Clinical trial NCT03841331
Conditions: Pruritus
Keywords: Pruritus
Sponsor: Vyne Therapeutics Inc.
Start date: 2019-01-22; Completion date: 2020-01-21
Enrollment: 233 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
A Randomized, Double-Blind, Placebo-Controlled Study of the Efficacy, Safety, and Tolerability of Serlopitant for the Treatment of Chronic Pruritus of Unknown Origin

Detailed description:

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

Protocol documents:
Prot_002.pdf: 
A Randomized, Double-Blind, Placebo-controlled Study Of The Efficacy, Safety, And 
Tolerability Of Serlopitant For The Treatment Of Chronic Pruritus Of Unknown Origin 
 
Protocol Version/Date: Version 3.0 / 11 Feb 2019 
 
NCT number: NCT03841331 


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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 CHRONIC PRURITUS OF UNKNOWN 
ORIGIN  
IND No.: 
 
 
117780 
ClinicalTrials.gov ID:  
[Placeholder] 
Protocol No.:  
 
MTI-117   
Protocol Version/Date: 
Version 3.0 / 11 Feb 2019 
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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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 CHRONIC PRURITUS OF UNKNOWN 
ORIGIN  
IND No.: 
 
 
117780 
ClinicalTrials.gov ID:  
[Placeholder] 
Protocol No.:  
 
MTI-117 
Protocol Version/Date:  
Version 3.0 / 11 Feb 2019 
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 Council 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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PROTOCOL SYNOPSIS 
Study Title: 
A Randomized, Double-Blind, Placebo-Controlled Study of the Efficacy, 
Safety, and Tolerability of Serlopitant for the Treatment of Chronic Pruritus of 
Unknown Origin 
Protocol Number: 
MTI-117 
Sponsor: 
Menlo Therapeutics Inc. 
Development Phase: 
Phase 2 
Study Objectives: 
Primary objective: To assess the efficacy of repeated oral doses of serlopitant in 
adult subjects with chronic pruritus of unknown origin. 
Secondary objective: To assess the safety and tolerability of repeated oral doses 
of serlopitant in adult subjects with chronic pruritus of unknown origin.  
Study Design: 
This is a double-blind, randomized, placebo-controlled study to assess the 
efficacy, safety, and tolerability of serlopitant for the treatment of chronic 
pruritus of unknown origin. Subjects who meet the study entry criteria will be 
randomized in a 1:1 ratio to receive daily oral doses of serlopitant 5 mg or 
placebo for 10 weeks. After completion of the treatment period or early 
discontinuation of study drug treatment, all subjects will enter a 5-week 
follow-up period.  
The study will consist of three periods, for a total study period of 18 weeks: 
• 
Screening period: 3 weeks 
• 
Treatment period: 10 weeks 
• 
Follow-up period: 5 weeks  
 
Informed consent will occur prior to any protocol-mandated procedures, 
including the stopping of any excluded therapies. This may occur prior to the 
Screening visit. 
During the screening period, all subjects will undergo eligibility evaluation and 
will be assessed for conditions associated with chronic pruritus. If the 
investigator deems that additional assessments are necessary to rule out specific 
conditions based on a subject’s history, physical examination, and/or screening 
labs (e.g. scabies skin preparations, urea breath test for Helicobacter pylori), the 
subject may not be randomized until these are completed and the pruritus is still 
considered to be of unknown origin.  
Subjects will be provided an eDiary at the Screening visit. Subjects must be 
willing and able to complete the eDiary every day within a consistent 
timeframe, and comply with restrictions on allowable concomitant therapies, for 
the duration of the study.  
At the Baseline visit (Day 1), eligible subjects will be randomly assigned to 
receive study drug (serlopitant 5 mg or placebo). Subjects will take a loading 
dose (3 tablets taken orally) at the site on the first day of the treatment period 
(Day 1). Starting on Day 2, subjects will take one tablet per day until the 
completion of the 10-week treatment period. Study drug may be taken with or 
without food. 
After the last dose of study drug, all subjects will enter a 5-week follow-up 
period and will undergo a follow-up visit at the conclusion of the follow-up 
period. 
The primary efficacy endpoint will be assessed at Week 10 of treatment.  


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Safety Review: 
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 200 subjects will be randomized in a 1:1 distribution.  
Randomization will be stratified by age and baseline WI-NRS scores. 
Randomization of subjects < 50 years of age will be capped at 25% of the total 
randomized population. This cap may be increased up to 33% of the total 
randomized population at the Sponsor’s discretion based on relative enrollment 
rates. 
Study Population: 
The study will consist of adult subjects with chronic pruritus of unknown origin.  
Inclusion Criteria (Subjects must meet the following criteria to be randomized 
into the study): 
1. Male or female, age 18 years or older at consent. 
2. The subject must have had ongoing pruritus for at least 6 months. 
3. The subject’s pruritus is assessed by the investigator to be of unknown 
origin at baseline.  
4. The pruritus must have been unresponsive to prior treatment with 
emollients. 
5. The pruritus must involve more than one dermatome (defined as an area of 
skin in which sensory nerves derive from a single spinal nerve root). 
Acceptable examples include right and left arm, occipital and frontal scalp, 
and upper and lower back. 
6. Worst-Itch Numeric Rating Scale (WI-NRS) score ≥ 7 in the 24-hour 
period prior to the Screening visit 
7. Average weekly Worst Itch Numeric Rating Scale (WI-NRS) score ≥ 7 in 
the week (7 days) immediately prior to randomization, as recorded in the 
eDiary. 
8. Willing and able to complete daily eDiary entries within a consistent 
timeframe for the duration of the study, as demonstrated by a ≥ 80% eDiary 
completion rate in the two weeks immediately prior to randomization. 
9. All females who are of childbearing potential must be willing to practice 
highly effective contraception (i.e., pregnancy prevention method with a 
failure rate of < 1% per year) from the time of the Screening visit until 
5 weeks after last study dosing.  
10. Adequate cognitive and physical ability, in the investigator’s opinion, to 
comply with study visits and study related requirements including 
providing written informed consent. 
 
Exclusion Criteria (Subjects who meet any of the following criteria are not 
eligible for participation in the study): 
1. Prior treatment with serlopitant or any other neurokinin-1 receptor 
antagonist. 
2. Known dermatologic or systemic condition(s), other than dry skin, that is 
considered by the investigator to be the primary cause of current pruritus.  
 


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3. Untreated or inadequately treated thyroid, adrenal, or pituitary disease or 
nodules, or history of thyroid malignancy. 
4. Use of an excluded therapy within 3 weeks prior to randomization (see 
Section 5.7). 
5. Treatment with any investigational therapy within 3 weeks prior to 
randomization. 
6. Serum creatinine, total bilirubin, alanine aminotransferase or aspartate 
aminotransferase > 2.5 times the upper limit of normal during screening. 
7. History of malignancy within 3 years prior to randomization, with the 
exception of actinic keratosis or completely treated and non-metastatic 
cutaneous squamous cell carcinoma or basal cell carcinoma of the skin. 
8. Any known major psychiatric diagnosis which, in the investigator’s 
opinion, may confound the assessment of serlopitant safety or efficacy or 
interfere with the subject’s ability to comply with protocol-mandated 
activities.  
9. Suicidal ideation within 3 years prior to randomization, or any history of 
suicide attempt. 
10. Known use of recreational drugs. 
11. Documented history of parasitic infection, including skin parasites such as 
scabies, within 12 weeks prior to randomization. 
12. Presence of clinically significant dementia, intellectual impairment, or 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. 
13. History of hypersensitivity to serlopitant or any of its components. 
14. Planned or anticipated major surgical procedure or other activity that would 
interfere with the subject’s ability to comply with protocol-mandated 
assessments (e.g. extended international travel) during the subject’s 
participation in the study. 
15. Pregnant or breastfeeding female. 
Study Drug: 
Serlopitant 5 mg oral tablets and matching placebo. 
Dosage:  
Serlopitant: 5 mg once daily by mouth for 10 weeks, following a 3-tablet 
(15 mg) loading dose on the first day of the treatment period. 
Matching placebo: Once daily by mouth for 10 weeks, following a 3-tablet 
loading dose on the first day of the treatment period. 
Primary Efficacy 
Endpoint: 
The primary efficacy endpoint is the WI-NRS 4-point responder rate at 
Week 10. 
Secondary Efficacy 
Endpoints: 
The secondary efficacy endpoints are as follows: 
• 
WI-NRS 4-point responder rate at Weeks 2, 4, 6, and 8  
• 
WI-NRS 3-point responder rate at Weeks 2, 4, 6, 8, and 10 
• 
Change from baseline in WI-NRS at Weeks 2, 4, 6, 8, and 10 
• 
Change from baseline in daily WI-NRS scores through Week 2 
• 
Change from baseline in WI-VAS at Weeks 2, 4, 6, and 10 


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Safety Endpoints: 
Safety endpoints are as follows: 
• 
Incidence of treatment-emergent adverse events and serious adverse events 
(SAEs) 
• 
Changes from baseline in clinical laboratory parameters following study 
drug exposure 
• 
Changes from baseline in vital sign and electrocardiogram (ECG) 
parameters following study drug exposure 
• 
Plasma concentrations of serlopitant and metabolites 
Exploratory Endpoints: 
The exploratory endpoints are as follows: 
• 
Change from baseline in the Epworth Sleepiness Scale (ESS) to Weeks 2, 4, 
6, and 10 
• 
Change from baseline in Static Patient Global Assessment of Itch Severity 
(sPGA) to Weeks 2, 4, 6, and 10 
• 
Patient Global Impression of Change in Itch Severity (PGIC) at Weeks 2, 4, 
6, and 10 
Decision Rule and 
Sample Size: 
This study will use a 5% one-sided alpha level.  
The target sample size of 200 randomized and dosed subjects (100 per group) 
has been determined based upon a 1:1 allocation of subjects to treatment groups 
and a 5% alpha level. Two hundred subjects results in at least 90% power 
assuming a placebo 4-point responder rate of 
% and a serlopitant 4-point 
responder rate of more than 
%. 
Statistical Methods: 
Efficacy analyses will be based upon an intent-to-treat philosophy. The primary 
efficacy population will be the full analysis population that will include all 
randomized subjects who were dispensed study drug. Subjects will be analyzed 
within the treatment group to which they are randomized. 
Efficacy Analyses: 
The primary efficacy endpoint is a binary variable taking on values of responder 
or non-responder. Subjects will be considered a responder if they have at least a 
4-point reduction in WI-NRS from baseline to Week 10. Missing data 
imputation will be used for subjects who fail to complete the eDiary at Week 10, 
unless the subject withdrew from the study due to a lack of efficacy, or the 
subject used rescue therapy (i.e. an excluded therapy to treat worsening of 
pruritus), in which case their responder status will be defined as non-responder. 
The primary endpoint will be summarized with descriptive statistics by 
treatment group and study week.  
The difference in the primary efficacy outcome measure between treatment 
groups will be tested using a Cochran Mantel Haenszel test controlling for the 
stratification factors. Testing of selected secondary efficacy endpoints will also 
be employed. 
CCI
CCI


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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. 
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.  
Clinical safety laboratory values will be measured by a central laboratory. 
Summary statistics for actual values and for changes from baseline will be 
tabulated for laboratory results by scheduled visit.  
Subjects with clinical laboratory values outside of the normal reference range at 
any post-baseline assessment will be summarized. Shifts from baseline 
laboratory values will be tabulated. 
The overall ECG assessment (abnormal or normal) will be summarized along 
with a summary of how many subjects developed a post treatment abnormal 
result.  
Study Sites: 
Approximately 40 study sites 
Expected Duration of 
Subject’s Participation 
18 weeks: 3 weeks of screening, 10 weeks of treatment, and a follow-up period 
of 5 weeks. 
 
This study will be conducted in accordance with the Guidelines of Good Clinical Practice (GCP). 


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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 ...........................................................................................................9 
LIST OF APPENDICES ..........................................................................................................12 
LIST OF FIGURES .................................................................................................................12 
LIST OF TABLES ...................................................................................................................12 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..........................................13 
1 
INTRODUCTION .................................................................................................15 
1.1 
Chronic Pruritus of Unknown Origin ..............................................................15 
1.2 
Substance P and the Neurokinin-1 Receptor ...................................................16 
1.3 
Serlopitant ........................................................................................................16 
1.3.1 
Serlopitant Background and Nonclinical Summary ............................16 
1.3.2 
Serlopitant Clinical Summary ..............................................................17 
1.3.3 
Serlopitant in Pruritus-Related Studies ................................................17 
2 
STUDY OBJECTIVES ..........................................................................................19 
3 
STUDY DESIGN...................................................................................................19 
3.1 
Overall Study Design .......................................................................................19 
3.2 
Rationale for Study Design and Dose Selection ..............................................20 
3.3 
Study Endpoints ...............................................................................................21 
3.3.1 
Primary Efficacy Endpoint ..................................................................21 
3.3.2 
Secondary Efficacy Endpoints .............................................................21 
3.3.3 
Safety Endpoints ..................................................................................21 
3.3.4 
Exploratory Endpoints .........................................................................22 
3.4 
Safety Review ..................................................................................................22 
3.4.1 
Safety Monitoring Team ......................................................................22 
4 
SELECTION OF STUDY POPULATION ...........................................................22 
4.1 
Study Population ..............................................................................................22 
4.2 
Inclusion Criteria .............................................................................................22 
4.3 
Exclusion Criteria ............................................................................................23 
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...............................................................................................24 
5.4 
Dose Modification ...........................................................................................24 
5.5 
Missed or Delayed Doses.................................................................................24 


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5.6 
Study Drug Discontinuation ............................................................................25 
5.7 
Prior, Concomitant, and Excluded Therapies ..................................................25 
5.7.1 
Allowed Therapies ...............................................................................26 
5.7.2 
Excluded Therapies ..............................................................................26 
5.7.3 
Rescue Therapies .................................................................................27 
5.8 
Assignment to Treatment .................................................................................27 
5.8.1 
Randomization .....................................................................................27 
5.8.2 
Blinding................................................................................................27 
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 
Itch Visual Analog Scale .....................................................................28 
6.1.3 
Static Patient Global Assessment of Itch Severity ...............................29 
6.1.4 
Patient Global Impression of Change in Itch Severity .........................29 
6.1.5 
Epworth Sleepiness Scale ....................................................................29 
6.2 
Safety Parameters .............................................................................................29 
6.2.1 
Vital Signs ............................................................................................29 
6.2.2 
Physical Examination...........................................................................29 
6.2.3 
Clinical Laboratory Assessments .........................................................30 
6.2.4 
Electrocardiogram ................................................................................31 
6.3 
Pharmacokinetic Measurements ......................................................................31 
6.4 
Subject Flow Diagram .....................................................................................31 
6.5 
Study Visits ......................................................................................................32 
6.5.1 
Screening Period ..................................................................................32 
6.5.2 
Screening Visit .....................................................................................33 
6.5.3 
Mid-Screening Telephone Contact ......................................................34 
6.5.4 
Baseline Visit .......................................................................................34 
6.5.5 
Week 1 Telephone Contact Visit .........................................................35 
6.5.6 
Week 2 Visit ........................................................................................35 
6.5.7 
Week 4 Visit ........................................................................................36 
6.5.8 
Week 6 Visit ........................................................................................37 
6.5.9 
Week 8 Telephone Contact Visit .........................................................37 
6.5.10 
Week 10 Visit ......................................................................................38 
6.5.11 
Follow-up Visit ....................................................................................38 
6.5.12 
Early Termination From the Study ......................................................39 
7 
ASSESSMENT OF SAFETY ................................................................................40 
7.1 
Definitions........................................................................................................40 


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7.1.1 
Adverse Event ......................................................................................40 
7.1.2 
Serious Adverse Event .........................................................................40 
7.1.3 
Abnormal Physical Exam, Laboratory, Vital Sign, and 
Electrocardiogram Findings .................................................................41 
7.1.4 
Deaths ..................................................................................................41 
7.1.5 
Pregnancies and Contraception Requirements for Females .................41 
7.1.6 
Worsening of Pruritus ..........................................................................43 
7.2 
Methods and Timing for Recording and Reporting Adverse Events ...............43 
7.2.1 
Adverse Event Reporting Period .........................................................43 
7.2.2 
Eliciting Adverse Events ......................................................................43 
7.2.3 
Assessment of Severity ........................................................................43 
7.2.4 
Assessment of Causality ......................................................................44 
7.3 
Follow-up of Adverse Events and Serious Adverse Events ............................45 
7.4 
Reporting Serious Adverse Events to the Sponsor and Institutional Review 
Board or Ethics Committee ..............................................................................45 
7.5 
Reporting Serious Adverse Events to Regulatory Authorities and Study 
Investigators .....................................................................................................45 
7.6 
Emergency Unblinding ....................................................................................45 
8 
STATISTICAL METHODS ..................................................................................46 
8.1 
Decision Rule and Sample Size .......................................................................46 
8.2 
Handling of Missing Data ................................................................................46 
8.3 
Analysis Populations ........................................................................................47 
8.4 
Subject Disposition ..........................................................................................47 
8.5 
Subject Characteristics .....................................................................................47 
8.6 
Prior and Concomitant Medications ................................................................47 
8.7 
Treatment Compliance and Extent of Exposure ..............................................47 
8.8 
Efficacy Analyses ............................................................................................48 
8.8.1 
WI-NRS ...............................................................................................48 
8.8.2 
Primary Efficacy ..................................................................................48 
8.8.3 
Secondary Efficacy and Exploratory ...................................................48 
8.9 
Safety Analyses ................................................................................................49 
8.9.1 
Adverse Events ....................................................................................49 
8.9.2 
Clinical Safety Laboratory Results ......................................................49 
8.9.3 
Vital Signs ............................................................................................49 
8.9.4 
Electrocardiograms ..............................................................................49 
8.9.5 
Physical Exams ....................................................................................49 
8.10 
Population Pharmacokinetics Analysis ............................................................50 
9 
ADMINISTRATIVE ASPECTS ...........................................................................50 
9.1 
Changes to the Protocol ...................................................................................50 


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9.2 
Study Termination ...........................................................................................50 
9.3 
Monitoring and Auditing Procedures...............................................................50 
9.4 
Transfer of Obligations ....................................................................................51 
9.5 
Informed Consent.............................................................................................51 
9.6 
Communication with the Institutional Review Board or Ethics Committee ...51 
9.7 
Disclosure and Confidentiality ........................................................................51 
9.8 
Records and Electronic Case Report Forms ....................................................52 
9.9 
Good Clinical Practices and Ethical Study Conduct ........................................52 
9.10 
End of Study Notification ................................................................................52 
9.11 
Publication of Results ......................................................................................53 
9.12 
Final Report .....................................................................................................53 
10 
REFERENCES ......................................................................................................54 
 
LIST OF APPENDICES 
Appendix A 
Schedule of Activities and Assessments ..............................................57 
Appendix B 
List of Strong CYP3A4 Inhibitors .......................................................59 
Appendix C 
Worst Itch Numeric Rating Scale Questionnaire .................................60 
Appendix D 
Epworth Sleepiness Scale ....................................................................61 
 
LIST OF FIGURES 
Figure 1 
Subject Flow Diagram ...............................................................................32 
 
LIST OF TABLES 
Table 1 
Adverse Event Grading ..............................................................................44 
Table 2 
Schedule of Visit Activities .......................................................................57 
Table 3 
Schedule of eDiary Assessments ...............................................................58 
 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
ACTH 
Adrenocorticotropic hormone, corticotropin 
ADL 
Activities of daily living 
AE 
Adverse event 
ALT 
Alanine aminotransferase  
AMH 
Anti-Mullerian hormone 
ANOVA 
Analysis of variance 
AST 
Aspartate aminotransferase 
ATC 
Anatomical Therapeutic Classification 
CMH 
Cochran Mantel Haenszel test 
CNS 
Central Nervous System 
CPUO 
Chronic Pruritus of Unknown Origin 
CRO 
Contract Research Organization 
CYP3A4 
Cytochrome P450 3A4 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
eDiary 
Electronic diary 
ESS 
Epworth Sleepiness Scale 
FSH 
Follicle-stimulating hormone 
GCP 
Good Clinical Practice 
HIV 
Human immunodeficiency virus 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Council on Harmonisation 
IRB 
Institutional Review Board 
ITT 
Intent-to-Treat 
IWRS 
Interactive Web Response System  
LDH 
Lactate dehydrogenase 
LFC 
Liquid filled capsule 
LH 
Luteinizing hormone 
LOCF 
Last Observation Carried Forward 
MCMC 
Markov Chain Monte Carlo 
MedDRA 
Medical Dictionary for Regulatory Activities  
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
NK1-R 
Neurokinin-1 receptor 
NOAEL 
No observed adverse effect level 
NRS 
Numeric Rating Scale  
PET 
Positron Emission Tomography 
PI 
Principal Investigator 
PD 
Pharmacodynamics 


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PDE-4 
Phosphodiesterase-4 
PK 
Pharmacokinetics 
PN 
Prurigo nodularis 
PP 
Per Protocol 
QOL 
Quality of life 
RO 
Receptor occupancy 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SP 
Substance P 
TEAE 
Treatment-emergent adverse event 
TSH 
Thyroid stimulating hormone 
ULN 
Upper limit of normal 
US 
United States 
VAS 
Visual Analog Scale 
WI-NRS 
Worst-Itch Numeric Rating Scale 
WI-VAS 
Worst-Itch Visual Analog Scale 


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1 
INTRODUCTION 
1.1 
Chronic Pruritus of Unknown Origin 
Pruritus, or itch, is defined as an unpleasant sensation that elicits the desire or reflex to 
scratch (Ikoma 2006). Scratching can result in removal of the epidermal and dermal layers of 
the skin, which is thought to be an evolutionary mechanism to dislodge potential parasites. 
Itch is also caused by many dermatological and systemic diseases that can produce a type of 
pruritus that can become chronic and debilitating (Hoon 2015). Epidemiological studies 
indicate that point prevalence for chronic pruritus range from 13% to 17%, with lifetime 
prevalence of 22% to 26% (Carr 2014). Pruritus can have a substantial negative effect on 
quality of life, including effects on “mood, concentration, eating habits, sexual function, and 
sleep,” (Carr 2014) and chronic pruritus has been shown to have an impact on quality of life 
similar to that of chronic pain (Kini 2011).  
Chronic pruritus may be associated with a variety of underlying conditions, including both 
dermatological and systemic diseases. Many of these conditions present with visible skin 
involvement, such as in atopic dermatitis. Others may be associated with pruritus in the 
absence of visible skin involvement, such as in Hodgkin’s disease. However, in 8–15% of 
patients with chronic pruritus, an underlying etiology cannot be identified (Weisshaar 2012). 
Terms in the scientific literature that have been used to describe this population include 
generalized pruritus of unknown origin, chronic idiopathic pruritus, and chronic itch of 
undetermined origin (Millington 2018, Xu 2016, Weisshaar 2009). Epidemiological studies 
have also shown that the prevalence of chronic pruritus increases with age (Ständer 2010), 
and the term chronic pruritus in the elderly has been used synonymously to describe elderly 
patients who present with no overt identified cause of pruritus, representing both a significant 
proportion of pruritus burden in the elderly, as well as a source of frustration for the affected 
patient and the treating physician alike (Ständer 2007, Berger 2013).  
Emerging evidence indicates that the aging process itself may be involved as a primary 
etiologic factor in chronic pruritus in the absence of other overt causes. Xerosis and other 
changes in skin barrier function, increasing sensorineural dysfunction, and senescent changes 
in the immune system have been implicated as contributory factors (Berger 2011, 
Shevchenko 2018, Xu 2016). It is likely that chronic pruritus of unknown origin and chronic 
pruritus in the elderly represent significantly overlapping populations, especially as the age 
range of 51–60 years is one of the peak age ranges associated with a lifetime prevalence of 
chronic pruritus (Matterne 2011). 
As the management of chronic pruritus is dependent on treatment of any underlying disease, 
chronic pruritus in the absence of an identified underlying disease or chronic pruritus in 
which the aging process itself may be the primary causal factor can make treatment of 
pruritus in these patients extremely challenging. No drugs are currently approved in the US 
for the primary treatment of pruritus, and off-label use of available therapies such as H1 
antihistamines, gabapentin, and immunosuppressants such as corticosteroids and biologics 
can require significant trade-offs in terms of efficacy, tolerability, safety, and cost 
(Weisshaar 2012). Issues with tolerability and safety are often magnified in management of 
chronic pruritus with advancing age (Pereira 2018). 


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1.2 
Substance P and the Neurokinin-1 Receptor 
Substance P is an undecapeptide that belongs to the tachykinin family of neuropeptides, a 
group that also includes neurokinin A and neurokinin B (Hökfelt 2001). SP has been 
implicated in a number of biological functions, both physiological and pathophysiological, 
including pruritus perception, vomiting reflex, pain perception, and immunomodulatory 
responses (Lotts 2014, Andoh 1998, Steinhoff 2014). 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 (Harrison 2001). The neurokinin-1 
receptor (NK1 receptor) in particular has been studied in great detail. The NK1 receptor is the 
primary receptor for SP in the human body, and is found on multiple cell types, include 
neurons in the central and peripheral nervous system and keratinocytes in the skin.  
NK1 receptor stimulation has been shown to be an important pathway for pruritus perception 
(Ständer 2015). Inhibition of this pathway results in decreased pruritus and scratching 
reflexes in animal models (Akiyama 2015). Preceding the development of serlopitant for 
pruritus-related conditions, a commercially available NK1 receptor antagonist (Emend USPI) 
has been used as a therapy to decrease pruritus in patients with chronic pruritus due to 
etiologies such as cutaneous T-cell lymphoma (Duval 2009, Torres 2012, Booken 2011) and 
erlotinib-induced pruritus (Santini 2012, Gerber 2010). 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 (Ständer 2010).  
1.3 
Serlopitant  
1.3.1 
Serlopitant Background and Nonclinical Summary 
Serlopitant is a small molecule, highly selective NK1-R antagonist that is administered orally 
and metabolized by cytochrome P-450 3A4 (CYP3A4), with a plasma half-life of 
45−86 hours. It binds with high affinity to the human NK1-R with a dissociation constant 
(Kd) of 46 pM; displacing SP binding with a half-maximal inhibition concentration (IC50) of 
61 pM. Serlopitant is a potent functional antagonist of SP-induced inositol phosphate 
generation. 
Serlopitant has been extensively studied in animal toxicology studies, including chronic 
toxicology and carcinogenicity studies. In non-clinical chronic toxicology studies in rats, 
mice and dogs, treatment related findings of potential clinical significance included increased 
salivation, decreased body weight gain and food consumption, slight changes in hematology 
and serum biochemistry parameters, mild increases in liver weight and mild 
histomorphologic changes. The histomorphologic changes were seen only in rats (not in dogs 
or mice) and included: very slight ovarian interstitial cell hypertrophy, mammary gland and 
uterine atrophy; decreased corpora lutea; increased histiocytes in lung and mesenteric lymph 
nodes; slight skeletal and cardiac muscle degeneration; slight increased hematopoiesis in 
bone marrow; and slight to moderate vacuolation in kidney tubules. These nonclinical 
findings occurred at systemic exposures exceeding those anticipated to provide efficacy of 
serlopitant for pruritus indications in humans (1 to 5 mg tablet daily). No cardiac lesions have 


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been observed in dog toxicity studies up to 9 months in duration nor in a 3-month mouse 
range-finding study and 2-year mouse carcinogenicity study at exposure higher than the 
lowest level which caused cardiotoxicity in rats. The no observed adverse effect level 
(NOAEL) in rats for histomorphological changes in the reproductive tract, mammary gland 
and bone marrow provides a 2.5-fold margin for the maximum-targeted exposure (5 mg 
tablet daily). The rat NOAEL for histomorphological changes in muscle and kidney provides 
a 5-fold margin for the maximum-targeted exposure (5 mg tablet daily).  
In summary, the nonclinical toxicity noted with serlopitant provides no contraindications to 
the continuation of clinical trials via the oral route. Findings in the developmental toxicity 
studies support inclusion of women of childbearing potential in clinical trials in accordance 
with the study protocol and local regulatory guidances.  
1.3.2 
Serlopitant Clinical Summary 
In humans, serlopitant has been administered to over 1500 individuals. Single doses up to 
400 mg have been well tolerated in young adult males and single doses up to 25 mg have 
been well tolerated in the elderly. 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 adult males and elderly subjects (males and females). Peak plasma 
concentrations after a single oral dose occurred at ~2 to 4 hours in both young adult and 
elderly subjects. A single loading dose of up to 15 mg serlopitant followed by 6 to 8 weeks of 
up to 5 mg daily serlopitant doses has been well tolerated in adults with chronic pruritus and 
prurigo nodularis. 
Pharmacokinetic data demonstrate good plasma exposures with oral dosing, linear 
dose-dependent increases in plasma concentration and systemic exposure, a plasma t1/2 
supportive of once daily dosing, and mild effects of concomitant food ingestion. Central 
nervous system (CNS) positron emission tomography (PET) studies have demonstrated good 
CNS penetrance and > 90% NK1 receptor occupancy (RO) at plasma exposures anticipated 
to be safe and well tolerated. Three long-lived active hydroxylated metabolites are observed 
in humans: M1/M1a (L-001256771), M2/M2a (L-001194442), and M3 (L-001426583). 
These metabolites were present at lower concentrations and were 2- to 9-fold less potent in 
vivo than the parent compound. The integrated pharmacokinetic/pharmacodynamic (PK/PD) 
analysis concluded that these metabolites are unlikely to contribute significantly to 
occupancy of the CNS NK1-R in humans. 
1.3.3 
Serlopitant in Pruritus-Related Studies 
Serlopitant has been evaluated in two completed Phase 2 studies of subjects with chronic 
pruritus (TCP-101 and TCP-102). Three additional Phase 2 studies in pruritus indications 
(history of atopic dermatitis, epidermolysis bullosa, and psoriasis) are clinically complete 
with study reports pending. 


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TCP-101 
TCP-101 was a double-blind, placebo-controlled, multi-center study that compared 
serlopitant 0.25 mg, 1 mg, or 5 mg vs. placebo for the treatment of chronic pruritus. A total 
of 257 adult subjects 18–65 years of age with chronic pruritus were randomized to receive 
one of the four dose groups in a 1:1:1:1 randomization. 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 VAS, summarized as a percentage change from 
baseline. 
Mean percent decreases from Baseline in VAS score were larger in the active-treatment 
groups versus placebo at every scheduled post-baseline study visit. Overall, the results were 
the most profound for the serlopitant 1 mg and 5 mg groups. For the percent change from 
Baseline in VAS pruritus scores (the primary efficacy variable), the Week 6 pairwise least 
squares mean difference compared to placebo was 5.8 mm, 13.2 mm, and 14.2 mm for 
serlopitant 0.25 mg, 1 mg, and 5 mg, respectively.  
The frequency of treatment-emergent adverse events (TEAEs) and study drug related adverse 
events (AEs) was higher in the serlopitant 1 mg and 5 mg groups compared to the serlopitant 
0.25 mg group, and the frequency in all three treatment groups were higher than in the 
placebo group. The frequency of AEs leading to study drug discontinuation was comparable 
in the serlopitant 5 mg and placebo group and higher than in the serlopitant 0.25 mg and 
1 mg groups. There was one serious adverse event (SAE) reported in the serlopitant 1 mg 
group (spontaneous abortion, considered not related). There were no deaths. The most 
common AEs in the serlopitant groups were diarrhea (6.2%, 1 mg group), upper respiratory 
tract infection (4.7%, 0.25 mg group), somnolence (4.7%, 5 mg group), nasopharyngitis 
(4.6%, 1 mg group), headache (4.7%, 5 mg group), urinary tract infection (3.1%, 5 mg 
group), dry mouth (3.1%, 1 mg group), nausea (3.1%, 1 mg group), arthralgia (3.1%, 
0.25 mg group), musculoskeletal pain (3.1%, 1 mg group) and pruritus (3.1%, 1 mg group). 
The most common AEs in the placebo group were headache (6.3%), nasopharyngitis (3.2%), 
upper respiratory tract infection (3.2%), urinary tract infection (3.2%) and asthma (3.2%).  
TCP-102 
TCP-102 was a randomized, double-blind, placebo-controlled multi-center study that 
evaluated serlopitant 5 mg vs. placebo for the treatment of prurigo nodularis (PN). A total of 
128 adult subjects 18-80 years of age with PN were randomized to receive serlopitant or 
placebo in a 1:1 randomization. Subjects received a loading dose of 3 tablets on Day 1 
followed by 1 tablet per day for 8 weeks. The primary efficacy endpoint was the average 
VAS score as recorded at the study visits. Results at Week 4 and Week 8 were the primary 
timepoints. 
Serlopitant 5 mg was superior to placebo for the reduction of pruritus as measured by change 
in average VAS from baseline. For the primary endpoint, change from baseline at Week 4 
and Week 8 by repeated measures analysis, the decrease from baseline was significantly 
greater in the serlopitant group than the placebo group, with a mean difference (serlopitant 
minus placebo) of -1.0 at Week 4 and -1.7 at Week 8. The mean difference at Week 2 was 


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also significant, -0.9. In a post-hoc analysis, 25.0% of placebo subjects and 54.4% of 
serlopitant subjects were 4-point responders on average VAS at Week 8. 
TEAEs were reported for 71.9% of serlopitant-treated subjects and 61.9% of placebo-treated 
subjects. The most frequently reported TEAEs in the serlopitant group were nasopharyngitis 
(17.2% serlopitant, 3.2% placebo), diarrhea (10.9% serlopitant, 4.8% placebo), and fatigue 
(9.4% serlopitant, 6.3% placebo). Treatment-related TEAEs were reported for 48.4% of 
serlopitant-treated subjects and 34.9% of placebo-treated subjects. The most frequently 
reported treatment-related TEAEs in the serlopitant group were fatigue (7.8%) and diarrhea, 
peripheral edema, dizziness, and headache (each 6.3%). Most TEAEs were mild or moderate; 
severe TEAEs were reported for 9.4% of serlopitant-treated subjects and 4.8% of 
placebo-treated subjects. There were no deaths during the study. Five subjects (3 serlopitant, 
2 placebo) had SAEs. The SAEs were actinic elastosis, depression, dizziness, and vertigo in 
the serlopitant group; and bradycardia, syncope, respiratory failure, and neurodermatitis in 
the placebo group. Nine subjects (3 serlopitant, 6 placebo) discontinued due to TEAEs. 
No clinically relevant changes were observed in chemistry, hematology, vital signs, or 
electrocardiogram (ECG) results. 
The results of the Phase 2 studies in subjects with PN and in subjects with chronic pruritus, 
together with the extensive safety experience with serlopitant to date and the scientific 
rationale for NK1-R inhibition in the treatment of pruritus, serve to support further evaluation 
of serlopitant for the treatment of chronic pruritus of unknown origin. 
Please refer to the Investigator’s Brochure (IB) for further information regarding serlopitant. 
2 
STUDY OBJECTIVES  
The primary objective of this study is to assess the efficacy of repeated oral doses of 
serlopitant in adult subjects with chronic pruritus of unknown origin. 
The secondary objective of this study is to assess the safety and tolerability of repeated oral 
doses of serlopitant in adult subjects with chronic pruritus of unknown origin.  
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 chronic pruritus of unknown origin. 
Approximately 200 subjects who meet the study entry criteria will be randomized in a 
1:1 ratio to receive daily oral doses of serlopitant 5 mg or placebo for 10 weeks. After 
completion of the treatment period or early discontinuation of study drug treatment, all 
subjects will enter a 5-week follow-up period. 


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This study will consist of three periods, for a total study period of 18 weeks: 
• Screening period: 3 weeks  
• Treatment period: 10 weeks 
• Follow-up period: 5 weeks 
 
Informed consent will occur prior to any protocol-mandated procedures, including the 
stopping of any excluded therapies. This may occur prior to the Screening visit. 
During the screening period, all subjects will undergo eligibility evaluation and will be 
assessed for conditions associated with chronic pruritus. If the investigator deems that 
additional assessments are necessary to rule out specific conditions based on a subject’s 
history, physical examination, and/or screening labs (e.g. scabies skin preparations, urea 
breath test for Helicobacter pylori), the subject may not be randomized until these are 
completed and the pruritus is still considered to be of unknown origin.  
Subjects will be provided an eDiary at the Screening visit. Subjects must be willing and able 
to complete the eDiary every day within a consistent 6-hour timeframe, and comply with 
restrictions on allowable concomitant therapies, for the duration of the study. eDiary 
compliance and WI-NRS scores will be used to determine study eligibility (see Section 4.1). 
At the Baseline visit (Day 1), eligible subjects will be randomly assigned to receive study 
drug (serlopitant 5 mg or placebo). Subjects will take a loading dose (3 tablets taken orally) 
at the site on the first day of the treatment period (Day 1). Starting on Day 2, subjects will 
take one tablet per day until the completion of the 10-week treatment period. Study drug may 
be taken with or without food. 
After the last dose of study drug, all subjects will enter a 5-week follow-up period and will 
undergo a follow-up visit at the conclusion of the follow-up period. The eDiary will continue 
to be completed during the follow-up period. 
The primary efficacy endpoint will be assessed at Week 10 of treatment.  
3.2 
Rationale for Study Design and Dose Selection 
In the TCP-102 study in patients with PN, serlopitant 5 mg taken daily for 8 weeks was 
superior to placebo for the reduction of pruritus, in both the overall study population as well 
as the subgroup of subjects with an atopic diathesis. Similarly, in the TCP-101 study in 
patients with chronic pruritus, serlopitant 5 mg and 1 mg taken daily for 6 weeks were 
superior to placebo for the reduction of pruritus, in both the overall study population and the 
subgroup of subjects with an atopic diathesis.  
In both the TCP-102 and TCP-101 studies, serlopitant was generally well-tolerated and 
demonstrated an overall favorable safety profile at the doses evaluated. 


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The current MTI-117 study is designed to investigate the efficacy, safety, and tolerability of 
serlopitant for the treatment of chronic pruritus of unknown origin. The 5 mg dose of 
serlopitant was selected for this study based on a combination of human central nervous 
system positron emission tomography receptor occupancy (RO) data for serlopitant generated 
in healthy young males (Study P002), which showed a serlopitant 4 mg LFC (equivalent to a 
5 mg tablet) once daily dose is likely to achieve ~ 94% NK1 RO at steady state, together with 
results of studies TCP-101 and TCP-102 that demonstrated a favorable efficacy, safety, and 
tolerability profile of serlopitant at this dose level in subjects with pruritus. Over 250 subjects 
have been exposed to serlopitant at doses of 5 mg tablet-equivalent daily for at least 6 weeks, 
and ~ 40 subjects have been exposed up to one year.  
3.3 
Study Endpoints 
3.3.1 
Primary Efficacy Endpoint 
The primary efficacy endpoint is the Worst-Itch Numeric Rating Scale (WI-NRS) 4-point 
responder rate at Week 10. 
3.3.2 
Secondary Efficacy Endpoints 
The secondary efficacy endpoints are as follows: 
• WI-NRS 4-point responder rate at Weeks 2 4, 6, and 8  
• WI-NRS 3-point responder rate at Weeks 2, 4, 6, 8, and 10 
• Change from baseline in WI-NRS at Weeks 2, 4, 6, 8, and 10 
• Change from baseline in daily WI-NRS scores through Week 2 
• Change from baseline in WI-VAS at Weeks 2, 4, 6, and 10 
 
3.3.3 
Safety Endpoints 
Safety endpoints are as follows: 
• Incidence of TEAEs and SAEs 
• Changes from baseline in clinical laboratory parameters following study drug exposure 
• Changes from baseline in vital sign and ECG parameters following study drug exposure 
• Plasma concentrations of serlopitant and metabolites 
 


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3.3.4 
Exploratory Endpoints 
The exploratory endpoints are as follows:  
• Change from baseline in the Epworth Sleepiness Scale (ESS) to Weeks 2, 4, 6, and 10 
• Change from baseline in Static Patient Global Assessment of Itch Severity (sPGA) to 
Weeks 2, 4, 6, and 10 
• Patient Global Impression of Change in Itch Severity (PGIC) at Weeks 2, 4, 6, and 10 
 
3.4 
Safety Review 
3.4.1 
Safety Monitoring Team 
An internal safety monitoring team consisting of representatives from Menlo Therapeutics 
Inc. and its designees will monitor blinded safety data on a regular basis throughout the 
study. 
4 
SELECTION OF STUDY POPULATION 
4.1 
Study Population 
Approximately 200 adult subjects with chronic pruritus of unknown origin will be enrolled in 
this study. 
4.2 
Inclusion Criteria 
Subjects must meet the following criteria to be randomized into the study: 
1. Male or female, age 18 years or older at consent. 
2. The subject must have had ongoing pruritus for at least 6 months.  
3. The subject’s pruritus is assessed by the investigator to be of unknown origin at baseline. 
4. The pruritus must have been unresponsive to prior treatment with emollients. 
5. The pruritus must involve more than one dermatome (defined as an area of skin in which 
sensory nerves derive from a single spinal nerve root). Acceptable examples include right 
and left arm, occipital and frontal scalp, and upper and lower back.  
6. Worst-Itch Numeric Rating Scale (WI-NRS) score ≥ 7 in the 24-hour period prior to the 
Screening visit 
7. Average weekly Worst Itch Numeric Rating Scale (WI-NRS) score ≥ 7 in the week 
(7 days) immediately prior to randomization, as recorded in the eDiary. 
8. Willing and able to complete daily eDiary entries within a consistent timeframe for the 
duration of the study, as demonstrated by a ≥ 80% eDiary completion rate in the two 
weeks immediately prior to randomization. 


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9. All females who are of childbearing potential must be willing to practice highly effective 
contraception (i.e., pregnancy prevention method with a failure rate of < 1% per year) 
from the time of the Screening visit until 5 weeks after last study dosing.  
10. Adequate cognitive and physical ability, in the investigator’s opinion, to comply with 
study visits and study related requirements including providing written informed consent. 
 
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 any other neurokinin-1 receptor antagonist. 
2. Known dermatologic or systemic condition(s), other than dry skin, that is considered by 
the investigator to be the primary cause of current pruritus .  
3. Untreated or inadequately treated thyroid, adrenal, or pituitary disease or nodules, or 
history of thyroid malignancy. 
4. Use of an excluded therapy within 3 weeks prior to randomization (see Section 5.7) 
5. Treatment with any investigational therapy within 3 weeks prior to randomization. 
6. Serum creatinine, total bilirubin, alanine aminotransferase or aspartate aminotransferase 
> 2.5 times the upper limit of normal during screening. 
7. History of malignancy within 3 years prior to randomization, with the exception of 
actinic keratosis or completely treated and non-metastatic cutaneous squamous cell 
carcinoma or basal cell carcinoma of the skin. 
8. Any known major psychiatric diagnosis which, in the investigator’s opinion, may 
confound the assessment of serlopitant safety or efficacy or interfere with the subject’s 
ability to comply with protocol-mandated activities.  
9. Suicidal ideation within 3 years prior to randomization, or any history of suicide attempt. 
10. Known use of recreational drugs. 
11. Documented history of parasitic infection, including skin parasites such as scabies, within 
12 weeks prior to randomization. 
12. Presence of clinically significant dementia, intellectual impairment, or 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. 
13. History of hypersensitivity to serlopitant or any of its components. 
14. Planned or anticipated major surgical procedure or other activity that would interfere with 
the subject’s ability to comply with protocol-mandated assessments (e.g. extended 
international travel) during the subject’s participation in the study. 
15. Pregnant or breastfeeding female. 
 


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5 
STUDY DRUG 
5.1 
Study Drug Supply, Route of Administration, and Storage 
The study drug in this study is serlopitant 5 mg or placebo in a film-coated tablet formulation 
for oral administration. The serlopitant tablets contain microcrystalline cellulose, mannitol, 
croscarmellose sodium, silicon dioxide, sodium lauryl sulfate, and magnesium stearate, and 
are film coated with Opadry® Brown. The placebo tablets contain microcrystalline cellulose, 
lactose monohydrate, and magnesium stearate, and are film coated with Opadry® Brown.  
The study drug will be provided in bottles for storage at room temperature (59–86°F, 
15−30°C). 
Each bottle provided will include 18 tablets. One bottle will be issued via Interactive Web 
Response System (IWRS) at each of Baseline, Week 2, and Week 4, and two bottles will be 
issued via IWRS at Week 6. A total of 5 bottles will be dispensed to subjects completing 
10 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. 
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 the site on the first day of the 
treatment period (Study Day 1). Starting on Study Day 2, subjects will be instructed to take 
one tablet per day orally until completion of the 10-week treatment period. Study drug may 
be taken with or without food. 
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 as a single tablet daily. If a 
dose is missed, that dose will be documented as a missed dose. Dosing should resume the 
next day as only a single tablet, as per protocol dosing instructions (i.e. there should be no 
attempt to make up for the missed dose). 


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5.6 
Study Drug Discontinuation 
Subjects should be discontinued from study drug treatment in the following situations: 
• A female subject desires to become pregnant at the current time, stops contraception or 
expels her intrauterine device/implant, or becomes pregnant  
• A female subject has new breast findings (e.g. a palpable mass or abnormal 
mammography, discharge), or has abnormal vaginal discharge or bleeding 
• The subject decides to discontinue study drug treatment, or withdraws consent from the 
study 
• The subject receives a strong CYP3A4 inhibitor (See Appendix B) 
• Any medical condition that may jeopardize the subject’s safety if study drug is continued, 
in the investigator’s and/or Sponsor’s opinion; this may include the development of 
persistently (2 successive occasions) abnormal thyroid function tests (TSH >10, or 
TSH > 6 with low free T4; TSH < 0.1, or TSH < 0.35 with high free T4); abnormal 
morning prolactin, cortisol, or corticotropin levels; or signs and symptoms of adrenal 
insufficiency 
• Discontinuation is deemed to be in the best interest of the subject, in the investigator’s 
and/or Sponsor’s opinion, including evidence that the subject does not meet 
inclusion/exclusion criteria intended primarily for safety reasons, or a persistent lack of 
adherence to study procedures 
 
The Sponsor or designee should be contacted within 24 hours of investigator’s awareness of 
any study drug treatment discontinuation. Investigators should make every effort to contact 
the Sponsor or designee before discontinuing study drug treatment, if possible. 
Subjects who discontinue treatment with study drug prior to completing the treatment period 
will enter a 5-week follow-up period following the last dose of study drug and will have a 
Follow-up visit (see Section 3.1, Section 6.5.10). Every effort should be made for subjects to 
complete the Follow-up visit after a subject has discontinued from study drug.  
5.7 
Prior, Concomitant, and Excluded Therapies 
Prior therapies (including over-the-counter medications) used to treat chronic pruritus of 
unknown origin within the prior 3 months, including those used during the screening period, 
will be recorded for each subject at the Baseline visit. 
Concomitant therapies include any therapies (including over-the-counter medications and 
bland emollients) 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. The use of 


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any concomitant medication must relate to the subject’s medical history or to an AE, except 
for vitamins/nutritional supplements, emollient use, and routine preventative immunizations.  
All therapies that will be continued as concomitant therapies should be captured in source 
documents within 1 week of the Screening visit. 
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.  
Use of gentle cleansers and bland emollients (including those with urea) is encouraged for all 
subjects. If bland emollient use is elected, it must be initiated at least 3 weeks (21 days) prior 
to Baseline visit and continued throughout the treatment period. 
Maintenance allergy immunotherapy will be allowed. 
Treatment with non-systemic corticosteroids or antihistamines that do not involve skin 
application (e.g. inhaled, intranasal, ophthalmic, or intra-articular) will be allowed.  
Leukotriene inhibitors will be allowed for treatment of conditions other than chronic pruritus 
of unknown origin (e.g. asthma). 
5.7.2 
Excluded Therapies 
The following therapies and activities are excluded from 3 weeks prior to randomization 
through the treatment and follow-up periods: 
• NK1 receptor antagonists (other than study drug) 
• Systemic or topical immunosuppressive/ immunomodulatory therapies (including but not 
limited to corticosteroids, PDE-4 inhibitors, cyclosporine, mycophenolate-mofetil, 
tacrolimus, pimecrolimus, calcipotriene, methotrexate, azathioprine, thalidomide, 
interferon-gamma, phototherapy). Build-up allergy immunotherapy will be excluded. 
• Any medications that, in the investigator’s and/or medical monitor’s opinion, are 
suspected of having a causal or contributory role in the subject’s pruritus. 
• Biologic therapies (other than therapies such as insulins, vaccines) 
• Strong CYP3A4 inhibitors (See Appendix B) 
• Use of an indoor tanning facility, or natural sun exposure resulting in significant tanning 
or sunburn 
• Any investigational therapy 
 


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The following therapies and activities are excluded from 3 weeks prior to randomization 
through the treatment period. Use is discouraged, though permitted, in the follow-up period: 
• Topical therapies or emollients with anti-pruritic properties (including but not limited to 
anti-histamines, menthol or menthol derivatives, polidocanol, camphor, pramoxine, 
cannabinoids, colloidal oatmeal baths, and capsaicin) 
• Systemic therapies with recognized anti-pruritic properties (including but not limited to 
H1 antihistamines, doxepin, gabapentin, pregabalin, cannabinoids, kappa-opioid receptor 
agonists, and mu-opioid receptor antagonists)  
 
Use of any excluded therapies (including those for the treatment of pruritus, or as rescue 
therapy) should be reported as soon as possible, and will be recorded as protocol deviations 
for subjects who receive them.  
5.7.3 
Rescue Therapies 
The initiation of non-study drug therapy to treat worsening of pruritus is strongly 
discouraged throughout the treatment period. However, should rescue therapy be required for 
the safety and well-being of the subject, such use will be recorded and analyzed (see 
Section 8.2). The subject may remain on study drug, unless the rescue therapy is an NK1 
receptor antagonist, a systemic biologic therapy, a strong CYP3A4 inhibitor, an 
investigational therapy, or any therapy that may jeopardize the subject’s safety if study drug 
is continued, in the investigator’s and/or Sponsor’s opinion. 
5.8 
Assignment to Treatment  
5.8.1 
Randomization 
At the baseline visit eligible subjects will be randomized to receive serlopitant 5 mg or 
placebo in a 1:1 ratio. Stratified permuted block randomization will be used. Randomization 
will be stratified by the subject’s reported WI-NRS score for the 1-week period prior to the 
Baseline visit (7 to < 8.5, 8.5 to 10), and by the subject’s age at the Baseline visit 
(18 to < 50 years, ≥ 50 years).  
Randomization of subjects < 50 years of age will be capped at 25% of the total randomized 
population. This cap may be increased up to 33% of the total randomized population at the 
Sponsor’s discretion based on relative enrollment rates. 
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 as required. The placebo will be formulated to be indistinguishable from the 
active study product. Study materials will be packaged and issued in a manner designed to 


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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. 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. Study site staff will also regularly review eDiary-based study drug 
compliance records throughout the study. A subject who has deviated significantly from the 
once-daily dosing regimen will be counseled. 
6 
STUDY SCHEDULE AND ASSESSMENTS 
When applicable, efficacy and safety instruments will be provided with instructions for 
administration, in study-specific manuals for site reference.  
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 
scale ranging from 0 (no itch) to 10 (worst itch imaginable). Higher scores indicate greater 
itch intensity. The questionnaire is provided in Appendix C.  
During the study, WI-NRS assessments will be reported by the subject via eDiary. Subjects 
will record their WI-NRS scores once daily at approximately the same time each day 
(+/- 3 hours) throughout the screening, treatment, and follow-up periods, as outlined in 
Appendix A. Subjects may be allowed to adjust the timing of eDiary completion within the 
first week of Screening as needed. Standardized training and instructions will be provided to 
all subjects prior to eDiary use.  
6.1.2 
Itch Visual Analog Scale 
The Itch VAS 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 worst itch on a 
100-mm horizontal line ranging from 0 mm (no itch) to 100 mm (worst itch imaginable). 
Higher scores indicate greater itch intensity. The VAS measurement will be summarized in 
centimeters. Standardized paper questionnaires will be distributed to sites and, in order to 
ensure consistency, cannot be copied, printed, or faxed.  


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During the study, WI-VAS assessments will be reported by the subject via a paper form 
administered at study visits. Standardized training and instructions will be provided to all 
subjects prior to administration of the WI-VAS assessments. 
6.1.3 
Static Patient Global Assessment of Itch Severity 
The Static Patient Global Assessment of Itch Severity (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 on paper according to the schedule in 
Appendix A. 
6.1.4 
Patient Global Impression of Change in Itch Severity 
The Patient Global Impression of Change in Itch Severity (PGIC) 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 on paper according to the schedule in Appendix A. 
6.1.5 
Epworth Sleepiness Scale 
The ESS is a QOL instrument intended to measure daytime sleepiness by use of a very short 
questionnaire (8 items each scored from 0–3). The ESS score can range from 0 to 24. Higher 
scores indicate greater daytime sleepiness. The questionnaire takes approximately 
2 to 3 minutes to complete, and is provided in Appendix D. The ESS questionnaire will be 
collected as outlined in Appendix A. 
6.2 
Safety Parameters 
Safety assessments will consist of monitoring and recording AEs and SAEs, vital signs, 
physical examinations, clinical laboratory assessments, ECGs, and other protocol-specified 
tests that are deemed critical to the safety evaluation of the study drug according to the 
schedule in Appendix A. 
6.2.1 
Vital Signs 
Vital signs will include measurements of heart rate, blood pressure, respiration rate, and 
temperature after the subject has been calmly resting (seated or supine) for a minimum of 
5 minutes. Vital signs will be assessed according to the schedule in Appendix A and at 
unscheduled study visits when clinically indicated. On study visits when clinical laboratory 
tests are performed, assessment of vital signs should precede blood draw.  
6.2.2 
Physical Examination 
Physical examinations, including height and weight measurements, will be performed 
according to the schedule in Appendix A and at unscheduled study visits when clinically 
indicated. A complete physical examination will be performed at the screening visit, while 
subsequent examinations will be abbreviated and targeted to changes in disease activity 


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and/or subjects’ symptoms. If targeted breast examinations are to be performed in female 
subjects, please perform breast examination after blood draw for clinical laboratory tests.  
6.2.3 
Clinical Laboratory Assessments 
Samples for clinical laboratory assessments will be collected according to the schedule 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, and are ideally 
performed in the morning, particularly at visits with endocrine assessments (Screening, 
Week 10, and Follow-up): 
• Hematology: hematocrit, hemoglobin, red blood cell count, red blood cell indices, 
platelets, white blood cell count, white blood cell differential (neutrophils, lymphocytes, 
monocytes, basophils, eosinophils)  
• Chemistry: sodium, potassium, chloride, bicarbonate, glucose, blood urea nitrogen, 
creatinine, calcium, phosphorus, magnesium, albumin, uric acid, total protein, ALT, 
AST, alkaline phosphatase, total bilirubin, lactate dehydrogenase (LDH), lipid panel 
• Iron studies: ferritin, serum iron  
• Serology: hepatitis B and C serology, HIV 
• Serum IgE 
• 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 
• Endocrine: TSH, free T4, cortisol, corticotropin (adrenocorticotropic hormone, ACTH), 
prolactin  
• Reproductive endocrinology (for all female subjects under 55 years of age at consent, 
who are not using hormonal contraception or other hormonal therapies at Screening): 
serum follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol, 
progesterone, anti-Mullerian hormone (AMH)  
• Optional study provided in lab test kits for use at Screening only: endomysial antibody 
with reflex to titer for subjects with signs or symptoms of dermatitis herpetiformis 
• Additional optional studies deemed necessary by the investigator to rule out specific 
conditions associated with chronic pruritus based on a subject’s history, physical 
examination, and/or screening labs may be performed; the investigator should discuss the 
need for such studies with the medical monitor during the Screening period. 


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• Standard cosyntropin stimulation testing should be performed on subjects with low 
cortisol level (i.e. < 3.0 mcg/dL); the investigator should discuss low cortisol (and 
relevant low corticotropin) results with the medical monitor. 
 
6.2.4 
Electrocardiogram  
A standard 12-lead ECG will be performed after the subject has been calmly resting in a 
supine position for a minimum of 5 minutes before obtaining the ECG. ECGs should precede 
measurement of vital signs and blood draw for clinical laboratory tests and will be performed 
according to the schedule in Appendix A and at unscheduled study visits when clinically 
indicated. ECGs will be read centrally. The ECG machine and detailed instructions will be 
provided by the ECG vendor. 
6.3 
Pharmacokinetic Measurements 
Sparse PK sampling will involve collecting one PK sample at the week 10 visit according to 
the schedule 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. The plasma concentrations of 
serlopitant and metabolites M1/M1a, M2/M2a and M3 will be determined and data used for 
population PK analysis. 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 assessments are performed throughout the study and are not confined to scheduled 
visits.  


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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. The timing of each study visit is relative to the day of randomization (Baseline). 
Unscheduled visits may be performed as necessary and may include procedures or 
assessments deemed necessary by the investigator. 
The eDiary 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 
Screening Period 
Informed consent will occur prior to any protocol-mandated procedures, including the 
stopping of any excluded therapies. This may occur prior to the Screening visit. 
The screening period for all subjects is 3 weeks to allow for washout of any excluded 
therapies. Subjects will have a telephone contact approximately 2 weeks prior to the 
scheduled Baseline visit to review inclusion and exclusion criteria, check on any 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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procedure-related adverse events, and remind them to complete the eDiary as previously 
instructed at the Screening visit.  
Screening procedures may be deferred with the medical monitor’s agreement should more 
than 3 weeks be required (e.g. to wash out of certain excluded therapies or to treat their 
underlying condition). Screening procedures may be repeated with the medical monitor’s 
agreement. 
The subject may be rescreened once with the medical monitor’s agreement. 
6.5.2 
Screening Visit 
The following screening procedures are to be performed at the Screening visit, preferably in 
the order shown below: 
• Obtain written informed consent prior to any protocol-mandated procedures, including 
the stopping of any excluded therapies 
• Collect demographic information (sex, date of birth, race, ethnicity)  
• Ask subject to complete the WI-NRS scale on paper 
• Register Screening visit into the IWRS 
• Obtain ECG  
• Obtain vital signs  
• Review subject’s medical history (including pruritus treatments in the past 3 months and 
current medications) 
- 
Record only significant/relevant medical history, to include the onset date of itch (as 
specifically as known)  
- 
Review for the presence of any underlying conditions that may exclude the subject 
from study eligibility  
- 
Female subjects should be queried regarding their childbearing potential and history 
of, or current, breast masses or abnormal discharge, and history of mammography 
(if applicable), and history of abnormal vaginal bleeding or discharge 
• Perform complete physical examination (including height and weight)  
• Perform a urine pregnancy test for females of childbearing potential (with positive or 
equivocal results confirmed by a serum pregnancy test) 
• Draw blood for clinical laboratory tests (morning blood sampling due to Endocrine 
assessments) 
- 
Reproductive endocrine labs for females under 55 years of age at consent who are not 
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- 
Endocrine  
- 
Hematology 
- 
Chemistry  
- 
Serology 
- 
Serum IgE 
- 
Iron studies 
- 
Optional: additional assessments (refer to Section 6.2.3) 
• Review subject’s tentative eligibility according to the Inclusion/Exclusion criteria 
- 
The results of all screening evaluations, including laboratory and ECG results, must 
be reviewed for clinical significance by the PI or designee, and may require further 
evaluation, prior to randomization of the subject on Baseline visit 
• Schedule the Baseline visit and all future study visits to ensure subject’s availability and 
visit compliance with the protocol visit windows 
• Provide eDiary with instructions  
• Confirm next scheduled visit  
 
6.5.3 
Mid-Screening Telephone Contact 
The Mid-Screening Telephone Contact occurs 15 days (- 3 days) prior to the Baseline visit. 
During this telephone contact the following procedures are to be performed: 
• Assess and record any changes in medications since the Screening visit 
• Review subject’s tentative eligibility according to Inclusion/Exclusion criteria 
• Assess AEs and record SAEs caused by protocol-mandated interventions 
• Review eDiary for compliance, re-train subject as needed 
• Confirm next scheduled visit 
 
6.5.4 
Baseline Visit 
The Baseline visit occurs 3 weeks (+3 days) after the screening visit. Eligibility must be 
confirmed prior to randomization. At the Baseline visit, the following procedures and 
assessments are to be performed, preferably in the order shown below: 
• Ask the subject to complete the WI-VAS, ESS, and sPGA questionnaires 
• Assess and record any changes in the subject’s concomitant medications 


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• Assess and record any changes in the subject’s medical history  
- 
Female subjects should be queried regarding history of, or current, breast masses or 
abnormal discharge, and history of mammography (if applicable), and history of 
abnormal vaginal bleeding or discharge 
• Assess AEs and record SAEs caused by protocol-mandated interventions 
• Obtain vital signs  
• Perform a urine pregnancy test for females of childbearing potential and confirm the 
subject has a negative urine pregnancy test result prior to randomization (with positive or 
equivocal results confirmed by a serum pregnancy test) 
• Confirm subject’s eligibility based on the inclusion/exclusion criteria (to include review 
of eDiary compliance for eligibility) 
• Randomize subject in IWRS if eligibility confirmed 
• Perform targeted physical examination, including weight 
• Dispense 1 bottle of study drug; subjects will take loading dose of 3 tablets while on site 
• Assess and record any post-dose AEs and SAEs 
• Confirm next scheduled visit 
 
6.5.5 
Week 1 Telephone Contact Visit 
The Week 1 visit is a telephone visit that occurs 7 days (± 3 days) after the Baseline visit. At 
the Week 1 visit, the following procedures and assessments are to be performed:  
• Assess and record any changes in the subject’s concomitant medications 
• Assess and record any AEs and SAEs 
• Review eDiary for compliance, re-train subject as needed 
• Review study drug compliance with re-training as required 
• Confirm next scheduled visit 
 
6.5.6 
Week 2 Visit 
The Week 2 visit occurs 14 days (-3/+1 days) after the Baseline visit. At the Week 2 visit, the 
following procedures and assessments are to be performed:  
• Ask the subject to complete the WI-VAS, ESS, sPGA, and PGIC questionnaires  


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• Assess and record any changes in the subject’s concomitant medications 
• Female subjects should be queried for presence of new breast masses or abnormal 
discharge, and abnormal vaginal bleeding or discharge 
• Obtain vital signs 
• Assess and record any AEs and SAEs 
• Review eDiary for compliance, re-train subject as needed 
• Review study drug compliance with re-training as required 
• Collect returned study drug 
• Utilize IWRS to assign 1 new bottle of study drug 
• Confirm next scheduled visit date 
 
6.5.7 
Week 4 Visit 
The Week 4 visit occurs 28 days (± 3 days) after the Baseline visit. At the Week 4 visit, the 
following procedures and assessments are to be performed: 
• Ask the subject to complete the WI-VAS, ESS, sPGA, and PGIC questionnaires  
• Assess and record any changes in the subject’s concomitant medications 
• Female subjects should be queried for presence of new breast masses or abnormal 
discharge, and abnormal vaginal bleeding or discharge 
• Obtain ECG 
• Obtain vital signs 
• Perform a urine pregnancy test for females of childbearing potential (with positive or 
equivocal results confirmed by a serum pregnancy test)  
• Draw blood for clinical laboratory tests  
- 
Hematology 
- 
Chemistry 
• Perform targeted physical examination, including weight 
• Assess and record any AEs and SAEs 
• Collect returned study drug 
• Utilize IWRS to assign 1 new bottle of study drug 


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• Review eDiary for compliance, re-train subject as needed 
• Review study drug compliance with re-training as required 
• Confirm next scheduled visit date 
 
6.5.8 
Week 6 Visit  
The Week 6 visit occurs 42 days (± 3 days) after the Baseline visit. At the Week 6 visit, the 
following procedures and assessments are to be performed: 
• Ask the subject to complete the WI-VAS, ESS, sPGA, and PGIC questionnaires  
• Assess and record any changes in the subject’s concomitant medications 
• Female subjects should be queried for presence of new breast masses or abnormal 
discharge, and abnormal vaginal bleeding or discharge 
• Obtain vital signs 
• Perform targeted physical examination, including weight 
• Assess and record any AEs and SAEs 
• Collect returned study drug 
• Utilize IWRS to assign 2 new bottles of study drug 
• Review eDiary for compliance, re-train subject as needed 
• Review study drug compliance with re-training as required 
• Confirm next scheduled visit date 
 
6.5.9 
Week 8 Telephone Contact Visit 
The Week 8 visit is a telephone visit that occurs 56 days (± 3 days) after the Baseline visit. 
At the Week 8 visit, the following procedures and assessments are to be performed: 
• Assess and record any changes in the subject’s concomitant medications 
• Assess and record any AEs and SAEs 
• Review eDiary for compliance, re-train subject as needed 
• Review study drug compliance with re-training as required 
• Confirm next scheduled visit 
 


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6.5.10 
Week 10 Visit 
The Week 10 visit occurs 70 days (+ 3 days) after the Baseline visit. At the Week 10 visit, 
the following procedures and assessments are to be performed: 
• Ask the subject to complete the WI-VAS, ESS, sPGA, and PGIC questionnaires 
• Assess and record any changes in the subject’s concomitant medications 
• Female subjects should be queried for presence of new breast masses or abnormal 
discharge, and abnormal vaginal bleeding or discharge 
• Assess and record any AEs and SAEs 
• Obtain vital signs  
• Perform a urine pregnancy test for females of childbearing potential and confirm the 
subject has a negative urine pregnancy test result prior to randomization (with positive or 
equivocal results confirmed by a serum pregnancy test) 
• Draw blood for clinical laboratory tests (morning blood sampling due to Endocrine 
assessments) 
- 
Reproductive endocrine labs for females under 55 years of age at consent who are not 
using hormonal contraception or other hormonal therapies at Screening 
- 
Endocrine  
- 
Hematology 
- 
Chemistry 
• Collect PK blood sample  
• Perform targeted physical examination, including weight 
• Review study drug compliance 
• Collect returned study drug 
• Review eDiary for compliance, re-train subject as needed 
• Confirm next scheduled visit 
 
6.5.11 
Follow-up Visit 
The required Follow-up visit occurs 35 days (+7 days) after the Week 10 visit or the last dose 
of study drug (for subjects who discontinue study drug early).  
At the Follow-up visit, the following procedures and assessments are to be performed: 
• Register visit into the IWRS 


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• Ask the subject to complete the WI-VAS, ESS, sPGA, and PGIC questionnaires 
• Assess and record any changes in the subject’s concomitant medications 
• Female subjects should be queried for presence of new breast masses or abnormal 
discharge, and abnormal vaginal bleeding or discharge 
• Obtain ECG 
• Obtain vital signs 
• Perform targeted physical examination, including weight 
• Perform a urine pregnancy test for females of childbearing potential (with positive or 
equivocal results confirmed by a serum pregnancy test) 
• Draw blood for clinical laboratory tests (morning blood sampling due to Endocrine 
assessments) 
- 
Reproductive endocrine labs for females under 55 years of age at consent who are not 
using hormonal contraception or other hormonal therapies at Screening  
- 
Endocrine  
- 
Hematology 
- 
Chemistry 
• Assess and record any AEs and SAEs 
• Collect eDiary device, review eDiary for compliance 
 
6.5.12 
Early Termination From the Study 
Early termination of a subject from the study may occur due to loss to follow-up, withdrawal 
of consent by the subject. In accordance with legal requirements and International Council on 
Harmonization (ICH) –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 provided, the 
reason (adverse event, study burden, lack of efficacy, other) a subject withdrew consent will 
be recorded in the electronic Case Report Form (eCRF). The PI or site staff must make every 
effort to contact subjects who are suspected of being lost to follow-up. Attempts to contact 
such subjects must be documented in the subject’s source documents. 


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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 treatment emergent exacerbations of pre-existing illnesses and AEs that occur as 
a result of protocol-mandated interventions. 
7.1.2 
Serious Adverse Event  
An AE 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 are not considered SAEs: a visit to the emergency room or other hospital 
department < 24 hours that does not result in admission (unless considered an important 
medical or life-threatening event), an elective surgery planned prior to signing consent, 
admission as per protocol for planned medical/surgical procedure, and/or routine health 
assessments requiring admission for baseline/trending of health status (e.g. routine 
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The terms “severe” and “serious” are not synonymous. Severity refers to the intensity of an 
AE (e.g. mild, moderate, or severe pain); the event itself may be of minor medical 
significance (e.g. severe back pain). “Serious” is a regulatory definition, as defined above. 
Seriousness (not severity) serves as the basis for defining regulatory reporting obligations.  
Severity and seriousness should be independently assessed when recording AEs and SAEs on 
the eCRF. 
7.1.3 
Abnormal Physical Exam, Laboratory, Vital Sign, and 
Electrocardiogram Findings  
Abnormal physical exam findings that are clinically significant and are identified prior to the 
first dose of study drug should be recorded as medical history. New or worsening clinically 
significant abnormal physical exam findings identified after the first dose of study drug 
should be recorded as AEs.  
Only abnormal laboratory, vital sign, and ECG findings that are considered clinically 
significant by the investigator (e.g. require active management or are associated with 
accompanying symptoms/signs) will be recorded as medical history or AEs on the eCRF. 
Abnormal laboratory, vital sign, and ECG findings that occur prior to the first dose of study 
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 (rather than listing individual test findings as AEs).  
Separate instances of the same clinically significant laboratory, vital sign, or ECG 
abnormality across visits should not be recorded as separate AEs or SAEs. 
7.1.4 
Deaths  
Any deaths that occur from the time of informed consent to the follow-up visit, regardless of 
attribution, must be reported within 24 hours of investigator’s awareness of the death. See 
Safety 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 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, unless permanently surgically sterile 
(e.g., hysterectomy, bilateral salpingectomy, bilateral oophorectomy). A postmenopausal 
state is defined as no menses for 12 months without an alternative medical cause in a 
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For the purposes of this study, acceptable contraception is defined below based on 
Nonclinical Safety Studies for the Conduct of Human Clinical Trials and Marketing 
Authorization for Pharmaceuticals: ICH M3(R2) dated January 2010, and other available 
guidelines (“U.S. Medical Eligibility Criteria for Contraceptive Use” 2010; 
“Recommendations related to contraception and pregnancy testing in clinical trials” 2014; 
“M3(R2) Nonclinical Safety Studies for the Conduct of Human Clinical Trials and Marketing 
Authorization for Pharmaceuticals” 2010):  
All female subjects of childbearing potential must use highly effective contraception, which 
includes the use of one or more of the following acceptable methods:  
1. Surgical sterilization (e.g., bilateral tubal occlusion or ligation, hysterectomy, bilateral 
salpingectomy, bilateral oophorectomy) 
2. Total (as opposed to periodic or cyclic) abstinence from heterosexual intercourse, 
only if planned for the entire duration of the study period and consistent with the 
preferred and usual lifestyle for the subject 
3. 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  
4. Intrauterine device/system  
5. Exclusive (sole) monogamous intercourse with a sterilized (i.e., vasectomized) or 
otherwise non-fertile (e.g., castrated) male partner; the male partner must have 
received medical assessment of the surgical success 
 
Progesterone-only oral contraceptives are excluded as a highly effective method of 
contraception, as they do not consistently inhibit ovulation. Male or female condoms with or 
without spermicide, and female caps, diaphragms, and sponges with spermicide, or 
combinations (double barrier) are also excluded as highly effective contraceptive methods. 
Any pregnancy occurring in a female subject or the female partner of a male subject, from 
the first study drug administration through the required follow-up visit must be reported 
within 24 hours of the investigator’s awareness of the pregnancy. See Safety 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 
Safety Form Completion Instructions for complete instructions.  


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7.1.6 
Worsening of Pruritus  
Pruritus should be recorded as an AE or SAE only if considered by the investigator to have 
worsened in severity beyond the subject’s typical fluctuations.  
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 required follow-up visit, only SAEs that are believed to be drug-
related should be reported. 
After informed consent, but prior to initiation of study drug, only SAEs considered by the 
investigator to be caused by a protocol-mandated intervention will be collected (e.g. SAEs 
related to invasive procedures such as blood collection). These procedure-related SAEs 
should only be reported on the source documents and SAE form, not on the AE 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) v5.0 (“Common 
Terminology Criteria for Adverse Events (CTCAE)” 2017) to describe the maximum 
intensity of the adverse event.  
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 
instrumental activities of daily living 
(ADLb) 
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) v5.0 
 
Note that severity, a measure of intensity, is not equivalent to seriousness, a regulatory 
definition of outcome. Regardless of severity, some AEs may meet the criteria for 
seriousness. See Section 7.1.2 for the definition of an SAE. 
If an adverse event changes in severity during the same study period (e.g., treatment period), 
only the highest severity grade will be recorded on the eCRF.  
7.2.4 
Assessment of Causality 
The investigator’s assessment of causality must be provided for all AEs (serious and 
non-serious). An investigator’s causality assessment is the determination of whether there 
exists a reasonable possibility that the investigational product caused or contributed to an AE. 
Causality of an AE will be assessed by the investigator using the following terms: 
• 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 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 Safety Form Report Completion Instructions for safety reporting instructions.  
The investigator must also comply with applicable requirements concerning reporting of 
SAEs to the 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 adverse events 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. 


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8 
STATISTICAL METHODS  
Endpoints will be summarized with descriptive statistics by treatment group and 
visit/timepoint. For continuous variables, the following information will be presented: 
n (number of subjects), mean, standard deviation, median, minimum and maximum. For 
categorical variables counts and percentages will be used. Summary statistics for imputed 
efficacy data will be reported based upon imputed data. 
Baseline for measures other than the eDiary daily measures will be the last recorded value 
prior to the start of treatment. For daily measures including the WI-NRS, baseline will be the 
average result measured over the week prior to treatment.  
A statistical analysis plan (SAP), describing all statistical analyses will be provided as a 
separate document. The SAP will be finalized prior to unblinding of the study treatments. 
8.1 
Decision Rule and Sample Size  
This study will use a 5% one-sided alpha level.  
The target sample size of 200 randomized and dosed subjects (100 per group) has been 
determined based upon a 1:1 allocation of subjects to treatment groups and a 5% one-alpha 
level. A sample size of two hundred subjects results in at least 90% power assuming a 
placebo Week 10 4-point responder rate of 
% and serlopitant 4-point responder rate of 
%. 
The sample size calculations have been performed in PASS 13 (“PASS 13 Power Analysis 
and Sample Size Software” 2014) and use a Chi-Squared 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 1988).  
8.2 
Handling of Missing Data  
Should a determination of treatment period (on treatment, pre-treatment, follow-up) be 
required for adverse events 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 WI-NRS endpoints, 
including the primary endpoint, may be missing. In this case, the WI-NRS change from 
baseline value will be imputed. The approach uses the subject’s last week with 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. Any missing changes will be imputed to produce and 
them combined with the prior known value to produce a change from baseline result. For 
CCI
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example, a placebo subject with known results at Week 4 but missing at Week 6 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 average placebo 
change from Week 4 to 6 (i.e. the average placebo decrease from Week 4 to 6). 
For the responder endpoints, the same imputation will be performed and the responder status 
determined based upon the change from baseline and the subject’s disposition and rescue 
medication status (See Section 8.8).  
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 population (FAP) and will include 
all randomized subjects who were dispensed study drug. 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 
Prior and Concomitant Medications  
Prior and concomitant medications will be coded by the World Health Organization Drug 
Dictionary to Anatomical Therapeutic Classification (ATC) and preferred drug name.  
Prior therapies (including over-the-counter medications) used to treat pruritus within the 
prior 3 months will be reported. Prior medications will be summarized by ATC level and 
preferred drug name and listed. 
Concomitant medications will be summarized by ATC level and preferred drug name and 
listed. Concomitant medication use will be quantified and analyzed. 
8.7 
Treatment Compliance and Extent of Exposure  
Compliance with study drug dosing will be determined based on tablet counts recorded on 
the eCRF. Compliance will be calculated by analyzing expected number of tablets returned 
versus actual number of tablets returned. Summaries of treatment exposure will also be 
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8.8 
Efficacy Analyses  
All efficacy endpoints will be summarized within the FAP using descriptive statistics by time 
point and treatment.  
8.8.1 
WI-NRS 
Subject record their WI-NRS measurements daily in an electronic diary. These daily 
measures are combined into weekly measures (Baseline, Weeks 2, 4, 6, 8, 10, Follow-up) 
by averaging the daily measurements. Change from baseline is the difference between 
baseline and the post baseline weeks. Missing data will be imputed as outlined in 
Section 8.2. From this change from baseline the binary responder status (responder / 
non-responder) is created. A subject is a 4-point responder if their change from baseline is 
≤ -4 (i.e. a decrease of at least 4). A 3-point responder is similarly defined. Subjects who 
withdraw from the study due to a lack of efficacy or require rescue therapy for treatment of 
worsening pruritus within four weeks prior to the timepoint will be defined as 
non-responders regardless of their change from baseline.  
The daily WI-NRS endpoint (change from baseline in daily WI-NRS scores through Week 2) 
is the change between the baseline WI-NRS (same baseline as the weekly measures) and the 
daily measures over the first two weeks.  
8.8.2 
Primary Efficacy 
The WI-NRS 4-point responder rate at Week 10 (primary endpoint) will be summarized by 
treatment group. The difference in responder rates between treatment arms will be tested 
using a CMH test controlling for the ‘as randomized’ stratification factors. Conceptually the 
hypotheses being tested are: 
H0:PPlacebo ≥ Pserlopitant  
Ha: PPlacebo < Pserlopitant 
where PPlacebo is the percent of placebo responders and Pserlopitant is the similar percent for 
serlopitant.  
Sensitivity analyses using other missing data rules will be performed. 
8.8.3 
Secondary Efficacy and Exploratory 
Secondary endpoints will be summarized with descriptive statistics by time point and 
treatment. These summary measures will include baseline, result at the time point and change 
from baseline as is appropriate for the endpoint. Missing data imputation will be limited to 
the WI-NRS and WI-VAS endpoints. 
The differences between treatment groups for the WI-NRS 4-point at Weeks 2, 4, 6, and 8, and 
3-point responder rates at Weeks 2, 4, 6, 8, and 10 will be tested using the CMH test identical 
to the one used for the primary endpoint.  


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The change from baseline to Weeks 2, 4, 6, 8, and 10 and Days 1–14 for the WI-NRS will be 
testing using an analysis of variance (ANOVA) model with treatment group and stratification 
factor as fixed effects. The change in WI-VAS to Weeks 2, 4, 6, and 10 will be tested using a 
similar ANOVA model. 
8.9 
Safety Analyses  
8.9.1 
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. 
8.9.2 
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. 
8.9.3 
Vital Signs  
The observed data and change from baseline for each measurement day will be summarized 
with descriptive statistics.  
8.9.4 
Electrocardiograms  
The overall ECG assessment (abnormal or normal) will be summarized and descriptively 
characterized, along with a summary of how many subjects developed a post treatment 
abnormal result.  
8.9.5 
Physical Exams  
Physical exam finds will be recorded by the sites within medical history or adverse events 
and are otherwise not summarized. 


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8.10 
Population Pharmacokinetics Analysis  
The plasma concentrations of serlopitant and metabolites will be combined with the data 
from other serlopitant clinical studies for population PK analysis with PK endpoint of 
individual model parameter estimates and covariates identification. A specific population PK 
data analysis plan will be developed that will outline the detailed approach to data handling, 
model development and diagnostics, individual model parameter estimation, exploration of 
covariate effects, and final model evaluation techniques. The population PK analysis report 
will not be a part of the clinical study report for MTI-117. 
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. The study may be terminated at the request of the US Food and Drug 
Administration, or if the approval to manufacture or to import study drug is revoked by those 
with jurisdiction. 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 may delegate certain aspects of study oversight to Contract Research 
Organizations (CROs). The specific responsibilities will be detailed in Transfer of 
Obligations documents.  
9.5 
Informed Consent 
The purpose of the study, the procedures to be carried out, and any potential risks of study 
participation will be described in non-technical terms in the ICF. After having reviewed and 
understood the ICF, subjects will be required to read, sign, and date an IRB-approved or 
EC-approved consent form before any study-specific procedures are carried out. Subjects 
will be assured that they may withdraw from the study at any time without jeopardizing 
medical care related to or required as a result of study participation. The original signed 
consent form will be maintained in the investigator site file. Copies of signed consent 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, ICF, 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 from subjects who 
wish to participate in the study.  
The investigator must ensure that the subjects be identified by a unique subject study 
number. Other study-related documents that may contain confidential participant information 
(e.g. signed ICFs) will be kept in strict confidence by the investigator and be stored in a 
secure location with access restricted to the study staff. 


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9.8 
Records and Electronic Case Report Forms 
All study data except central laboratory, PK, IWRS, eDiary, and ECG data will be recorded 
in an eCRF system (note: collection of central laboratory and PK blood draws will be 
recorded in the eCRF). 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 or EC within 90 days 
from the end of the clinical study. The end of the clinical study is defined as the last study 
visit for the last subject. 


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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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2012;92:563–81. 
 


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APPENDIX A 
SCHEDULE OF ACTIVITIES AND ASSESSMENTS 
Table 2 
Schedule of Visit Activities 
Examination 
Screening 
Mid-
ScreeningTC  
(-3 days) 
Baseline1  
(+3 days) 
Week 1TC (± 
3 days) 
Week 2 (-3 
/+1 days) 
Week 4 (± 
3 days) 
Week 6 (± 
3 days) 
Week 8TC 
(± 3 days) 
Week 10 
(+ 3 
days) 
F/U2 
Demographics 
X 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
Paper WI-NRS3 
X 
 
 
 
 
 
 
 
 
 
WI-VAS  
 
 
X 
 
X 
X 
X 
 
X 
X 
ESS  
 
 
X 
 
X 
X 
X 
 
X 
X 
sPGA 
 
 
X 
 
X 
X 
X 
 
X 
X 
PGIC 
 
 
 
 
X 
X 
X 
 
X 
X 
ECG 
X 
 
 
 
 
X 
 
 
 
X 
Vital signs 
X 
 
X 
 
X 
X 
X 
 
X 
X 
Medical history (and prior medications)  
X 
X 
X 
 
 
 
 
 
 
 
Physical exam4 
X 
 
X 
 
 
X 
X 
 
X 
X 
Concomitant medications 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Labs5  
X 
 
 
 
 
X 
 
 
X 
X 
Urine pregnancy test6 
X 
 
X 
 
 
X 
 
  
X 
X 
PK blood draw  
 
 
 
 
 
 
 
 
X 
 
Review of I/E criteria 
X 
X 
X 
 
 
 
 
 
 
 
Dispense/collect eDiary  
X 
 
 
 
  
 
 
 
 
X  
eDiary review/compliance7 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dispense and/or collect study drug 
 
 
X 
 
X 
X 
X 
 
X 
 
Review study drug compliance 
 
 
 
X 
X 
X 
X 
X 
X 
 
AEs/SAEs8 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
TCTelephone Contact: The Mid-Screening telephone contact should occur at least 15 days prior to the scheduled Baseline visit.  
1All visits and windows should be scheduled based on the Baseline Visit (Day 1) 
2The Follow-up (F/U) visit occurs 35 days (+ 7 days) after the Week 10 visit or the last dose of study drug for subjects who discontinue study drug early.  
3WI-NRS at Screening visit will be collected manually on paper for Inclusion/Exclusion criteria. All subsequent WI-NRS are collected daily via eDiary. 
4Screening physical exam is complete and includes height and weight; other physical exams are targeted and include weight.  
5Labs are ideally performed in the morning, particularly at visits with endocrine assessments (including Reproductive Endocrinology for females under 55 at age of consent who are not using 
hormonal contraception or other hormonal therapies at Screening) at Screening, Week 10, and Follow Up).  
6Female subjects of childbearing potential only. Serum pregnancy test is required for positive or equivocal results. 
7See Table 3 for eDiary assessments 
8During the period between informed consent and first study drug dose, only SAEs caused by a protocol-mandated intervention will be collected. 


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Table 3 
Schedule of eDiary Assessments 
An eDiary device is provided to subjects at the Screening visit and collected at the Follow-up visit.  
Device 
Assessment 
Frequency and Duration of Assessment 
eDiary 
WI-NRS 
Once daily from Screening visit through the Follow-up visit 
eDiary 
Dosing 
Once daily from Baseline visit through Week 10 visit or study drug discontinuation 
 
 


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APPENDIX B 
LIST OF STRONG CYP3A4 INHIBITORS 
The list of strong CYP3A4 inhibitors is based on the FDA list effective September 26, 2016, 
Examples of clinical inhibitors for P450-mediated metabolisms (for concomitant use clinical 
DDI studies and/or drug labeling (“Examples of clinical inhibitors for P450-mediated 
metabolisms (for concomitant use clinical DDI studies and/or drug labeling (9/26/2016)”).  
Note: This Appendix may be replaced if applicable (e.g., if updated by the FDA) through site 
communications without requiring a protocol amendment. 
1. 
boceprevir 
2. 
clarithromycin 
3. 
cobicistat 
4. 
conivaptan 
5. 
danoprevir and ritonavir 
6. 
diltiazem 
7. 
elvitegravir and ritonavir 
8. 
idelalisib 
9. 
indinavir and ritonavir 
10. 
itraconazolea 
11. 
ketoconazolea 
12. 
lopinavir and ritonavir 
13. 
nefazodone 
14. 
nelfinavir 
15. 
paritaprevir and ritonavir and (ombitasvir and/or dasabuvir) 
16. 
posaconazolea 
17. 
ritonavir 
18. 
saquinavir and ritonavir 
19. 
telaprevir 
20. 
tipranavir and ritonavir 
21. 
troleandomycin 
22. 
voriconazolea 
23. 
regular grapefruit juice consumption (note: The effect of grapefruit juice varies 
widely among brands and is concentration-, dose-, and preparation-dependent. 
Grapefruit juice may be a strong or a moderate CYP3A inhibitor depending on the 
preparation)b 
 
a 
When administered topically, it may not be considered a strong CYP3A4 inhibitor due to limited systemic 
absorption. 
b 
The occasional consumption of grapefruit juice or the consumption of grapefruit or other citrus fruits (e.g., 
pomelo, lemon, lime, Seville orange, bitter orange, starfruit) is not contraindicated. 
 


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APPENDIX C 
WORST ITCH NUMERIC RATING SCALE QUESTIONNAIRE 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
    
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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APPENDIX D 
EPWORTH SLEEPINESS SCALE   
 
 
 
 
 
 
 
 
  
 
  
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
  
 
  
 
  
   
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
  
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 

SAP_003.pdf: 
A Randomized, Double-Blind, Placebo-controlled Study Of The Efficacy, Safety, And 
Tolerability Of Serlopitant For The Treatment Of Chronic Pruritus Of Unknown Origin 
 
Protocol Version/Date: Version 1.0 / 30 Jan 2020 
 
NCT number: NCT03841331 




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TABLE OF CONTENTS 
STATISTICAL ANALYSIS PLAN ..........................................................................................1 
TABLE OF CONTENTS ...........................................................................................................2 
LIST OF TABLES .....................................................................................................................3 
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 .........................................6 
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 
Worst Itch - Numeric Rating Scale ......................................................10 
2.3.3 
Worst Itch - Visual Analog Scale ........................................................11 
2.3.4 
Epworth Sleepiness Scale ....................................................................11 
2.3.5 
Static Patient Global Assessment of Itch Severity ...............................11 
2.3.6 
Patient Global Impression of Change in Itch Severity .........................11 
2.3.7 
Safety Parameters .................................................................................11 
2.3.8 
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 
Intercurrent Event ............................................................................................15 
2.7 
Handling of Missing Data ................................................................................16 
2.8 
Sensitivity Analyses, Subgroups and Covariates .............................................16 
2.9 
Safety Analyses ................................................................................................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 
WI-VAS ...............................................................................................22 
3.4.4 
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 
Pharmacokinetic Analyses ...............................................................................24 
4 
REFERENCES ......................................................................................................25 
APPROVAL SHEET ...............................................................................................................26 
 
LIST OF TABLES 
Table 1 
Schedule of Visit Activities .........................................................................6 
Table 2 
Data Capture Systems ................................................................................10 
Table 3 
Analysis Windows .....................................................................................13 
Table 4 
Daily Windows ..........................................................................................14 
 
 
 
 


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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
AE 
Adverse event 
ALT 
Alanine aminotransferase  
AMH 
Anti-Mullerian hormone 
ANOVA 
Analysis of variance 
AST 
Aspartate aminotransferase 
ATC 
Anatomical Therapeutic Classification 
CMH 
Cochran Mantel Haenszel test 
CNS 
Central Nervous System 
CPUO 
Chronic Pruritus of Unknown Origin 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
eDiary 
Electronic diary 
ESS 
Epworth Sleepiness Scale 
FSH 
Follicle-stimulating hormone 
HIV 
Human immunodeficiency virus 
IRT 
Interactive Response Technology 
ITT 
Intent-to-Treat 
IWRS 
Interactive Web Response System  
LDH 
Lactate dehydrogenase 
LH 
Luteinizing hormone 
LOCF 
Last Observation Carried Forward 
MCMC 
Markov Chain Monte Carlo 
MedDRA 
Medical Dictionary for Regulatory Activities  
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
NRS 
Numeric Rating Scale  
PD 
Pharmacodynamics 
PGIC 
Patient Global Impression of Change 
PK 
Pharmacokinetics 
SAE 
Serious adverse event 
sPGA 
Static Patient Global Assessment 
TEAE 
Treatment-emergent adverse event 
TSH 
Thyroid stimulating hormone 
VAS 
Visual Analog Scale 
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 with 
chronic pruritus of unknown origin. Pruritus, or itch, is defined as an unpleasant sensation 
that elicits the desire or reflex to scratch (Ikoma 2006). Chronic pruritus may be associated 
with a variety of underlying conditions, including both dermatological and systemic diseases. 
However, in 8-15% of patients with chronic pruritus, an underlying etiology cannot be 
identified (Weisshaar 2012).  
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 1,500 subjects.   
1.2 
Objectives 
Study MTI-117 contains primary and secondary objectives.   
• The primary objective of this study is to assess the efficacy of repeated oral doses of 
serlopitant in adult subjects with chronic pruritus of unknown origin. 
• The secondary objective of this study is to assess the safety and tolerability of repeated 
oral doses of serlopitant in adult subjects with chronic pruritus of unknown origin.  
 
1.3 
Study Design 
This is a double-blind, randomized, placebo-controlled study. Subjects will be randomized in 
a 1:1 ratio to receive daily oral doses of serlopitant 5 mg or placebo for 10 weeks. After 
completion of the treatment period or early discontinuation of study drug treatment, all 
subjects will enter a 5-week follow-up period. 
The study will consist of three periods, for a total study period of 18 weeks: 
• Screening period: 3 weeks 
• Treatment period: 10 weeks 
• Follow-up period: 5 weeks 
 
Informed consent may occur prior to the Screening visit. During the screening period, 
subjects will be assessed for conditions associated with chronic pruritus. If the investigator 
deems that additional assessments are necessary to rule out specific conditions the subject 
may not be randomized until these are completed and the pruritus is still considered to be of 
unknown origin. 


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Subjects will be provided an electronic diary (eDiary) at the Screening visit and are to 
complete the diary daily until the end of study participation. See Section 2.3.1 for more 
detail. At the Baseline visit (Day 1), subjects will take a loading dose (3 tablets taken orally) 
at the site.  Starting on Day 2, subjects will take one tablet per day until Week 10 or until the 
study drug is discontinued. 
The primary efficacy endpoint is the Worst-Itch Numeric Rating Scale (WI-NRS) 4-point 
responder rate at Week 10.  This endpoint is based upon the WI-NRS results entered into the 
eDiary. Other efficacy endpoints are captured within the case report forms.  Safety endpoints 
are captured within the case report form or central laboratories. 
An abbreviated schedule of activities for the study can be found in Table 1, with greater 
details of the schedule available in the protocol. 
Table 1 
Schedule of Visit Activities 
Examination 
Screening 
Baseline 
Week 2  Week 4  Week 6  Week 10 
F/U 
Demographics 
X 
 
 
 
 
 
 
Paper WI-NRS 
X 
 
 
 
 
 
 
Daily WI-NRS 
X 
WI-VAS / ESS / sPGA 
 
X 
X 
X 
X 
X 
X 
PGIC 
 
 
X 
X 
X 
X 
X 
ECG 
X 
 
 
X 
 
 
X 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
Medical history / prior and 
current medications 
X 
X 
 
 
 
 
 
Physical exam 
X 
X 
 
X 
X 
X 
X 
Concomitant medications / 
emollients  
 
X 
X 
X 
X 
X 
X 
Hematology/Chemistry 
X 
 
 
X 
 
X 
X 
Endocrine/Reproductive 
X 
 
 
 
 
X 
X 
Serology, Serum IgE, Iron, 
Other labs 
X 
 
 
 
 
 
 
Urine pregnancy test 
X 
X 
 
X 
 
X 
X 
PK blood draw  
 
 
 
 
 
X 
 
Dispense / collect study drug 
 
X 
X 
X 
X 
X 
 
AEs/SAEs 
X 
 
1.4 
Method of Assigning Subjects to Treatment Groups 
Subjects will be randomized to serlopitant 5 mg or placebo in a 1:1 ratio. Stratified permuted 
block randomization will be used. Randomization will be stratified by the subject’s reported 
WI-NRS score for the 1-week period prior to the Baseline visit (7 to < 8.5, 8.5 to 10), and by 
the subject’s age at the Baseline visit (18 to < 50 years, ≥ 50 years).  Randomization of 
subjects < 50 years of age will be capped at 25% of the total randomized population. This cap 
may be increased up to 33% of the total randomized population at the Sponsor’s discretion.  
An Interactive Web Response System will be used to perform the randomization.  


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1.5 
Treatment Blinding 
This is a double-blind study. Unless required for safety reporting, 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.  The 
investigator can unblind individual subjects for emergency medical purposes.  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-value is less than 
5% then the null hypothesis of no treatment effect is rejected. If the one-sided p-value is 
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 200 randomized and dosed subjects (100 per group) has been 
determined based upon a 1:1 allocation of subjects to treatment groups and a 5% one-sided 
alpha level. A sample size of 200 subjects results in at least 90% power assuming a placebo 
4-point responder rate of 
% and serlopitant 4-point responder rate of 
% at Week 10. 
The sample size calculations have been performed in PASS 13 (“PASS 13 Power Analysis 
and Sample Size Software” 2014) and used a Chi-Squared 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). 
CCI
CCI


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2 
STATISTICAL METHODS 
2.1 
Populations Analyzed 
Five analysis populations will be defined.  These populations are: 
• Screened Population – All subjects who provide informed consent. 
• Randomized Population – All subjects who are randomized.  Subjects will be analyzed 
within the treatment group to which they are randomized. 
• Screen Failures – All screened subjects who are not randomized. 
• Full Analysis Population (FAP) – Subset of subjects in the randomized population who 
were dispensed 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 both placebo and serlopitant they will be 
summarized in the serlopitant treatment group.  
 
2.2 
Study Drug Dosing and Compliance 
Study drug accountability (i.e. how many tablets were dispensed and returned, date of first 
and last dose) will be recorded in the case report form.  Additionally, subjects will record 
daily dosing within the eDiary.  The tablet counts reported within the CRF will be used as the 
dosing and compliance data source.  From these data the duration of treatment, number of 
tablets used, and compliance with treatment will be determined.  The duration of treatment is 
last dose date – first dose date + 1. 
Compliance will be calculated as, 
𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶(%) =
𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇 𝑈𝑈𝑈𝑈𝑈𝑈𝑈𝑈
𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇 𝐸𝐸𝐸𝐸𝐸𝐸 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑−𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇 𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑+ 3  . 
The number of tablets used will be based upon the counts within the electronic data capture 
(eDC).  For each bottle, the difference between the tablets dispensed and returned minus any 
tablets lost will be the tablets used for that bottle.  The total number of tablets used will be 
the sum across bottles.  Should a subject not return a bottle, it will be assumed that they 
returned the average number of tablets that were returned in their other bottles.  Subjects with 
no returned bottles will have missing tablet count and compliance (i.e. no effort will be made 
to impute values).  
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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The eDiary dosing data will be used by study site personnel to monitor dosing in real time 
but will not be used for dosing and compliance calculations.  The days of dosing as measured 
by the eDiary will be summarized. 
2.3 
Study Endpoints 
The study endpoints are listed below, with greater detail concerning these endpoints provided 
in Sections 2.3.2 to 2.3.8. 
Primary Efficacy Endpoint 
The primary efficacy endpoint is the WI-NRS 4-point responder rate at Week 10. 
Secondary Efficacy Endpoints 
The key secondary efficacy endpoints are as follows: 
• WI-NRS 4-point responder rate at Weeks 2 4, 6, and 8 
• WI-NRS 3-point responder rate at Weeks 2, 4, 6, 8, and 10 
• Change from baseline in WI-NRS at Weeks 2, 4, 6, 8, and 10 
• Change from baseline in daily WI-NRS scores through Week 2 
• Change from baseline in WI-VAS at Weeks 2, 4, 6, and 10  
 
Safety Endpoints 
Safety endpoints include the following: 
• Incidence of TEAEs and SAEs 
• Changes from baseline in clinical laboratory parameters following study drug exposure 
• Changes from baseline in vital sign and ECG parameters following study drug exposure 
• Plasma concentrations of serlopitant and metabolites  
 
Exploratory Endpoints 
The exploratory endpoints include the following: 
• Change from baseline in the Epworth Sleepiness Scale (ESS) to Weeks 2, 4, 6, and 10 
• Change from baseline in Static Patient Global Assessment of Itch Severity (sPGA) to 
Weeks 2, 4, 6, and 10 
• Patient Global Impression of Change in Itch Severity (PGIC) at Weeks 2, 4, 6, and 10 


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2.3.1 
Endpoint Data Capture  
The study endpoints will be captured within the eDC system, from central laboratories, 
within the IRT system, or a subject eDiary (see Table 2).  The eDiary will be used to capture 
the WI-NRS data daily.  From these measures the primary endpoint will be created.  This 
system will also calculate and provide two measures to the study sites that are required for 
eligibility determinations: eDiary compliance and baseline 1-week average WI-NRS score. 
Table 2 
Data Capture Systems 
Examination 
eDC 
Central Laboratory 
IRT system 
eDiary 
Demographics 
X 
 
 
 
Paper WI-NRS 
X 
 
 
 
Daily WI-NRS 
 
 
 
X 
WI-VAS / ESS / sPGA 
X 
 
 
 
PGIC 
X 
 
 
 
ECG 
X 
X 
 
 
Vital signs 
X 
 
 
 
Medical history / prior medications 
X 
 
 
 
Physical exam 
X 
 
 
 
Concomitant medications  
X 
 
 
 
Laboratory Results 
 
X 
 
 
Urine pregnancy test 
X 
 
 
 
PK blood draw  
 
X 
 
 
Dispense / collect study drug 
X 
 
 
 
AEs/SAEs 
X 
 
 
 
Randomization 
 
 
X 
 
 
2.3.2 
Worst 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 worst intensity of their itch on an 
11-point scale ranging from 0 (no itch) to 10 (worst itch imaginable). Higher scores indicate 
greater itch intensity during that 24 period. During the study, WI-NRS assessments will be 
reported by the subject via eDiary. The daily NRS results will be summarized.  The daily 
results will be averaged to create weekly measures outlined in Section 2.4.  A 4-point 
responder is a subject who had at least a 4-point reduction in score between the week and 
baseline. A 3-point responder is similarly defined. The intercurrent rules outlined in 
Section 2.6 will be applied to the responder rate endpoints. 
A ‘paper WI-NRS’ will be captured at screening to be used as part of the eligibility criteria.  
This measure will not be used within the efficacy calculations. 


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2.3.3 
Worst Itch - Visual Analog Scale 
The Itch VAS is a validated, self-reported, instrument for measurement of itch intensity. It 
uses a 24-hour recall period and asks subjects to rate the worst intensity of their itch on a 
100-mm horizontal line ranging from 0 mm (no itch) to 100 mm (worst itch imaginable). 
Higher scores indicate greater itch intensity. The VAS measurement will be summarized in 
centimeters. WI-VAS assessments will be reported by the subject via a paper form 
administered at study visits.   
2.3.4 
Epworth Sleepiness Scale 
The ESS is a quality of life instrument intended to measure daytime sleepiness by use of a 
very short questionnaire (8 items each scored from 0-3). Each of the eight items have four 
possible responses: no chance of dozing (0), slight chance of dozing (1), moderate chance of 
dozing (2), high chance of dozing (3).  The ESS total score is the sum of the responses to 
each item and can range from 0 to 24.  If an individual item is missing, the total score will be 
missing.  Higher scores indicate greater daytime sleepiness.  
The total score can be interpreted as follows  
(http://epworthsleepinessscale.com/about-the-ess/):  
• 0-10: Normal Daytime Sleepiness  
• 11-12: Mild Excessive Daytime Sleepiness   
• 13-15: Moderate Excessive Daytime Sleepiness  
• 16-24: Severe Excessive Daytime Sleepiness 
 
2.3.5 
Static Patient Global Assessment of Itch Severity 
The Static Patient Global Assessment of Itch Severity (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.  
2.3.6 
Patient Global Impression of Change in Itch Severity 
The Patient Global Impression of Change in Itch Severity (PGIC) 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).  
2.3.7 
Safety Parameters 
The following safety parameters are captured within this study. 


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2.3.7.1 
Adverse Events and Serious Adverse Events 
The following is a brief summary of terms associated with adverse events.  Greater details 
concerning these terms can be found in the protocol. 
An AE is any untoward medical occurrence associated with the use of a drug in humans, 
whether or not it is considered drug related. An AE is considered treatment emergent, TEAE, 
if it began on the day of first treatment or after. For AEs that occur on the first day of dosing, 
the AE will be considered TEAE if the study site indicates that the event occurred after the 
first study drug dosing. An AE is considered “serious” if it results in death, is a life-
threatening AE, results in hospitalization or prolongation of hospitalization, persistent or 
significant incapacity or substantial disruption of the ability to conduct normal life functions, 
a congenital anomaly/ birth defect or is an important medical event. 
AEs and SAEs will be recorded from the first study drug administration through the end of 
the follow-up period. After informed consent but prior to initiation of study drug, only SAEs 
considered by the investigator to be caused by a protocol-mandated intervention will be 
collected.  
AEs will be graded for severity using the National Cancer Institute Common Terminology 
Criteria for Adverse Events (NCI CTCAE) v5.0 to describe the maximum intensity of the 
adverse event.  As such, severity will be reported as Mild, Moderate, Severe, Very Severe, 
Life Threatening or Disabling, Death Related. 
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 and Likely Unrelated. 
Adverse events and medical history will be coded using MedDRA version 21.0.    
2.3.7.2 
Other Safety Endpoints 
• Vital signs:  
- 
Systolic Blood Pressure, Diastolic Blood Pressure, Heart Rate, Respiration Rate, 
Height, Weight, Temperature and presence of a clinically significant abnormal 
values.  
• 12-Lead Electrocardiogram:  
- 
RR, PR, QRS, QT, HR, QTcB, QTcF, and the ECG interpretation.  A central read 
cardiologist assessment of normal vs abnormal will be available as well as an 
investigator assessment of clinically significant vs not clinically significant.   
• Physical examination abnormalities identified as preexisting before treatment will be 
recorded as medical history. Abnormalities identified after treatment will be recorded as 
adverse events. 


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• Laboratory samples will include: 
- 
Hematology, Chemistry, Immunochemistry and Urine Pregnancy. 
 
2.3.8 
Pharmacokinetic Measurements 
There will be one PK sample at the Week 10 visit. The plasma concentrations of serlopitant 
and metabolites M1/M1a, M2/M2a and M3 will be determined. 
2.4 
Study Day and Visit Windows 
Summary tables will report data based upon the protocol scheduled time points (Baseline, 
Weeks 2, 4, 6, 10 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 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 
Screening 
< Day – 7 
First 
Baseline 
Day -7 to 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 
 
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.  The baseline of an endpoint (see Section 3.2) may not always occur at 
the baseline visit. 


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The eDiary WI-NRS assessments will be summarized at Baseline, Week 2, 4, 6, 10, 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 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 
Baselinea 
Day -7 to -1 
or 
Day -6 to -1, Day 1 
Day -11 to -8 
or 
Day -10 to -7 
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 
Week 8 
Day 47 to Day 53 
Day 54 to Day 57 
Week 10 
Day 64 to Day 70 
Day 60 to Day 63 
a 
If the diary was completed prior to dosing on Day 1 then the baseline range includes the day of dosing 
(Day 1) otherwise the baseline range does not include Day 1. 
 
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.  
2.5 
Statistical Assessment of the Study Objectives 
The efficacy endpoints will be summarized within the FAP 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.  No multiplicity adjustment will be used, and the 
p-values reported for the key secondary endpoints will be descriptive in nature. 
2.5.1 
Primary Analysis 
The difference in the primary efficacy outcome measure (WI-NRS 4-point responder rate at 
Week 10) between treatment groups will be summarized by treatment group. The difference 
in responder rates between treatment arms will be tested using a Cochran-Mantel-Haenszel 
(CMH) test controlling for the ‘as randomized’ stratification factors. Conceptually, the 
hypotheses being tested are:  
H0:πp ≥ πs 
 
Ha: πp < πs 
 
where πp is the placebo responder rate at Week 10 and πs is the similar measure for 
serlopitant.  






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• Baseline WI-NRS (< 8.5, >= 8.5) 
• Duration of chronic pruritus (< 1 yr, 1-5yrs,>5 yrs) 
 
Additionally, the WI-NRS responder rates at Week 10 will be summarized for subject with 
and without the following post baseline events. These are post-baseline factors and may be 
correlated with treatment outcomes.    
• Study Disposition 
- 
Completed study 
- 
Did not complete the study  
• Ever require / did not require rescue therapy for treatment of worsening pruritus  
• Treatment completion (completed treatment, did not complete treatment). 
 
To investigate the impact of missing data, missing WI-NRS data will be derived using the 
method of Markov Chain Monte Carlo (MCMC) multiple imputation.  Imputation will be 
conducted within each treatment group independently, so the pattern of missing observations 
in one treatment group cannot influence missing value estimations in another. The MCMC 
imputation will use the observed results at each timepoint. For each imputation process, 
1000 imputations will be performed. To mimic the original missing data algorithm, the 
continuous values will be imputed and the responder status will be determined. The 
intercurrent events rules (see Section 2.6) will continue to be used. A CMH test, identical to 
the test used for the primary endpoint, will be used based upon the imputed responder status.  
2.9 
Safety Analyses 
Safety endpoints will be summarized with descriptive statistics. All safety summaries and 
analyses will be performed using the safety population. Vital signs, laboratory, and ECG 
results will be summarized by timepoint and treatment. Adverse events and concomitant 
medications/procedures will be summarized overall. 
Prior and concomitant medications and procedures will be coded by the World Health 
Organization (WHO) Drug Dictionary version 2018/Q3. Medications and procedures will be 
considered concomitant unless they ended prior to treatment. 
 


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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 and concomitant medications will be 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 FAP population, and all safety analyses will be based upon 
the safety population.  
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, hence baseline.  Baseline for the daily measures that are recorded 
in the eDiary are 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 who attended each visit as determined by the presence 
of a vital signs result.  
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: 
• Age – continuous and categories (≤ 64 years, > 64 years) and (< 50 years, ≥ 50 years). 
• Race 
• Ethnicity 
• Sex 
• Height 
• Weight 
• Baseline WI-NRS – continuous and categories (< 8.5, >= 8.5) 
• Screening WI-NRS 
• Baseline WI-VAS 
• Length of chronic pruritus – continuous and categories (<1 yr, 1-5 yrs, >5 yrs) 
• Location of pruritus 
• Randomization strata 
• Protocol version screened under 
 
The reproductive measures (e.g. child bearing potential, surgical sterilization procedure, 
method of contraception, female subject specific medical history) will be listed but otherwise 
not tabulated. 
The serology, serum IgE, iron, other labs and additional tests sites perform to confirm entry 
criteria results will be listed but otherwise not tabulated. 
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.  


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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 and procedures will be summarized by treatment group. All 
medications/procedures, including prior medications/procedures, will be provided in listings.  
A table will be produced to summarize rescue medications used for intercurrent events 
defined in Section 2.6. 
3.3.4 
Medical History 
Medical history will be tabulated by system organ class, preferred terms and treatment group 
and provided in a listing.  The female specific medical history will be listed separately from 
other medical history. 
3.3.5 
Clinical Study Treatment 
The total tablets used, duration of treatment, and compliance (see Section 2.2) will be 
summarized.  The days of dosing as measured by the eDiary will be summarized.  All eDC 
study drug data will be listed, including lost tablets.  The days of dosing from the eDiary will 
be listed, but the daily results will not. 
3.4 
Analysis of Efficacy Endpoints 
3.4.1 
Calculation Examples for Daily Measures 
Below are examples of how the eDiary WI-NRS weekly results 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. 
3. Example 3 (incomplete data) 


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a. The subject has results for less than seven days in the original range (e.g. x39, x40, x42) 
and does not have enough in the extended range to reach seven results overall (e.g. 
x44, x46).  In this example the subject is missing diary data on days 36, 37, 38, 41, 43 
and 45. 
◦ 
The average for Week 6 is (x39+x40+ x42+ x44+ x46)/5. 
4. Example 4 (no data) 
a. The subject does not complete the diary from day 60 onwards.  
b. The average for Week 10 is missing and the missing data rules (Section 2.7) are used. 
 
3.4.2 
WI-NRS  
The WI-NRS endpoints (result, change from baseline, 3-point and 4-point responders) will be 
summarized at the primary time point (Week 10) as well as at Weeks 2, 4, 6, 8 and Follow-
up. The summary measures will include 95% Wald confidence intervals for the treatment 
difference and a p-value for the treatment difference (for the change from baseline and 
responder rate measures). The baseline WI-NRS will also be summarized, but no confidence 
interval will be produced. A graph of the mean WI-NRS results and mean change from 
baseline results and the 4-point responder rate (baseline included with a rate of zero) by 
timepoint and treatment will be produced. 
The WI-NRS scores for days 1 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. Daily WI-NRS results will be summarized in a table based upon 
availability of the data regardless of any intercurrent events. 
The test used for the 3 and 4-point responder rates at Weeks 2, 4, 6, 8 and 10 is a CMH test 
controlling for the ‘as randomized’ stratification factors. The ‘as randomized’ stratification 
factors are based upon the stratification cell that the subject was randomized to. The 
differences 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.  
The estimated treatment effect from this test will be a weighted average based upon the 
equation provided in Section 2.5. 
The WI-NRS 4-point responder rates at Week 10 will be summarized within the subgroups 
and separately by the post baseline factors outlined in Section 2.8. Forest plots based upon 
the same groups will also be produced. 
A missing data sensitivity analysis will be conducted using the multiple imputation method 
outlined in Section 2.8.  This analysis will include summary statistics by time points for the 
4-point WI-NRS responder rate and the continuous WI-NRS measures as well as testing for 
the 4-point WI-NRS responder endpoint at Week 10.  The following steps will be followed: 




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3.5 
Analysis of Safety Endpoints 
3.5.1 
Adverse Events 
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.  TEAEs leading to treatment 
discontinuation will be provided in a separate listing.   
3.5.2 
Clinical Laboratory Evaluations 
Clinical laboratory results will be summarized by type of laboratory assessment (hematology, 
chemistry, endocrine), timepoint, and treatment. Summary statistics for actual values and 
changes from baseline will be tabulated by analysis window. Shifts from baseline clinical 
laboratory values based upon the normal range will be tabulated for each post baseline 
sample timepoint. 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 positive pregnancy tests results will be produced. 


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3.7 
Pharmacokinetic Analyses 
Plasma concentrations at week 10 will be summarized. The bioanalytical laboratory will 
provide the plasma concentration data for serlopitant and 3 metabolites in ng/mL. Plasma 
concentrations will be converted to nmol/L (nM) by the Statistician using the following 
equation: 
Plasma serlopitant concentration in nM = [(plasma serlopitant 
concentration in ng/mL) / (MW of 555.54 ng/nmol)] x (1000 mL/L) 
 
The same conversion will be followed for each metabolite concentration using the MW of 
 ng/nmol. Results will be summarized using Geometric Mean and Coefficient of 
variation (CV). The formulas used are shown below.  Below BLQ values will be set to ½ of 
the BLQ values (i.e., 
 ng/mL = 
nM).  
Geometric Coefficient of Variation Formula:  
Geo CV = ඥ𝑒𝑒𝑒𝑒𝑒𝑒(ln (𝐺𝐺𝐺𝐺𝐺𝐺𝐺𝐺𝐺𝐺))2 −1 × 100% 
Geometric Mean Formula:  
Geo Mean = ඥ𝑦𝑦1 × 𝑦𝑦2 × 𝑦𝑦3 × … × 𝑦𝑦𝑁𝑁
𝑁𝑁
 = 𝑒𝑒𝑒𝑒𝑒𝑒[ln(𝑦𝑦1)+
+ln(𝑦𝑦𝑛𝑛)
𝑛𝑛
] 
Geometric Standard Deviation Formula:  
Geo SD = 𝑒𝑒𝑒𝑒𝑒𝑒(𝑆𝑆𝑆𝑆(ln(𝑦𝑦1) ln(𝑦𝑦2) ln(𝑦𝑦3)… ln(𝑦𝑦𝑥𝑥))) 
 
CCI
CCI
CCI


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4 
REFERENCES 
The following litterature references cited in this document are available upon request. 
Ikoma A, Steinhoff M, Ständer S, et al. The neurobiology of itch. Nat Rev Neurosci 
2006;7:535-547. 
PASS 13 Power Analysis and Sample Size Software (2014). NCSS, LLC. Kaysville, Utah, 
USA, ncss.com/software/pass. 
Matts JP, Lachin JM. Properties of permuted-block randomization in clinical trials. Control 
Clin Trials. 1988;9(4):327-44. 
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. 
Weisshaar E et al. European guideline on chronic pruritus. Acta Derm Venereol 2012;92:563-
81.