGA-AD is an instrument used to assess the overall severity of atopic dermatitis at a 
given time point, as determined by the investigator. It consists of a 6-point scale ranging 
from 0 (clear) to 5 (very severe). An IGA-AD responder is defined as a subject with a score 
of “clear” or “almost clear” and at least a 2-grade reduction from baseline score. 


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2.3.9 
Safety Parameters 
Vital signs will include measurements of heart rate, sitting blood pressure, respiration rate, 
and temperature. A standard 12-lead ECG will be performed and centrally read. From this 
central read the following parameters will be available: RR, PR, QRS, QT, HR, QTcB, 
QTcF, and the “interpretation” (Normal or Abnormal). If the result is considered abnormal, 
the specific findings will also be provided. Physical examination abnormalities identified as 
preexisting before treatment will be recorded as medical history. Laboratory results identified 
as clinically significant and abnormal before treatment will be recorded as medical history or 
associated with an ongoing historical event.   Clinically significant new or worsened 
abnormalities that appear after treatment will be recorded as AEs. 
Vital signs, ECG parameters and relevant interpretations, and laboratory results will be listed. 
2.3.10 
Pharmacokinetic Measurements 
Blood samples for pharmacokinetic (PK) measurements will be collected as outlined in 
Table 2.  
2.4 
Study Day and Visit Windows 
Summary tables will report data based upon the protocol scheduled time points (Weeks 2, 4, 
6 and Follow-up). Assessment will be assigned to these time points based upon the study day 
they are performed on. The derivation of study day depends upon whether the event occurred 
prior to or after treatment. This results in the first day of treatment being on day 1 and the day 
prior to the first day of treatment being day -1.  For events that occur prior to the first day of 
treatment the following definition is used, 
Study day = date of assessment - date of first treatment. 
 
For events that occur on or after the first day of treatment, a plus one is added, 
Study day = date of assessment - date of first treatment + 1. 
 
The analysis windows used to report non-daily endpoints as well as ItchyQoL, sPGA and 
PGIC are outlined in Table 3.  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 3 
Analysis Windows 
Visit 
Range 
Target Day 
Baseline 
Day ≤1  
Day 1 
Week 2 
Day 2 to Day 21 
Day 15 
Week 4 
Day 22 to Day 35 
Day 29 
Week 6 
Day 36 to Day 57 
Day 43 
Week 10 
> Day 57 
Day 71 
 


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In addition to the analysis windows, data will be summarized at Follow-Up. 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. While a Week 10 analysis window is defined, data tables will be 
limited to Baseline, Week 2, 4, 6 and Follow-up. 
eDiary and actigraphy daily results (WI-NRS, AI-NRS, night-time scratching, sleep 
efficiency and mean activity during the sleep) will be summarized at Baseline, Week 2, 4, 6 
and Follow-up. The seven days leading up to the time point (see Table 4 range), will be used 
to create the summary measures unless the subject does not have at least seven results. In this 
case as many observations as are available within the complete data range will be used and 
additional data from the extended range (see Table 4) will be used until seven data points are 
achieved or the end of the extended range is reached. An example of this algorithm can be 
found in Section 3.4.1. 
Table 4 
Daily Windows 
Visit 
Range (complete data) 
Extended Range 
Baseline 
Day -7 to -1 
Day -11 to -8 
Week 2 
Day 8 to Day 14 
Day 15 to Day 18 
Week 4 
Day 22 to Day 28 
Day 29 to Day 32 
Week 6 
Day 36 to Day 42 
Day 43 to Day 46 
 
An additional ‘Follow-Up’ timepoint will also be created. This timepoint includes the last 
7 post treatment observations that are at least 7 days after the end of treatment.   
For the WI-NRS and AI-NRS endpoints results from within the windows provided in Table 4 
and at Follow-up may not be used based upon the confounding logic outlined in Section 2.6. 
2.5 
Statistical Assessment of the Study Objectives 
The efficacy endpoints will be summarized within the FAS using descriptive statistics by 
time point and treatment. For the primary and key secondary endpoints these statistics will 
include 95% confidence intervals for the treatment difference. Testing will also be used for 
the primary and key secondary endpoints. 
2.5.1 
Primary Analysis 
The difference in the primary efficacy outcome measure (WI-NRS change from baseline to 
Week 6) between treatment groups will be tested using an analysis of variance (ANOVA) 
model controlling for the stratification factors. A main effects model with an interaction term 
(treatment by stratification factors) and a Type II hypothesis will be used. More precisely this 
ANOVA model uses the following as a stratified adjusted measure of the change from 
baseline for a given treatment group: 
∆= ∑
𝑛𝑛1𝑗𝑗𝑛𝑛2𝑗𝑗
𝑛𝑛1𝑗𝑗+𝑛𝑛2𝑗𝑗
4
𝑗𝑗=1
∆𝑗𝑗 , 


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where j represents the stratification cells, n is the sample size for treatment 1 and 2 and ∆j is 
the change measure for stratum j.  Should a site make an error during randomization and 
select the wrong stratification factor (e.g. select the White stratification cell for a non-White 
subject) the test will use how the subject was randomized. All other summaries of race (e.g. 
baseline characteristics or subgroup analyses) will be based upon the correct race group and 
not the as randomized group. 
Conceptually the hypotheses being tested for this study are: 
H0:∆Placebo ≥ ∆Serlopitant 
Ha: ∆Placebo < ∆Serlopitant 
where ∆Placebo is the placebo change from baseline to Week 6 and ∆Serlopitant is the similar 
measure for serlopitant. Each serlopitant treatment group (1 mg and 5 mg) will be compared 
to placebo separately.  
The primary endpoint will utilize the analysis windows outlined in Section 2.4, the 
confounding rules outlined in Section 2.6 and the missing data rules outlined in Section 2.7.   
2.5.2 
Secondary Analyses 
The differences between treatment groups for the key secondary endpoints will be tested using 
the same ANOVA model as used for the primary endpoint (change in ItchyQoL) or a 
Cochran Mantel Haenszel (CMH) test (WI-NRS 4-point responder rate) controlling for the 
‘as randomized’ stratification factors.  A CMH test will also be conducted for the WI-NRS 3-
point responder rate, AI-NRS 4-point responder rate, and AI-NRS 3-point responder rate. 
2.6 
Confounding Event 
The use of excluded therapies / procedures or clinically significant changes in the dose or 
frequency of allowed adjunctive therapies can result in a change in pruritus. In the statistical 
plan the use of excluded therapies / procedures or clinically significant changes in the dose or 
frequency of allowed adjunctive therapies is called a confounding event.  Short treatment (up 
to 3 days) of an excluded medication for indications other than atopic dermatitis or pruritus 
(see protocol for specific medications) is not considered a confounding event. Should a 
confounding event occur, the cause of changes in pruritus can no longer be clearly attributed 
to the randomized treatment. As such, the results from the WI-NRS/AI-NRS following this 
confounding event (i.e. on the day the confounding event occurred or after) will not be 
included in the analysis.   
Confounding events will be identified by a blinded clinical review of the concomitant 
medication and procedures data prior to database lock. 
2.7 
Handling of Missing Data 
Summary statistics will generally be reported based upon observed data. Should a 
determination of treatment period (on treatment, pre-treatment) be required for adverse 
events or concomitant medication but the corresponding date is missing, or is a partial date, 


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the event/medication will be considered on treatment unless the portions of the date that are 
available indicate this is not possible. 
If a subject fails to complete their eDiary for a week or more, or a confounding event occurs 
the WI-NRS and AI-NRS endpoints, including the primary endpoint, may be missing. In this 
case, their change from baseline value will be imputed. The subject’s data prior to 
confounding will be used. From that point forward their trajectory will be imputed based 
upon the trajectory of their treatment group. The imputation approach first determines the 
average change for each time point (i.e. Weeks 2, 4, 6) for each treatment group. The 
difference between weeks n-1 and n will be considered the change for Week n. These change 
measure will be used to ‘fill in’ the missing weeks between the last completed week (pre-
confounding) and Week 6. Hence, a placebo subject who receives excluded therapy in Week 
4 will have their Week 6 WI-NRS change from baseline imputed as ∆4+∆(4, 6), where ∆4 is the 
observed change from baseline result for the subject up to Week 4 and ∆(4-6) is the placebo 
change from Week 4 to 6 (i.e. the average placebo decrease from Week 4 to 6). 
Missing data imputation will only be used for the WI-NRS and AI-NRS endpoints.    
2.8 
Sensitivity Analyses, Subgroups and Covariates 
Descriptive statistics for the change in WI-NRS at Week 6 will be provided for the subgroups 
indicated below. Forest plots of the difference and confidence interval for this difference will 
also be created. The subgroups include,  
• Sex 
• Age Group (< 18 years, 18 to 64 years, > 64 years)  
• Race  
- 
All race groups with less than 30 subjects will be combined with ‘Other’ 
- 
A White versus Non-White comparison will be made 
• Baseline WI-NRS  
• Baseline IGA-AD 
• Use of allowed concomitant medications as outlined in Section 5.7.1 of the protocol 
• Treatment completion (completed treatment, did not complete treatment). 
To investigate the impact of missing data / confounding sensitivity analyses will be 
performed for the WI-NRS endpoint. These methods include, 
1. Multiple imputation, MI, methods will be used to recalculate the p-values at Week 6.  
2. The summary statistics will be produced where the missing data is imputed using  
a. Data after the confounding event are excluded with no imputation 


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b. Last Observation Carried Forward (LOCF), 
c. Baseline Observation Carried Forward (BOCF).  
2.9 
Safety Analyses 
Safety endpoints will be summarized with descriptive statistics. All safety summaries and 
analyses will be performed using the safety population.  
Prior and Concomitant medications will be coded by the World Health Organization (WHO) 
Drug Dictionary version 2012/Q4. Adverse Events and Medical History will be coded using 
MedDRA version 17.1 (or later).  
2.10 
Interim Analysis 
An independent Data Monitoring Committee (iDMC) will monitor unblinded safety data. 
The iDMC may make recommendations to the Sponsor to continue or terminate the study 
based upon the outcomes of the data reviews. The iDMC is not tasked with stopping the 
study early for efficacy or for stopping for futility. Greater detail concerning the iDMC can 
be found in the iDMC charter. 
 


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3 
SUMMARY TABLES, LISTINGS, AND FIGURES 
3.1 
General Conventions 
Unless otherwise stated, summary statistics including the number of subjects (n), mean, 
standard deviation, median, minimum and maximum will be presented for continuous 
variables. Generally, the minimum and maximum values will be presented to the same 
decimal precision as the raw values, the mean and median values to one more, and the 
standard deviation, to two more decimal places than the raw values. For categorical variables, 
per category, the absolute counts (n) and percentages (%) of subjects with data. Percentages 
will be presented to one decimal place. 
For AEs, medical history (prior and concomitant diseases) and concomitant medications 
reported on a per-subject basis, the denominator for the percentage calculation will be the 
number of subjects at risk in each treatment group. A subject will be considered at risk if the 
subject is in the analysis set and in the subgroup of interest. 
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 population and all safety will be based upon the safety 
population. The safety and demographic tables will include a total serlopitant (1 mg and 5 mg 
doses) and a total column (total serlopitant and placebo) along with the treatment columns. 
3.2 
Definition of Baseline 
Unless specified elsewhere, baseline is defined as the last available measurement prior to 
administration of study drug. For events that occur on the same day as the first administration 
of study drug (i.e. assessments performed at the Baseline visit) the assessment will be 
classified as pre-treatment and hence baseline.  Baseline for the daily measures recorded in 
the eDiary and actigraphy device is defined in Table 4. 
3.3 
Clinical Study Subjects 
3.3.1 
Subject Disposition and Analysis Populations. 
The number of subjects randomized, treated, and discontinued early, will be summarized 
within all randomized subjects. The reason for early termination will be summarized. 
Additionally, a summary of subjects present at each visit as determined by the presence of a 
vital signs result, will be provided.  
A listing of entry criteria that were not met will be produced. The listed criteria will include 
the criteria language. A table of the violated entry criteria for randomized subjects will be 
produced as well as a table that summarizes the screen failure reasons for screen failure 
subjects. 
The number of subjects in each analysis population will be summarized.  


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3.3.2 
Demographics and Baseline Characteristics 
Demographic and baseline characteristics will be summarized descriptively by treatment 
group. This will include the following items: 
1. Demographic variables 
a. Age 
b. Race 
c. Ethnicity 
d. Sex 
e. Height 
f. Weight 
◦ 
Baseline WI-NRS  
◦ 
Presence or absence of active AD 
◦ 
Baseline IGA-AD  
◦ 
Age at AD diagnoses 
◦ 
AD severity relative to prior 3 and 12 months 
◦ 
Family history of atopy (eczema, asthma, allergic rhinitis) 
◦ 
Prior Treatments of AD (e.g. antibiotics, antihistamines, corticosteroids, 
biologics, immunomodulatory agents) 
 
3.3.3 
Concomitant Medications and Procedures 
Medications and procedures with a stop date before the treatment dosing date will be 
considered prior medications/procedures. Medications/procedures with a start or stop date on 
or after the treatment dosing date will be considered concomitant. All 
medications/procedures marked as ongoing are concomitant.  
A medication/procedure with an incomplete stop date will be considered concomitant if: 
1. Month is missing and year is equal to or after the year of treatment dosing date 
2. Day is missing and year is equal to the year of the treatment dosing date and month is 
equal to or after the month of the treatment dosing date. 
 
All concomitant medications will be summarized by treatment group. All medications, 
including prior medications, will be provided in listings.  
A table and listing will be produced to summarize confounding events as defined in 
Section 2.6. 


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A table and listing will be produced to summarize the allowed concomitant medications 
(antihistamines, topical steroids, topical calcineurin inhibitors, emollients). 
A table and listing will be produced to summarize topical adjunctive therapies. 
Procedures and non-medication therapies will be listed. A listing of confounding procedures / 
non-medication therapies will be provided. 
3.3.4 
Medical History 
Medical history will be tabulated by system organ class, preferred terms and treatment group.  
3.3.5 
Clinical Study Treatment 
The total tablets used, duration of treatment (Last dose date – first dose date + 1), number of 
subjects with dosing errors and compliance (see Section 2.2) will be summarized. Tablets 
used will be calculated by summing the number of days the subject indicates medication was 
used and based upon tablet counts reported in the CRF. For the first treatment day of the 
diary-based calculation, if a subject indicates they used treatment it will be assumed three 
tablets were taken. The kit numbers provided in the eDC system will be used to identify 
dosing errors. Should an error occur the tablet counts provided in the eDC system will be 
used to determine treatment assignment for the safety population.   
3.4 
Analysis of Efficacy Endpoints 
3.4.1 
Calculation Examples for Daily Measures 
Below are examples of how the eDiary and actigraphy endpoints will be calculated based 
upon windows outlined in Table 4 and rules outlined in Section 2.4.   
1. Example 1 (complete data) 
a. The subject has results for all seven days leading up to the visit (e.g. x8, x9, x10, x11, 
x12, x13, x14).   
b. The average for Week 2 is (x8+ x9+ x10+ x11 +x12+ x13 +x14)/7. 
2. Example 2 (incomplete data, completed in the extended range) 
a. The subject has results for less than seven days in the original range (e.g. x22, x24, x25, 
x27, x28) but have enough in the extended range to reach seven results overall (e.g. x29, 
x31).  In this example the subject is missing diary data on days 23, 26, and 30. 
b. The average for Week 4 is (x22+ x24+ x25+ x27 +x28+ x29 +x31)/7. 


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3. Example 3 (incomplete data) 
a. The subject has results for less than seven days in the original range (e.g. x40, x42) and 
does not have enough in the extended range to reach seven results overall (e.g. x44, 
x48, x49).  In this example the subject is missing diary data on days 36, 37, 38, 39, 41, 
43, 45, 46, 47 and 49. 
◦ 
The average for Week 6 is (x40+ x42+ x44+ x48 +x49)/5. 
4. Example 4 (confounding event) 
a. The subject has results for all seven days leading up to the visit but has a confounding 
event part way through window (e.g. x8, x9, x10, x11, x12, x13, x14 all exist but excluded 
medication or therapy was received on day 11).   
b. The average for Week 2 is (x8+ x9+ x10)/3. 
5. Example 5 (no data) 
a. The subject does not complete the diary after day 10 or had a confounding event 
before day 10.  
b. The average for Weeks 4 and 6 are missing. 
 
3.4.2 
WI-NRS  
The WI-NRS endpoints (result, change from baseline, percent change from baseline, 3-point 
and 4-point responders) will be summarized at the primary time point, Week 6, as well as at 
Week 2, 4 and Follow-up. The summary measures will include 95% Wald confidence 
intervals for the treatment difference. The baseline WI-NRS will also be summarized, though 
no confidence interval will be produced. A graph of the mean WI-NRS results and change 
from baseline results by timepoint and treatment will be produced as well as a cumulative 
distribution function plot (CDF plot) of the Week 6 results. 
The WI-NRS scores for days -7 to 14 will be plotted by averaging the available data across 
subjects within treatment group and study day. These results will be summarized in a table 
along with change from baseline where baseline is defined in the identical manner used for 
the weekly measures, see Table 4. 
The summary measures for the WI-NRS change from baseline results and the 4-point 
responder rate will be produced using four endpoint derivation methods, one primary method 
and three sensitivity measures. The difference between these methods is how the weekly 
measures are calculated. The primary derivation method uses all reported data prior to use of 
excluded therapy or changes to allowed adjunctive therapies and the missing data imputation 
rules outlined in Section 2.7. Sensitivity analyses as defined in Section 2.8 will also be 
conducted. 
Testing will be used for the change from baseline and 4-point responder rates endpoints at 
Week 6. The test used for the 4-point responder rate (primary endpoint) is a CMH test 
controlling for the ‘as randomized’ stratification factors. The ‘as randomized’ stratification 
factors are based upon the stratification cell the subject was randomized two. The differences 


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between treatment groups for the change from baseline measure will be tested using an 
ANOVA model controlling for the stratification factors. A main effects model with an 
interaction term (treatment by stratification factors) and a Type II hypothesis will be used. 
Each serlopitant treatment group (1 mg and 5 mg) will be compared to placebo separately 
and the multiplicity rules outlined in Section 1.6 will be used to interpret these p-values. 
‘Sensitivity’ p-values will be constructed using multiple imputation (MI) methodology. This 
approach imputes randomly generated values instead of the fixed value. Using the example 
from Section 2.6 (i.e. a subject had data up to Week 4 but is missing their Week 6 results: 
∆4+∆(4, 6)), at least 1,000 random realizations of ∆(4, 6) will be generated using code similar to 
the following, 
proc mi nimpute=1000; 
class trt; 
monotone reg(x); 
var trt x; 
 
From these realizations of ∆(4, 6) the change from baseline to Week 6 will be calculated s. 
Hence, there will be at least 1,000 random realizations of the responder status. The p-value 
from the MI analysis will be calculated using the SAS software procedure mianalyze. 
Finally, the change in WI-NRS results will be summarized within the subgroups outlined in 
Section 2.8. Forest plots based upon the same subgroups will also be produced. 
3.4.3 
ItchyQol 
The ItchyQol endpoint will be summarized at Baseline, Week 2, 4, 6 and Follow-up. The 
summary measures will include 95% Wald confidence intervals of the treatment difference. 
In addition, a graph of the mean score by treatment and timepoint will be produced along 
with a graph of change from baseline. The difference between serlopitant 1 mg and 5 mg 
individual versus placebo at Week 6 will be tested with the identical ANOVA model as used 
for the change from baseline WI-NRS endpoint. 
3.4.4 
Additional and Exploratory Endpoints 
The additional and exploratory endpoints (AI-NRS, sPGA, IGA-AD, 5-D Pruritus Scale, 
Actigraphy endpoints) will be summarized at baseline, Week 2, 4, 6 and Follow-up. The 
result as well as change from baseline will be summarized. The PGIC endpoint is a change 
measure so only the results at each time point will be summarized. As the 5-D Pruritus Scale 
was introduced into the study part way through the study, only subjects with a baseline value 
will be included in the summary table. 
For the IGA-AD endpoint a separate analysis will be performed where the result is 
dichotomized to responder/non-responder. This measure will be summarized at Week 2, 4, 6 
and Follow-up and be limited to subjects with a mild or greater assessment at baseline. 


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3.5 
Analysis of Safety Endpoints 
3.5.1 
Adverse Events 
AEs and SAEs will be recorded from the first study drug administration through the 
Follow-up visit. A treatment-emergent AE (TEAE) is an AE which started on or after the 
date of the first treatment. An overview of AEs, which includes subject incidence of TEAEs, 
treatment-related TEAEs, serious TEAEs, TEAEs by toxicity grade and TEAEs leading to 
permanent discontinuation of treatment. For TEAEs presented by toxicity grade, the worst 
grade during the clinical study will be presented for each subject. 
The subject incidence of TEAEs, treatment-related TEAEs and TEAEs leading to permanent 
discontinuation of treatment will be summarized by system organ class and preferred term.   
Treatment-emergent AEs will also be summarized in a table by toxicity grade. For TEAEs 
presented by toxicity grade, the worst grade for each event during the clinical study will be 
presented for each subject.  
All AEs will be presented as a listing by subject. A separate listing of pruritus and atopic 
dermatitis adverse events (as identified by the investigator) will be presented. TEAEs leading 
to treatment discontinuation will be provided in a separate listing.   
SAEs will be listed and summarized in a similar manner to TEAEs.   
3.5.2 
Clinical Laboratory Evaluations 
Summary statistics for actual values and for changes from baseline will be tabulated for 
clinical laboratory results by analysis window. Shifts from baseline clinical laboratory values 
based upon the normal range will be tabulated. These tables will utilize the normal ranges 
provided for the individual sample.  
3.5.3 
Vital Signs 
The observed data at baseline and change from baseline for each measurement day will be 
summarized with descriptive statistics.  
3.5.4 
Electrocardiogram Results 
The overall ECG assessment (abnormal or normal) will be summarized by treatment and 
analysis window. The QTcF values will be summarized by treatment and analysis window as 
both the QTcF value and change from baseline. A summary of the number of subjects with a 
value > 450, 480 and 500 and the numbers of subjects with change from baseline values > 30 
and 60 by treatment and analysis window will be produced.  
3.6 
Pregnancy 
A listing of pregnancy tests results will be produced. 


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3.7 
Psychometric Analyses  
A psychometric assessment of the WI-NRS will be conducted outside of this analysis plan. 
3.8 
Pharmacokinetic Analyses 
Plasma concentrations will be summarized by time-point and treatment. 
 


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4 
REFERENCES 
The following litterature references cited in this document are available upon request. 
1. Lewis-Jones S. Quality of life and childhood atopic dermatitis: the misery of living with 
childhood eczema. Int J Clin Pract. 2006;60(8):984-92. 
2. Ständer S, Luger TA. NK-1 antagonists and itch. Handb Exp Pharmacol. 2015;226:237-
55. doi: 10.1007/978-3-662-44605-8_14. 
3. PASS 13 Power Analysis and Sample Size Software (2014). NCSS, LLC. Kaysville, 
Utah, USA, ncss.com/software/pass. 
4. Matts JP, Lachin JM. Properties of permuted-block randomization in clinical trials. 
Control Clin Trials. 1988;9(4):327-44. 
5. Elman S, Hynan LS, Gabriel V, and Mayo MJ. The 5-D Itch Scale: a New Measure of 
Pruritus. Br J Dermatol. 2010;162:587-593. 
6. Moreau A, Anderer P, Ross M, Cerny A, Almazan T, Peterson B. Detection of nocturnal 
scratching movements in patients with atopic dermatitis using accelerometers and 
recurrent neural networks. IEEE J Biomed Health Inform. 2017;162:587-593. 
 


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APPROVAL SHEET 
 
Product: 
Serlopitant 
Protocol Number: 
MTI-103 
SAP Version: 
2.0 
Version Date: 
07 February 2018 
 
 
The individuals signing below have reviewed and approve this statistical analysis plan.  
 
 
 
Statistician 
 
Date 
 
 
 
 
 
 
 
 
 
Senior Vice President, Clinical Development 
 
Date 
 
 
 
 
 
 
 
 
Clinical Operations Manager 
 
Date