Serlopitant for the treatment of chronic

pruritus: Results of a randomized,

multicenter, placebo-controlled
phase 2 clinical trial
Gil Yosipovitch, MD,a Sonja St€ander, MD,b Matthew B. Kerby, PhD,c James W. Larrick, MD, PhD,d
Andrew J. Perlman, MD, PhD,d Edward F. Schnipper, MD,d Xiaoming Zhang, PhD,c
Jean Y. Tang, MD, PhD,e Thomas Luger, MD,f and Martin Steinhoff, MD, PhDg,h
Miami, Florida; M€unster, Germany; Redwood City, South San Francisco, Stanford, and San Diego,
California; and Doha, Qatar

Background: The substance P/neurokinin 1 receptor pathway is critical in chronic pruritus; anecdotal
evidence suggests that antagonism of this pathway can reduce chronic itch.

Objective: To assess the safety and efficacy of the substance P/neurokinin 1 receptor antagonist serlopitant
in treating chronic pruritus.

Methods: Eligible patients with severe chronic pruritus who were refractory to antihistamines or topical
steroids were randomized to serlopitant, 0.25, 1, or 5 mg, or to placebo, administered once daily for
6 weeks as monotherapy or with midpotency steroids and emollients. The primary efficacy end point was
percentage change in visual analog scale pruritus score from baseline.

From Miami Itch Center, Department of Dermatology and
Cutaneous Surgery, Miller School of Medicine, University of
Miamia; Center for Chronic Pruritus, Department of Derma-
tology, University Hospital M€ unsterb; Menlo Therapeutics Inc,
Redwood Cityc; Velocity Pharmaceutical Development, LLC,
South San Franciscod; Department of Clinical Dermatology,
Stanford University, Redwood Citye; Department of Derma-
tology, University Hospital M€ unsterf; Department of Derma-
tology, University of California San Diegog; and the Department
of Dermatology, Weill Cornell University-Qatar, Hamad Medical
Corporation, Doha.h
Drs Yosipovitch and St€ander are cofirst authors.
Funding sources: Supported by Menlo Therapeutics Inc. Medical
writing and editorial assistance were provided by ApotheCom
(New York, NY) and funded by Menlo Therapeutics Inc.
Disclosure: Dr Yosipovitch has received grant/research support for
his role as an investigator from Menlo Therapeutics Inc, Vanda
Pharmaceuticals, Kiniksa Pharmaceuticals, and Sun Pharma, and
he has received honoraria for participation in advisory boards
for Menlo Therapeutics Inc, Trevi, Novartis, Pfizer, OPKO Health
Inc, Sanofi, Galderma, and Sienna. Dr St€ander has received
grants/research support and honoraria for her role as an
investigator and consultant from Menlo Therapeutics Inc; she
has received honoraria for participation in advisory boards for
Menlo Therapeutics Inc and has received patient fees from
Menlo Therapeutics Inc. Dr Kerby has received personal fees
from Velocity Pharmaceutical Development and is a share-
holder and consultant to Menlo Therapeutics Inc. Dr Larrick is a
cofounder of and owns stock in Menlo Therapeutics Inc. Drs
Perlman and Schnipper are employees of Velocity Pharmaceu-
tical Development, and they have received stock from Menlo
Therapeutics Inc for their roles as advisors and consultants. Dr
Zhang has received personal fees from Velocity Pharmaceutical
Development; he is a shareholder and employee of Menlo
Therapeutics Inc, and he reports patents issued to Menlo
Therapeutics Inc. Dr Luger has received grant/research support
for his role as an investigator from AbbVie, Celgene, Eli Lily,
Janssen-Cilag, Mylan/Meda Pharmaceuticals, MSD, Novartis,
and Pfizer, and he has received honoraria for participation in
advisory boards for AbbVie, Celgene, CERIES, Eli Lilly, Galderma,
Janssen-Cilag, La Roche Posay, Mylan/Meda, Novartis, and
Pfizer and honoraria for his role as a speaker for AbbVie,
Celgene, Galderma, Janssen-Cilag, La Roche Posay, Mylan/
Meda, MSD, Novartis, and Pfizer. Dr Steinhoff has received
honoraria for his role as a speaker from Menlo Therapeutics Inc,
Galderma, and Eli Lily; for serving as a consultant for Menlo
Therapeutics Inc; and for participating in advisory boards for
Menlo Therapeutics Inc, Galderma, and Pierre Fabre Labora-
tories. Dr Tang has no conflicts of interest to disclose.
This work was submitted to and presented in part at the 26th
European Academy of Dermatology and Venereology
Congress, September 13-17, 2017, in Geneva, Switzerland,
and presented at the Ninth World Congress on Itch, October
15-17, 2017, in Wroclaw, Poland.
Accepted for publication February 4, 2018.
Reprint requests: Martin Steinhoff, MD, PhD, Department of
Dermatology and Venereology, Hamad Medical Corporation,
Weill Cornell Medicine-Qatar and Qatar University, Doha, Qatar.
E-mail: MSteinhoff@hamad.qa.
Published online February 17, 2018.
0190-9622
Ó 2018 by the American Academy of Dermatology, Inc. This is an
open access article under the CC BY-NC-ND license (http://
creativecommons.org/licenses/by-nc-nd/4.0/).
https://doi.org/10.1016/j.jaad.2018.02.030

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Results: Serlopitant treatment resulted in a dose-dependent decrease in pruritus. The mean percentage
decreases from baseline visual analog scale pruritus scores were statistically significantly larger with the
1- and 5-mg doses of serlopitant (P = .022 and P = .013, respectively) than with placebo at week 6. No
significant safety or tolerability differences were detected among the groups.

Limitations: The sample size was insufficient for subgroup analyses of the efficacy of serlopitant for
chronic pruritus on the basis of underlying conditions.

Conclusions: Serlopitant, 1 mg and 5 mg daily, was associated with a statistically significant reduction in
chronic pruritus and was well tolerated (NCT01951274). ( J Am Acad Dermatol 2018;78:882-91.)

Key words: chronic pruritus; itch; neurokinin 1 receptor; NK1 receptor; NK1 receptor antagonist;
serlopitant; substance P.

Pruritus is a prevalent and Serlopitant is an NK1R

debilitating symptom of a CAPSULE SUMMARY antagonist that was originally
number of dermatologic, developed for chronic use for
neurologic, systemic, and d The substance P/neurokinin 1 receptor the treatment of overactive
psychiatric disorders,1 in- pathway is pivotal in histamine- bladder, and in a phase 2 trial
cluding atopic dermatitis, independent pruritus. it was found to be generally
psoriasis, and kidney dis- d This study demonstrated a statistically well tolerated.17 On the basis
1-3
ease. Chronic pruritus may significant reduction in chronic pruritus of our evolving understand-
result in sleeplessness, with the oral neurokinin 1 receptor ing of the role of the NK1R in
inability to work, aggression, antagonist serlopitant at 1 and 5 mg pruritus,6,7 studies demon-
anxiety, depression, and given once daily. strating a reduction in pruri-
low quality of life.1,4,5 tus with NK1R inhibition,10-14
d Serlopitant has potential as a therapeutic
Symptomatic relief of pruritus and the serlopitant safety
agent for the treatment of chronic
is uniformly elusive. There data,17 a clinical study was
pruritus.
are no drugs approved spe- conducted to assess the effi-
cifically for the treatment of cacy of serlopitant for the
chronic pruritus, and the ther- treatment of chronic pruritus.
apies used often have limited efficacy and can be Here, we report results from the phase 2, multicenter
associated with significant side effects. Thus, patients clinical trial of serlopitant for chronic pruritus.
often experience severe long-lasting pruritus without
improvement, intensifying the negative impact on METHODS
quality of life and psychosomatic reactions.1,6 Study design and patients
Over the past decade, our understanding of neu- A total of 25 US centers (listed in the Supplemental
ral and cellular circuitries involved in pruritus has Table I; available at http://www.jaad.org) partici-
significantly expanded.6,7 The tachykinin substance pated in this randomized, double-blind, 6-week,
P (SP) and its receptor, neurokinin 1 receptor placebo-controlled study (NCT01951274) investi-
(NK1R), are well established as a pivotal pathway gating the safety and efficacy of 3 different doses of
in histamine-independent pruritus.8,9 serlopitant versus placebo for severe chronic
Multiple case reports suggest that patients pruritus. Patients aged 18 to 65 years who were in
with chronic pruritus respond to treatment with good health and had pruritus for 6 weeks or more
aprepitant,10-14 the first approved NK1R antagonist. that was unresponsive to treatment with current
However, aprepitant is indicated only for use therapies such as antihistamines or topical steroids
in chemotherapy-induced nausea and vomiting (considered first-line therapies for pruritus18) and a
(treatment courses are limited to 3-day cycles), and score of 7 cm or higher on the visual analog scale
its use is restricted by the potential for significant (VAS) for pruritus at baseline were eligible. Patients
metabolic drug interactions and its nonlinear with serum creatinine, aspartate aminotransferase, or
pharmacokinetic profile.15,16 alanine aminotransferase levels higher than twice
884 Yosipovitch et al J AM ACAD DERMATOL
MAY 2018

The study protocol was approved by the institu-

Abbreviations used:
tional review board overseeing each site (approval
DLQI: Dermatology Life Quality Index number, 28493; date, August 29, 2013). All patients
e-diary: electronic diary
NK1R: neurokinin 1 receptor were required to give their written informed consent
NRS: numeric rating scale in accordance with Good Clinical Practice and the
PGA: Physician’s Global Assessment local regulatory requirements.
PSSQ-I: Pittsburgh Sleep Symptom Question-
naire-Insomnia
SGA: Subject’s Global Assessment Randomization and masking
SP: substance P Almac Group, Inc (Craigavon, UK) was respon-
VAS: visual analog scale
sible for patient randomization and material logistics.
An interactive web-based response system was used
to randomly assign study patients in a 1:1:1:1 ratio to
the upper limit of normal were excluded. Thus, receive serlopitant, 0.25, 1, or 5 mg, or placebo
enrollment of patients with uremic19 or cholestatic20 (Fig 1) (for additional details, see the Supplemental
pruritus was minimized to reduce possible con- Data; available at: http://www.jaad.org).
founding effects from these specific comorbidities.
Patients with pruritus of neuropathic or psychogenic Procedures
etiology or drug-induced pruritus were also After a 2-week washout period, patients received
excluded. a loading dose of 3 tablets at baseline (day 1),

Patients screened
N = 368

Not randomized
n = 111

Serlopitant Serlopitant Serlopitant

Placebo 0.25 mg 1 mg 5 mg
n = 64 n = 64 n = 65 n = 64

Discontinued treatment Discontinued treatment Discontinued treatment Discontinued treatment

n=9 n=7 n=9 n = 10
Adverse event (n = 3) Adverse event (n = 0) Adverse event (n = 1) Adverse event (n = 1)
Lost to follow-up (n = 1) Lost to follow-up (n = 2) Lost to follow-up (n = 1) Lost to follow-up (n = 2)
Noncompliance (n = 1) Other (n = 1) Other (n = 1) Other (n = 0)
Other (n = 1) Protocol violation (n = 0) Protocol violation (n = 1) Protocol violation (n = 0)
Voluntary withdrawal (n = 3) Voluntary withdrawal (n = 4) Voluntary withdrawal (n = 5) Voluntary withdrawal (n = 7)*

Completed Completed Completed Completed

study study study study
n = 55 n = 57 n = 56 n = 54

Randomization Last dose 4-week final

Screening Loading dose Last daily score follow-up
Daily dose
Washout

Week –2 0 2 4 6 8 10
Fig 1. Enrollment and outcomes. *One patient in the serlopitant 5-mg group (14-007)
discontinued participation in the study after stopping study treatment because of an adverse
event. This patient’s reason for discontinuation of the study is recorded as voluntary
withdrawal.
J AM ACAD DERMATOL Yosipovitch et al 885
VOLUME 78, NUMBER 5

Table I. Demographic and clinical characteristics of patients at baseline

Serlopitant
Combined
Placebo 0.25 mg 1 mg 5 mg serlopitant-treated
Demographics (n = 64) (n = 64) (n = 65) (n = 64) population (n = 193)
Age, y
Mean (6SD) 44.48 (613.23) 45.09 (614.01) 42.49 (614.08) 42.94 (613.96) 43.50 (613.99)
Median 48.0 50.0 43.0 44.5 45.0
Minimum 19.0 18.0 18.0 18.0 18.0
Maximum 64.0 63.0 65.0 65.0 65.0
Sex
Male 25 (39.1) 24 (37.5) 27 (41.5) 25 (39.1) 76 (39.4)
Female 39 (60.9) 40 (62.5) 38 (58.5) 39 (60.9) 117 (60.6)
Race
White 43 (67.2) 43 (67.2) 38 (58.5) 43 (67.2) 124 (64.2)
Black or African American 14 (21.9) 16 (25.0) 21 (32.3) 19 (29.7) 56 (29.0)
Asian 5 (7.8) 2 (3.1) 2 (3.1) 1 (1.6) 5 (2.6)
American Indian or Alaska Native 0 1 (1.6) 1 (1.5) 0 2 (1.0)
Other 2 (3.1) 2 (3.1) 3 (4.6) 1 (1.6) 6 (3.1)
Ethnic origin
Hispanic or Latino 12 (18.8) 18 (28.1) 17 (26.2) 11 (17.2) 46 (23.8)
Non-Hispanic or Latino 52 (81.3) 46 (71.9) 48 (73.8) 53 (82.8) 147 (76.2)
Atopic diathesis
No 42 (65.6) 40 (62.5) 37 (56.9) 37 (57.8) 114 (59.1)
Yes 22 (34.4) 24 (37.5) 28 (43.1) 27 (42.2) 79 (40.9)

Data are n (%) or median.

SD, Standard deviation.

Table II. Common TEAEs ($2% of patients in any treatment group)

Serlopitant
TEAE Placebo (n = 63) 0.25 mg (n = 64) 1 mg (n = 65) 5 mg (n = 64)
Patients with any TEAE, n (%) 16 (25.4) 21 (32.8) 24 (36.9) 24 (37.5)
Somnolence 1 (1.6) 1 (1.6) 3 (4.6) 3 (4.7)
Diarrhea 1 (1.6) 0 4 (6.2) 2 (3.1)
Headache 4 (6.3) 1 (1.6) 3 (4.6) 1 (1.6)
Nasopharyngitis 2 (3.2) 2 (3.1) 3 (4.6) 0
Upper respiratory tract 2 (3.2) 3 (4.7) 0 1 (1.6)
infection
Pruritus 1 (1.6) 2 (3.1) 2 (3.1) 0
Urinary tract infection 2 (3.2) 0 0 2 (3.1)
Nausea 1 (1.6) 0 2 (3.1) 0
Arthralgia 1 (1.6) 2 (3.1) 0 0
Dry mouth 0 0 2 (3.1) 0
Musculoskeletal pain 0 0 2 (3.1) 0
Asthma 2 (3.2) 0 0 0

Counts reflect numbers of patients reporting 1 or more TEAEs that map to Medical Dictionary for Regulatory Activities preferred terms.
A patient may be counted once only in each row of the table. Because only the most common TEAEs are shown in detail, counts do not sum
to equal the number reported as ‘‘any TEAE.’’
TEAE, Treatment-emergent adverse event.

followed by 6 weeks of once-daily tablets before
bedtime. Blood samples, vital signs, and electrocar-
diograms were collected during clinic visits at
baseline and at weeks 1, 2, 4, and 6. Patients scored
their pruritus intensity twice daily using both a VAS
and an 11-point numeric rating scale (NRS) within an
electronic diary (e-diary). Date and time stamps
ensured proper reporting of electronic score results.
At each visit to the clinic, patients completed a
Subject’s Global Assessment (SGA) of pruritus
886 Yosipovitch et al J AM ACAD DERMATOL
MAY 2018

Fig 2. Time course of change from baseline. Response by treatment group: mean percentage
change from baseline in visual analog scale (VAS) pruritus score (A) and mean percentage
J AM ACAD DERMATOL Yosipovitch et al 887
VOLUME 78, NUMBER 5

Table III. Efficacy by treatment groups at week 6 for VAS pruritus score percentage change from baseline
Serlopitant
Statistical measure Placebo (n = 64) 0.25 mg (n = 64) 1 mg (n = 65) 5 mg (n = 64)
LS means 28.3 34.1 41.4 42.5
Standard error 4.1 4.1 4.0 4.1
Pairwise LS mean difference (95% CI) d 5.8 ( 5.4 to 17.1) 13.2 (1.9-24.4) 14.2 (3.0-25.5)
P value d .309 .022 .013

Primary end point: score on VAS reported by patients. Intention-to-treat analyses are shown.
CI, Confidence interval; LS, least squares; VAS, visual analog scale.

severity (none, mild, moderate, or severe), a
Dermatology Life Quality Index (DLQI) survey,21
and the Pittsburgh Sleep Symptom Questionnaire-
Insomnia (PSSQ-I).22 Physicians completed a
Physician’s Global Assessment (PGA) survey with
an 11-point scale measuring change from baseline.
The PGA asks physicians to rate the change in lesions
(if any) from plus 5 (markedly improved) to minus 5
(markedly worse). Follow-up assessment was per-
formed 4 weeks after treatment (week 10). Dose
selection and pharmacokinetic methodology are
described in the Supplemental Data.
Outcomes
The primary efficacy end point was the percent-
age change in VAS pruritus scores from baseline,
comparing serlopitant to placebo by using patients’
reports of pruritus intensity. Secondary efficacy end
points included the NRS pruritus score and total
score and domains of the DLQI, the PSSQ-I, the SGA,
and the PGA. Safety was assessed through the
monitoring of adverse or serious adverse events,
laboratory assessments, vital signs, electrocardio-
grams, serum levels of serlopitant, and abbreviated
physical examinations.
Statistical analysis
VAS pruritus score was reported in an e-diary
twice per day. Baseline for VAS was the average of
2 days of measurements before study drug adminis-
tration. The baseline for all measurements other than
the VAS was the last measurement before adminis-
tration of the study drug. For analysis of VAS
reduction, the average of 2 daily measurements
was used to create daily measures that were com-
bined to make weekly measures. Intention-to-treat
principles were used for the primary analyses of
efficacy for all randomized patients (N = 257). The
statistical analysis was prepared by using a repeated
measures linear mixed-effects model. Pairwise esti-
mates of differences between each serlopitant dose
and placebo, associated confidence intervals, and P
values were computed by using SAS software
(version 9.1 or higher, SAS Institute, Inc, Cary, NC)
for each pairwise comparison of serlopitant dose
versus placebo. P values of .05 or less were regarded
as statistically significant. No multiplicity adjustments
were used. Missing data were not imputed. See the
Supplemental Data for additional details.
RESULTS
From October 1, 2013, to December 2, 2014, a
total of 368 patients were screened; 111 were not
randomized because of screen failure, and 257 were
randomized to receive placebo (n = 64) or serlopi-
tant, 0.25 mg (n = 64), 1 mg (n = 65), or 5 mg (n = 64).
Of those 257 patients, 222 (86.4%) completed the
study (Fig 1). Treatments were discontinued for 9
(14.1%), 7 (10.9%), 9 (13.8%), and 10 (15.6%)
patients from the 4 arms, respectively. Reasons for
discontinuation included adverse events, loss to
follow-up, protocol violation, voluntary withdrawal,
or other. Those enrolled in the study had a mean age
of 43.7 years; 156 (60.7%) were female, and 167
(65.0%) self-identified as white (Table I). Study
groups were balanced for age, sex, race, ethnicity,

=
change from baseline in numeric rating scale (NRS) pruritus score (B). Data shown are
estimates of the pairwise difference of least squares means and were generated by using a
mixed-model analysis of covariance test with significance set at .05 level. One patient from the
placebo group (20-004), 2 from the serlopitant 1-mg group (04-003 and 12-010), and 1 from the
serlopitant 5-mg group (12-014), although part of the intention-to-treat population, were
removed from the analysis. Patient 20-004 was randomized in error and did not receive study
medication, patient 04-003 did not receive an e-diary during screening and had no baseline
data, and patients 12-010 and 12-014 did not complete any e-diary information after screening.
LS, least squares means; SE, standard error.
888 Yosipovitch et al
and history of atopic diathesis. Patients had a
history of chronic pruritus associated with
various dermatologic and nondermatologic condi-
tions (Supplemental Table II; available at http//:www.
jaad.org). Supplemental Table III (available at http//
:www.jaad.org) lists the concomitant medications
used most frequently during the study.
Serlopitant was generally well tolerated, as as-
sessed in all patients who received at least 1 dose of
study medication (Supplemental Table IV; available
at http//:www.jaad.org). Most reported adverse
events were mild or moderate; no treatment-
related serious adverse events were reported
(Table II). No evidence of clinically meaningful
trends in laboratory abnormalities or changes in
vital signs was detected. Treatment-related adverse
events occurred in 9.5% of patients (n = 6) in the
placebo group and in 10.9% (n = 7), 13.8% (n = 9),
and 12.5% (n = 8) of patients in the serlopitant 0.25-
mg, serlopitant 1-mg, and serlopitant 5-mg groups,
respectively. Adverse events accounted for 6 pre-
mature discontinuations (2 each in the placebo and
serlopitant 5-mg groups and 1 each in the serlopi-
tant 0.25-mg and serlopitant 1-mg groups) out of 35
total discontinuations. Of the patients who discon-
tinued participation in the study, 2 had events
considered unrelated to study treatment and 4 had
events considered to be possibly or probably
treatment related (headache and hypoesthesia
[n = 1], diarrhea [n = 1], diarrhea and gastrointestinal
pain [n = 1], and panic attack [n = 1]). A seventh
discontinuation was recorded for a patient found to
have a pre-existing condition (hypothyroidism) at
the baseline/randomization study visit before
administration of the study medication and there-
fore was not included in the patient count for
treatment.
At week 6, the mean percentage decreases from
baseline in VAS pruritus score were statistically
significantly greater in the serlopitant 1-mg
(P = .022) and serlopitant 5-mg (P = .013) dose
groups versus in the placebo group (Fig 2, A and
Table III). A statistically significant difference from
placebo emerged as early as week 3 of the study
(1-mg dose, P = .042) (Fig 2, A and Supplemental
Table V; available at http//:www.jaad.org). At week 6,
43%, 38%, and 53% of patients in the serlopitant 0.25-
mg, serlopitant 1-mg, and serlopitant 5-mg dose
groups, respectively, reported a 4-cm decrease in
average VAS pruritus score versus only 26% of
placebo-treated patients (Fig 3, A). The statistically
significant difference in improvement of VAS pruritus
scores between serlopitant and placebo remained
through the follow-up visit 4 weeks after completion
of study treatment (Supplemental Table V).
J AM ACAD DERMATOL
MAY 2018
The mean percentage changes from baseline in
NRS pruritus score (Fig 2, B and Supplemental
Table VI; available at http//:www.jaad.org) showed
larger decreases from baseline in the active treatment
groups compared with the placebo group at weeks 1
through 6; these differences were statistically signif-
icant for the serlopitant 1-mg and serlopitant 5-mg
groups at weeks 4, 5, and 6. At week 6, 46% of
patients in the serlopitant 5-mg dose group reported
a 4-point decrease in average NRS pruritus
score versus 23% of patients who received placebo
(Fig 3, B).
A prespecified subgroup analysis of patients with
a history of atopic diathesis (ie, atopic dermatitis,
allergy, and/or asthma) revealed that serlopitant
provided a greater reduction in pruritus, as measured
by both VAS and NRS pruritus scores, compared with
placebo at weeks 1 through 6 and week 10 (data not
shown), with statistically significantly greater reduc-
tions in pruritus observed with serlopitant, 5 mg, at
weeks 4, 5, and 6 (P\.05). These results were similar
to those for the overall study population.
The mean overall DLQI score and mean individ-
ual domain scores decreased (indicating improve-
ment) throughout the study in all treatment groups
(Supplemental Table VII; available at http//:www.
jaad.org). The mean overall DLQI score was lower in
the active treatment groups than in the placebo
group at weeks 1 through 6 and week 10.
Statistically significant improvements were observed
in the overall DLQI score at week 4 for the serlopitant
1-mg group and in the active treatment groups for
some individual DLQI domains.
As assessed by the SGA, pruritus improved from
baseline in all treatment groups. The differences in
the distribution of SGA ratings of pruritus severity
relative to the placebo group, although not statisti-
cally significant, favored therapy (data not shown).
Results of the PSSQ-I questionnaire at week 6
indicated that approximately 50% fewer patients in
the active arms than in the placebo arm met the
criteria for having insomnia (Supplemental Fig 1;
available at http//:www.jaad.org). The percentages
of patients who had insomnia decreased from
baseline in every treatment group. At week 6, the
differences relative to placebo were statistically sig-
nificant for serlopitant, 1 mg, (sleep symptom
criteria, daytime impairment criteria, and overall-
insomnia disorder) and serlopitant, 5 mg, (sleep
symptom criteria).
PGA scores for all serlopitant treatment groups
(n = 170) at the week 6 visit indicated that 44.1% of
patients ‘‘improved’’ and 9.4% became ‘‘worse’’
compared with 44.6% and 14.3%, respectively, for
the placebo group. Of those who improved, 15.3% of
J AM ACAD DERMATOL Yosipovitch et al 889
VOLUME 78, NUMBER 5

60

55 52.8

50
VAS pruritus score from baseline at week 6, %
Patients with a ≥4-cm reduction of average

45 42.6

38.2
40

35

30
25.9

25

20

15

10

0
Placebo 0.25 mg 1 mg 5 mg

A Serlopitant

50
46.2
45
Patients with a ≥4-point reduction of average NRS

40 38.5
pruritus score from baseline at week 6, %

35
32.7

30

25
22.6

20

15

10

0
Placebo 0.25 mg 1 mg 5 mg

Serlopitant
B
Fig 3. Changes from baseline at week 6. Percentage of patients reporting a 4-cm or greater
reduction in visual analog scale (VAS) pruritus score, by treatment group (A), and percentage of
patients reporting a 4-point or more reduction in numeric rating scale (NRS) pruritus score, by
treatment group (B). Differences analyzed with least squares means tests in comparison with
placebo. One patient from the placebo group (20-004), 2 from the serlopitant 1-mg group
(04-003 and 12-010), and 1 from the serlopitant 5-mg group (12-014), although part of the
intention-to-treat population, were removed from the analysis because they had no baseline or
postbaseline VAS data.
890 Yosipovitch et al
serlopitant-treated patients were markedly improved
or largely improved compared with 3.6% of placebo-
treated patients.
The results presented here are based on the
intention-to-treat population and therefore include
all enrolled individuals.
DISCUSSION
Serlopitant was well tolerated and provided a
significant antipruritic effect in patients with severe
chronic pruritus arising from a broad variety of
etiologies that was refractory to anthistamines and
corticosteroids. Results of the present study support
the hypothesis that interrupting pruritus signaling by
inhibiting the NK1R attenuates chronic pruritus derived
from multiple primary causes.10 Approximately 45% of
patients presented with a dermatologic diagnosis;
however, a similar percentage had received no derma-
tologic diagnosis to explain their long-standing symp-
toms. Nondermatologic causes were possible, but
classification of patients was not required.
Efficacy outcomes were similar across multiple
measures of pruritus, as well as in the prespecified
subgroup analysis of patients with a history of atopic
diathesis. Statistically significant differences from
baseline VAS pruritus scores were observed as early
as week 3 of treatment and remained 4 weeks
following completion of study treatment, with no
rebound in pruritus observed. The largest reduction
in pruritus scores consistently occurred in the
serlopitant 1- and serlopitant 5-mg groups.
Responder analysis using a 4-cm VAS reduction
threshold demonstrated that a substantial portion of
patients experienced a clinically relevant improve-
ment in symptoms during treatment with serlopitant.
The minimal important difference for clinical
improvement of chronic pruritus ranks between a
drop of 2 to 3 cm on the VAS or 2 to 3 points on the
NRS, as demonstrated in a recent psychometric
study.23,24 In fact, a score reduction of at least 4 cm
or at least 4 points was recorded at the 5-mg
serlopitant dose for more than 50% of the patients
scored by VAS and nearly 50% of those scored by the
NRS, respectively.
The 25% reduction from baseline in VAS pruritus
score in the placebo group is in line with the average
24% placebo response per a meta-analysis of multi-
ple clinical trials involving patients with chronic
pruritus.25
Although only the serlopitant 1-mg group
showed a statistically significant difference from
the placebo group in overall DLQI score, a number
of individual domain scores did demonstrate statis-
tically significant differences. Several factors may
potentially influence the overall DLQI scores. The
J AM ACAD DERMATOL
MAY 2018
DLQI is widely used for the evaluation of quality of
life in patients with pruritic conditions; however,
concerns have been raised regarding the lack of
unidimensionality and item bias based on age, sex,
and nationality.26-28 Whether this affected results
from this study has not been determined. The
incidence of insomnia was reduced by more than
50% in the serlopitant 1- and serlopitant 5-mg
treatment arms at 6 weeks on the basis of responses
to the PSSQ-I questionnaire, indicating significant
symptomatic relief (Supplemental Fig 1). The PGA
did not show a statistically significant effect at week
6; however, skin lesions were not required for
inclusion and not all patients had skin lesions at
study entry.
Serlopitant was well tolerated; the most common
treatment-emergent adverse events in the active-
treatment groups were somnolence and diarrhea.
The present study affirmed the safety profile of
serlopitant; additionally, its safety is supported
by data from multiple phase 1 (unpublished) and
phase 2 trials that enrolled more than 1000 patients,
some of whom took serlopitant for up to 1 year.17
Because of the complex and multifactorial nature
of pruritus pathogenesis, treatment of pruritus,
especially severe and/or chronic pruritus, can be
challenging.1,29,30 Many of the currently available
therapies used for chronic pruritus have limited
efficacy, and some have significant side effects.1,31
Therefore, there is a significant unmet need for a
safe, effective treatment for chronic pruritus.
In conclusion, serlopitant, a novel, potent, oral
NK1R antagonist, was well tolerated and demon-
strated positive results in the treatment of severe
chronic pruritus in this multicenter, placebo-
controlled, double-blind, randomized clinical trial.
Additional studies of serlopitant for the treatment of
pruritus are currently underway.
The authors would like to thank the Almac Group (for
patient randomization and material logistics), Novella
Clinical (formerly TKL Research, Inc, for research site and
data collection management), and HPA Inc and Joe
Hirman, PhD (for statistical analysis) for their contributions
to the study and manuscript. Medical writing and editorial
assistance were provided by Kristina Wasson-Blader, PhD,
Davelene Israel-Hanniford, PhD (ApotheCom), and
Stephanie Leveene (ApotheCom), and funded by Menlo
Therapeutics.
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2013;368(17):1625-1634.
2. Mollanazar NK, Smith PK, Yosipovitch G. Mediators of chronic
pruritus in atopic dermatitis: getting the itch out? Clin Rev
Allergy Immunol. 2016;51(3):263-292.
J AM ACAD DERMATOL
VOLUME 78, NUMBER 5
3. Matterne U, Apfelbacher CJ, Loerbroks A, et al. Prevalence,
correlates and characteristics of chronic pruritus: a population-
based cross-sectional study. Acta Derm Venereol. 2011;91(6):
674-679.
4. Furue M, Ebata T, Ikoma A, et al. Verbalizing extremes of the
visual analogue scale for pruritus: a consensus statement. Acta
Derm Venereol. 2013;93(2):214-215.
5. Grundmann S, St€ander S. Chronic pruritus: clinics and treat-
ment. Ann Dermatol. 2011;23(1):1-11.
6. Bautista DM, Wilson SR, Hoon MA. Why we scratch an itch: the
molecules, cells and circuits of itch. Nat Neurosci. 2014;17(2):
175-182.
7. Ikoma A, Steinhoff M, St€ander S, Yosipovitch G, Schmelz M.
The neurobiology of itch. Nat Rev Neurosci. 2006;7(7):
535-547.
8. Andoh T, Nagasawa T, Satoh M, Kuraishi Y. Substance P
induction of itch-associated response mediated by cutaneous
NK1 tachykinin receptors in mice. J Pharmacol Exp Ther. 1998;
286(3):1140-1145.
9. Steinhoff M, von Mentzer B, Geppetti P, Pothoulakis C,
Bunnett NW. Tachykinins and their receptors: contributions
to physiological control and the mechanisms of disease.
Physiol Rev. 2014;94(1):265-301.
10. St€ander S, Siepmann D, Herrgott I, Sunderk€ otter C, Luger TA.
Targeting the neurokinin receptor 1 with aprepitant: a novel
antipruritic strategy. PLoS One. 2010;5(6):e10968.
11. Lotts T, St€ander S. Research in practice: substance P
antagonism in chronic pruritus. J Dtsch Dermatol Ges. 2014;
12(7):557-559.
12. Duval A, Dubertret L. Aprepitant as an antipruritic agent?
N Engl J Med. 2009;361(14):1415-1416.
13. Booken N, Heck M, Nicolay JP, Klemke CD, Goerdt S, Utikal J.
Oral aprepitant in the therapy of refractory pruritus in
erythrodermic cutaneous T-cell lymphoma. Br J Dermatol.
2011;164(3):665-667.
14. Ally MS, Gamba CS, Peng DH, Tang JY. The use of aprepitant in
brachioradial pruritus. JAMA Dermatol. 2013;149(5):627-628.
15. Emend [package insert]. Whitehouse Station, NJ: Merck Sharp
& Dohme Corp; 2017.
16. Mir O, Coriat R. Aprepitant for pruritus: drugedrug interactions
matter. Lancet Oncol. 2012;13(10):964-965.
17. Frenkl TL, Zhu H, Reiss T, Seltzer O, Rosenberg E, Green S. A
multicenter, double-blind, randomized, placebo controlled
trial of a neurokinin-1 receptor antagonist for overactive
bladder. J Urol. 2010;184(2):616-622.
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18. Weisshaar E, Szepietowski JC, Darsow U, et al. European
guideline on chronic pruritus. Acta Derm Venereol. 2012;
92(5):563-581.
19. Lugon JR. Uremic pruritus: a review. Hemodial Int. 2005;9(2):
180-188.
20. Bergasa NV. The itch of liver disease. Semin Cutan Med Surg.
2011;30(2):93-98.
21. Finlay AY, Basra MKA, Piguet V, Salek MS. Dermatology Life
Quality Index (DLQI): a paradigm shift to patient-centered
outcomes. J Invest Dermatol. 2012;132(10):2464-2645.
22. Okun ML, Kravitz HM, Sowers MF, Moul DE, Buysse DJ, Hall M.
Psychometric evaluation of the Insomnia Symptom Question-
naire: a self-report measure to identify chronic insomnia. J Clin
Sleep Med. 2009;5(1):41-51.
23. Reich A, Riepe C, Anastasiadou Z, et al. Itch assessment with
visual analogue scale and numerical rating scale: determina-
tion of minimal clinically important difference in chronic itch.
Acta Derm Venereol. 2016;96(7):978-980.
24. Kimball AB, Naegeli AN, Edson-Heredia E, et al. Psychometric
properties of the Itch Numeric Rating Scale in patients with
moderate-to-severe plaque psoriasis. Br J Dermatol. 2016;
175(1):157-162.
25. van Laarhoven AIM, van der Sman-Mauriks IM, Donders ART,
Pronk MC, van de Kerkhof PCM, Evers AWM. Placebo effects on
itch: a meta-analysis of clinical trials of patients with derma-
tological conditions. J Invest Dermatol. 2015;135(5):1234-1243.
26. Liu Y, Li T, An J, Zeng W, Xiao S. Rasch analysis holds no brief for
the use of the Dermatology Life Quality Index (DLQI) in Chinese
neurodermatitis patients. Health Qual Life Outcomes. 2016;14:17.
27. Twiss J, Meads DM, Preston EP, Crawford SR, McKenna SP. Can
we rely on the Dermatology Life Quality Index as a measure of
the impact of psoriasis or atopic dermatitis? J Invest Dermatol.
2012;132(1):76-84.
28. Nijsten T, Meads DM, de Korte J, et al. Cross-cultural inequivalence
of dermatology-specific health-related quality of life instruments
in psoriasis patients. J Invest Dermatol. 2007;127(10):2315-2322.
29. St€ander S, Weisshaar E, Mettang T, et al. Clinical classification
of itch: a position paper of the International Forum for the
Study of Itch. Acta Derm Venereol. 2007;87(4):291-294.
30. St€ander S, Weisshaar E, Luger TA. Neurophysiological and
neurochemical basis of modern pruritus treatment. Exp
Dermatol. 2008;17(3):161-169.
31. Stull C, Lavery MJ, Yosipovitch G. Advances in therapeutic
strategies for the treatment of pruritus. Expert Opin Pharmacother.
2016;17(5):671-687.
891.e1 Yosipovitch et al
SUPPLEMENTAL DATA: METHODS
Randomization and masking
Randomization was performed by using the
Almac Group, Inc (Craigavon, UK) validated
interactive web-based response system IXRS, which
automates the random assignment of treatment
groups to bottle numbers that are blinded to
investigators and patients by encoding (Almac
Clinical Technologies, Souderton, PA). Treatment
assignment was concealed from the patients, the
investigators and their staff, and the clinical research
team. The placebo tablets were formulated to be
indistinguishable from serlopitant tablets (Almac,
Craigavon, UK).
Procedures
Patients using stable doses of midpotency topical
steroids at screening could continue their use
during the study, and they could also continue the
use of lotions. Dose selection was based on an
unpublished phase 1 Merck study measuring brain
neurokinin 1 receptor occupancy of serlopitant.
Positron emission tomography quantified neuro-
kinin 1 receptor blockade by serlopitant using a
tracer molecule, 18[F]SPA-RQ. After 14 days of
dosing in healthy young men, a 5-mg dose of
serlopitant achieved more than 94% brain receptor
occupancy. Although the dosing required to
suppress pruritic activity is unknown, the expected
brain receptor occupancy for the 0.25-mg and 1-mg
doses are 46% and 75%, respectively. Loading dose
was administered at the study site. In the present
study, a pharmacokinetic analysis was conducted at
4 weeks to analyze blood serum levels.
In the Pittsburgh Sleep Symptom Questionnaire-
Insomnia (PSSQ-I), sleep disorders were characterized
in terms of sleep symptom criteria, duration criteria,
daytime impairment criteria, and overall insomnia
disorder. The Physician’s Global Assessment survey
provided a measure of skin condition in the pruritic
area(s). The investigators were instructed to record no
change from baseline at postbaseline assessments for
patients who had no visibly affected skin at baseline,
as skin cannot improve from normal-appearing/not
affected. Any worsening of the skin condition would
be recorded as a negative change.
Statistical analysis
The sample size was based on a 2-sided alpha
level of 5% and 80% power, a 10% dropout rate, a
mean percent reduction of 50% for serlopitant versus
30% for placebo, and a standard deviation of 35.5.
Sample size estimates were based on published
data from an open-label study using aprepitant.S1
J AM ACAD DERMATOL
MAY 2018
All statistical analyses were conducted with SAS
software (version 9.1 or higher, SAS Institute Inc,
Cary, NC).
Primary efficacy
The primary efficacy variable, pruritus severity as
measured on a visual analog scale (VAS), was
recorded twice daily in an electronic diary. These
measures were combined to make daily and weekly
measures by averaging the available results on the
given study days and study weeks. The weekly
measures were used to create the primary percent-
age change from baseline end point. The statistical
analysis of the primary efficacy VAS end point was
prepared by using a repeated measures linear
mixed-effects model ‘‘mixed model.’’ A cell means
parameterization, with a parameter for each
combination of dose and week, and a random effect
for patient was used. Estimates of treatment effect
on VAS were prepared by using pairwise estimates
of differences (difference of least square means)
between each dose and placebo at each study week.
Confidence intervals and P values for each pairwise
2-sided comparison of serlopitant dose versus
placebo for each week were produced. The primary
time point of interest was week 6. Multiplicity
adjustments for the multiple treatment groups and
time points were not performed. Missing data were
not imputed.
Secondary efficacy
Secondary efficacy end points included the
severity of pruritus as rated by the 11-point numeric
rating scale, the Dermatology Life Quality Index
score, the PSSQ-I, the Subject’s Global Assessment,
and the Physician’s Global Assessment. The Numeric
Rating Scale data were treated as continuous, and a
statistical analysis was prepared by using a linear
mixed-effects model (defined as model I), as
described for the primary efficacy analysis. The
Dermatology Life Quality Index domains were
expressed as a percentage defined in the scoring
instructions. S2 The data were treated as continuous,
and the analysis of the overall score was prepared by
using a linear mixed-effects model (similar to
model I). The PSSQ-I was scored according to
the developer’s instructions, and the data were
summarized by percentage of subjects with insomnia
disorder.
RESULTS
A pharmacokinetic anomaly in which a number of
patients in the serlopitant treatment groups had no
detectable levels of serlopitant in their blood samples
was identified.
J AM ACAD DERMATOL
VOLUME 78, NUMBER 5
A comprehensive, independent audit was con-
ducted; it included a review of compliance at
multiple study sites, study conduct, statistical
programming, monitoring, data management, and
other procedures. The audit determined that the
pharmacokinetic issue was limited to a single site
and confirmed that there were no systemic
compliance issues in the study. Minor statistical
programming errors were identified and corrected.
The independent auditor confirmed the initial
efficacy and safety findings of the study. The
significance and study outcomes are consistent
regardless of whether the patients from this clinical
site were included or excluded from the overall study
population.
Yosipovitch et al 891.e2
LIST OF INVESTIGATORS AND OTHER
IMPORTANT PARTICIPANTS
Patients were enrolled at 26 sites in the United
States; 2 additional sites in Ireland were closed
without any patients being randomized. The names
and institutional affiliations of the principal investi-
gators are listed in Supplemental Table I.
REFERENCES
S1. St€ander S, Siepmann D, Herrgott I, Sunderk€ otter C, Luger TA.
Targeting the neurokinin receptor 1 with aprepitant: a novel
antipruritic strategy. PLoS One. 2010;5(6):e10968.
S2. Finlay AY, Basra MKA, Piguet V, Salek MS. Dermatology Life
Quality Index (DLQI): a paradigm shift to patient-centered
outcomes. J Invest Dermatol. 2012;132(10):2464-2465.
891.e3 Yosipovitch et al J AM ACAD DERMATOL
MAY 2018

50
Placebo 0.25 mg serlopitant 1 mg serlopitant 5 mg serlopitant

45 43.8

40.6
40 39.1
38.5 38.3 *P = .016
ITT population with insomnia disorder, %

Active comparison to placebo

35
32.3
31.6 31.7

30 28.6
28.1
27.4

25.5
25 23.8 23.7
22.8

20.7
20.0
20 19.6

17.2
16.1 *
15 14.0
14.5
13.0

10.5
10

0
Baseline Week 1 Week 2 Week 4 Week 6 Week 10 follow-up

Supplemental Fig 1. Secondary end point results of the Pittsburgh Sleep Symptom Questionnaire-
Insomnia, shown by week and cohort. Results trend toward less insomnia in treatment
arms. Pittsburgh Sleep Symptom Questionnaire-Insomnia results are supportive of other study
findings. No data were collected at weeks 3 and 5, as patients did not visit the clinic then. *P = .016
in comparison with placebo. ITT, Intention-to-treat.
J AM ACAD DERMATOL Yosipovitch et al 891.e4
VOLUME 78, NUMBER 5

Supplemental Table I. Study sites, principal investigators, and site locations

Site Number Principal investigator Site location
01 Diane Baker, MD Baker Allergy, Asthma and Dermatology Research Center, LLC, 3975 SW Mercantile Dr,
Suite 165, Lake Oswego, OR 97035
02 Suzanne Bruce, MD Suzanne Bruce and Associates, PA, 1900 St. James Place, Suite 650, Houston, TX 77056
03 Steven Davis, MD Dermatology Clinical Research Center of San Antonio, 7810 Louis Pasteur Dr, Suite
200, San Antonio, TX 78229
04 Sunil Dhawan, MD Center for Dermatology Clinical Research, Inc, 2557 Mowry Ave, Suite 25, Fremont, CA
94538
05 Zoe Draelos, MD Dermatology Consulting Services, 2444 North Main St, High Point, NC 27262
06 Jeffrey Fromowitz, MD Dermatology of Boca, 4601 North Federal Highway, Boca Raton, FL 33431
07 Richard Gower, MD MaryCliff Allergy Specialist, 823 West 7th Ave, Spokane, WA 99204
08 Steven Grekin, DO Grekin Skin Institute, 13450 East 12 Mile Rd, Warren, MI 48088
09 Scott Guenthner, MD The Indiana Clinical Trials Center, PC, 1100 Southfield Dr, Suite 1240, Plainfield, IN
46168
10 David Hassman, DO Comprehensive Clinical Research, 175 Cross Keys Rd, Centennial Center Building,
Room 300B, Berlin, NJ 08009
11 Steven Kempers, MD Minnesota Clinical Study Center, 7205 University Ave NE, Fridley, MN 55432
12 Yvonne Knight, MD WestEnd Dermatology Associates, 3811 Gaskins Rd, Richmond, VA 23233
13 Edward Lain, MD Pflugerville Dermatology, 302 North Heatherwilde Blvd, Suite 200, Pflugerville, TX
78660
14 Robert Nossa, MD The Dermatology Group PC, 60 Pompton Ave, Verona, NJ 07044
15 Marina Raikhel, MD Torrance Clinical Research Institute Inc, 25043 Narbonne Ave, Lomita, CA 90717
16 Marta Rendon, MD Skin Care Research, 880 NW 13th St, #3C, Boca Raton, FL 33486
17 Stephen Shideler, MD Shideler Clinical Research Center, 755 West Carmel Dr, Suite 101, Carmel, IN 46032
18 Tissa Hata, MD University of California San Diego Dermatology, 8899 University Center Lane, Suite
350, San Diego, CA 92122
19 Herschel Stoller, MD Quality Clinical Research Inc, 10110 Nicholas St, Suite 103, Omaha, NE 68114
20 Jean Tang, MD* Stanford Medicine Outpatient Center, Medical Dermatology, 450 Broadway St,
Redwood City, CA 94063
21 John H. Tu, MD Skin Search of Rochester, Inc., 100 White Spruce Blvd, Rochester, NY 14623
22 Kelley Yokum, MD Olympian Clinical Research, 4238 West Kennedy Blvd, Tampa, FL 33609
23 Jaime Weisman, MD Advanced Medical Research, Inc., 875 Johnson Ferry Rd, Suite 180, Atlanta, GA 30342
24 Gil Yosipovitch, MD* Temple University, 3322 North Broad St, Suite 212, Philadelphia, PA 19140
25 Artis Truett III, MD Pedia Research, LLC, 2821 New Harford Rd, Owensboro, KY 42303
(site closed)
26 Brian Berman, MD The Center for Clinical and Cosmetic Research, 2925 Aventura Blvd, Suite 205,
Aventura, FL 33180
27 Professor Martin University College Dublin Clinical Research Centre, Mater Misericordiae University
Steinhoff Hospital, Catherine McAuley Education and Research Centre, 21 Nelson St, Dublin
(site closed)* D07 A8NN, Ireland
28 Professor Martin University College Dublin Clinical Research Centre, St Vincent’s University Hospital,
Steinhoff Elm Park, Dublin D04 YN26, Ireland
(site closed)*

*Member of the Menlo Therapeutics Inc Scientific Advisory Board.

891.e5 Yosipovitch et al J AM ACAD DERMATOL
MAY 2018

Supplemental Table II. Summary of medical history: Skin and subcutaneous tissue disorders in the safety
population
Serlopitant
Combined
serlopitant-treated
Dermatologic disorders Placebo (n = 63) 0.25 mg (n = 64) 1 mg (n = 65) 5 mg (n = 64) population (n = 193)
Skin and subcutaneous tissue disorders 33 (52.4) 34 (53.1) 31 (47.7) 27 (42.2) 92 (47.7)
Atopic dermatitis* 21 (33.3) 22 (34.4) 21 (32.3) 17 (26.5) 60 (31.1)
Various types of eczemay 6 (9.5) 2 (3.1) 6 (9.2) 4 (6.3) 12 (6.2)
Miscellaneousz 6 (9.5) 4 (6.3) 6 (9.2) 3 (4.7) 13 (6.7)
Psoriasis 5 (7.9) 5 (7.8) 5 (7.7) 3 (4.7) 13 (6.7)
Acne 2 (3.2) 1 (1.6) 4 (6.2) 2 (3.1) 7 (3.6)
Dry skin 0 1 (1.6) 3 (4.6) 0 4 (2.1)
Lichenification 1 (1.6) 0 1 (1.5) 3 (4.7) 4 (2.1)
Keloid scar 0 1 (1.6) 0 2 (3.1) 3 (1.6)
Seborrheic dermatitis 1 (1.6) 2 (3.1) 1 (1.5) 0 3 (1.6)
Alopecia 1 (1.6) 1 (1.6) 1 (1.5) 0 2 (1.0)
Lichen planus 1 (1.6) 2 (3.1) 0 0 2 (1.0)
Actinic keratosis 1 (1.6) 0 0 1 (1.6) 1 (0.5)
Alopecia areata 0 1 (1.6) 0 0 1 (0.5)
Cutaneous lupus erythematosus 0 0 1 (1.5) 0 1 (0.5)
Hidradenitis 0 1 (1.6) 0 0 1 (0.5)
Idiopathic angioedema 0 0 1 (1.5) 0 1 (0.5)
Milia 0 1 (1.6) 0 0 1 (0.5)
Palmoplantar keratoderma 0 0 1 (1.5) 0 1 (0.5)
Rosacea 0 1 (1.6) 0 0 1 (1.5)
Sebaceous gland disorder 0 1 (1.6) 0 0 1 (0.5)
Urticaria 1 (1.6) 0 0 1 (1.6) 1 (0.5)
Keratosis pilaris 2 (3.2) 0 0 0 0
Mechanical urticaria 1 (1.6) 0 0 0 0
Photosensitivity reaction 1 (1.6) 0 0 0 0
Stasis dermatitis 1 (1.6) 0 0 0 0
Vitiligo 1 (1.6) 0 0 0 0

Data are expressed as n (%).

MedDRA, Medical Dictionary for Regulatory Activities.
*Includes MedDRA terms dermatitis atopic, eczema, and neurodermatitis.
y
Includes MedDRA terms dermatitis, dermatitis contact, dyshidrotic eczema, eczema asteatotic, eczema nummular.
z
Includes MedDRA terms pruritus, erythema, rash, rash erythematous, rash pruritic, skin hyperpigmentation, skin hypopigmentation,
trichorrhexis, hyperkeratosis, petechiae.
J AM ACAD DERMATOL Yosipovitch et al 891.e6
VOLUME 78, NUMBER 5

Supplemental Table III. Most frequent concomitant medications in the safety population
Serlopitant
Combined
serlopitant-treated
Concomitant medications Placebo (n = 63) 0.25 mg (n = 64) 1 mg (n = 65) 5 mg (n = 64) population (n = 193)
Patients taking any concomitant medication 38 (60.3) 47 (73.4) 49 (75.4) 38 (59.4) 134 (69.4)
Anti-inflammatory and antirheumatic 8 (12.7) 13 (20.3) 17 (26.2) 7 (10.9) 37 (19.2)
products
Ibuprofen 6 (9.5) 7 (10.9) 8 (12.3) 5 (7.8) 20 (10.4)
Naproxen sodium 4 (6.3) 2 (3.1) 2 (3.1) 0 4 (2.1)
Naproxen 0 0 5 (7.7) 1 (1.6) 6 (3.1)
Corticosteroids, dermatologic preparations 8 (12.7) 8 (12.5) 11 (16.9) 8 (12.5) 27 (14.0)
Triamcinolone 3 (4.8) 3 (4.7) 5 (7.7) 2 (3.1) 10 (5.2)
Hydrocortisone 1 (1.6) 4 (6.3) 4 (6.2) 1 (1.6) 9 (4.7)
Vitamins 10 (15.9) 4 (6.3) 8 (12.3) 7 (10.9) 19 (9.8)
Multivitamins, plain 7 (11.1) 3 (4.7) 6 (9.2) 4 (6.3) 13 (6.7)
Drugs for acid-related disorders 6 (9.5) 5 (7.8) 9 (13.8) 3 (4.7) 17 (8.8)
Omeprazole 4 (6.3) 4 (6.3) 3 (4.6) 1 (1.6) 8 (4.1)
Agents acting on the renin-angiotensin 5 (7.9) 9 (14.1) 4 (6.2) 4 (6.3) 17 (8.8)
system
Lisinopril 1 (1.6) 4 (6.3) 2 (3.1) 2 (3.1) 8 (4.1)
Drugs for obstructive airway diseases 4 (6.3) 4 (6.3) 9 (13.8) 3 (4.7) 16 (8.3)
Salbutamol 1 (1.6) 1 (1.6) 6 (9.2) 1 (1.6) 8 (4.1)
Diuretics 4 (6.3) 2 (3.1) 4 (6.2) 6 (9.4) 12 (6.2)
Hydrochlorothiazide 3 (4.8) 0 3 (4.6) 5 (7.8) 8 (4.1)
Drugs used in diabetes 3 (4.8) 9 (14.1) 3 (4.6) 1 (1.6) 13 (6.7)
Metformin 2 (3.2) 5 (7.8) 3 (4.6) 1 (1.6) 9 (4.7)
Antianemic preparations 5 (7.9) 2 (3.1) 3 (4.6) 3 (4.7) 8 (4.1)
Cyanocobalamin 5 (7.9) 1 (1.6) 2 (3.1) 0 3 (1.6)
Antithrombotics 4 (6.3) 2 (3.1) 5 (7.7) 1 (1.6) 8 (4.1)
Acetylsalicylic acid 3 (4.8) 2 (3.1) 5 (7.7) 1 (1.6) 8 (4.1)

Data are expressed as n (%). Concomitant medications are defined as medications having stop dates on or after the start of study medication.
891.e7 Yosipovitch et al J AM ACAD DERMATOL
MAY 2018

Supplemental Table IV. Summary of all AEs in study patients

Serlopitant
AEs Placebo (n = 63) 0.25 mg (n = 64) 1 mg (n = 65) 5 mg (n = 64)
Patients with any AE, n (%) 16 (25.4) 21 (32.8) 24 (36.9) 24 (37.5)
Number of AEs 33 35 50 37
Patients with any treatment-emergent AE, n (%) 16 (25.4) 21 (32.8) 24 (36.9) 24 (37.5)
Number of AEs 33 35 50 37
Patients with any treatment-related TEAE, n (%)* 6 (9.5) 7 (10.9) 9 (13.8) 8 (12.5)
Number of AEs 7 10 13 14
Patients with any serious TEAE, n (%) 0 0 1 (1.5) 0
Number of serious TEAEs 0 0 1 0
Patients with any severe TEAE, n (%) 0 1 (1.6) 0 1 (1.6)
Number of severe TEAEs 0 1 0 1
Patients with any TEAE leading to discontinuation of 2 (3.2) 1 (1.6) 1 (1.5) 2 (3.1)
study medication, n (%)
Number of TEAEs leading to discontinuation of 3 1 1 1
study medication

AE, Adverse event; TEAE, treatment-emergent adverse event.

*Treatment-related TEAEs include definitely related, probably related, and possibly related events.
J AM ACAD DERMATOL Yosipovitch et al 891.e8
VOLUME 78, NUMBER 5

Supplemental Table V. Percentage change from baseline in VAS pruritus score using linear mixed-effects
model (cell means)dITT population by treatment week
Serlopitant
Week Parameter Placebo (n = 63) 0.25 mg (n = 64) 1 mg (n = 63) 5 mg (n = 63)
Model I: cell means*
1 LS means 4.1 9.1 11.8 12.0
Standard error 3.9 3.9 3.9 3.9
Pairwise LS mean difference (95% CI)y d 5.0 ( 5.9 to 15.8) 7.6 ( 3.2 to 18.5) 7.8 ( 3.0 to 18.7)
P value d .368 .168 .157
2 LS means 12.1 14.9 22.0 20.3
Standard error 4.0 4.0 4.0 4.0
Pairwise LS mean difference (95% CI)y d 2.8 ( 8.3 to 13.8) 9.9 ( 1.1 to 20.9) 8.2 ( 2.8 to 19.2)
P value d .625 .079 .144
3 LS means 18.7 21.4 30.2 28.8
Standard error 4.0 4.0 4.0 4.0
Pairwise LS mean difference (95% CI)y d 2.7 ( 8.4 to 13.8) 11.5 (0.4-22.6) 10.1 ( 1.0 to 21.2)
P value d .637 .042 .073
4 LS means 21.6 29.0 33.1 34.2
Standard error 4.0 4.0 4.0 4.0
Pairwise LS mean difference (95% CI)y d 7.4 ( 3.7 to 18.5) 11.5 (0.5-22.6) 12.6 (1.5-23.7)
P value d .191 .040 .026
5 LS means 25.8 32.4 38.0 37.3
Standard error 4.0 4.0 4.0 4.0
Pairwise LS mean difference (95% CI)y d 6.6 ( 4.6 to 17.7) 12.2 (1.0-23.4) 11.4 (0.2-22.6)
P value d .248 .033 .045
6 LS means 28.3 34.1 41.4 42.5
Standard error 4.1 4.1 4.0 4.1
Pairwise LS mean difference (95% CI)y d 5.8 ( 5.4-17.1) 13.2 (1.9-24.4) 14.2 (3.0-25.5)
P value d .309 .022 .013
10 LS means 31.0 38.4 41.5 42.7
Standard error 4.1 4.0 4.0 4.1
Pairwise LS mean difference (95% CI)y d 7.4 ( 3.8 to 18.6) 10.5 ( 0.7 to 21.8) 11.7 (0.4-23.0)
P value d .194 .066 .042

The VAS from the e-diary was recorded in millimeters. One patient from the placebo group (20-004), 2 from the serlopitant 1-mg group (04-
003 and 12-010), and 1 from the serlopitant 5-mg group (12-014), although part of the ITT population were removed from the analysis.
Patient 20-004 was randomized in error and did not receive study medication, patient 04-003 did not receive an e-diary during screening
and had no baseline data, and patients 12-010 and 12-014 did not complete any e-diary information after screening.
CI, Confidence interval; e-diary, electronic diary; ITT, intention-to-treat; LS, least squares; VAS, visual analog scale.
*Model 1 included a parameter for each combination of dose and week and a random effect for patient.
y
Placebo group is the reference.
891.e9 Yosipovitch et al J AM ACAD DERMATOL
MAY 2018

Supplemental Table VI. Percentage change from baseline in NRS score using linear mixed-effects model (cell
means)dITT population by treatment week
Serlopitant
Week Parameter Placebo (n = 63) 0.25 mg (n = 64) 1 mg (n = 63) 5 mg (n = 63)
Model I: cell means*
1 LS means 7.1 11.0 12.3 11.8
Standard error 3.4 3.4 3.4 3.4
Pairwise LS mean difference (95% CI)y d 4.0 ( 5.5 to 13.5) 5.3 ( 4.2 to 14.7) 4.7 ( 4.8 to 14.2)
P value d .408 .276 .329
2 LS means 14.7 16.8 21.4 20.6
Standard error 3.4 3.5 3.5 3.4
Pairwise LS mean difference (95% CI)y d 2.0 ( 7.6 to 11.6) 6.6 ( 3.0 to 16.2) 5.8 ( 3.7 to 15.4)
P value d .683 .175 .232
3 LS means 20.6 23.3 29.1 28.2
Standard error 3.5 3.5 3.5 3.5
Pairwise LS mean difference (95% CI)y d 2.7 ( 7.0 to 12.3) 8.5 ( 1.1 to 18.1) 7.6 ( 2.0 to 17.3)
P value d .589 .083 .119
4 LS means 22.2 30.4 32.0 32.3
Standard error 3.4 3.5 3.5 3.5
Pairwise LS mean difference (95% CI)y d 8.2 ( 1.5 to 17.8) 9.8 (0.2-19.4) 10.0 (0.4-19.7)
P value d .097 .045 .041
5 LS means 26.4 32.7 36.3 36.0
Standard error 3.5 3.5 3.5 3.5
Pairwise LS mean difference (95% CI)y d 6.3 ( 3.4 to 15.9) 9.9 (0.3-19.6) 9.7 (0.0-19.3)
P value d .203 .044 .050
6 LS means 28.7 35.8 39.4 39.0
Standard error 3.5 3.5 3.5 3.5
Pairwise LS mean difference (95% CI)y d 7.1 ( 2.7 to 16.9) 10.7 (1.0-20.4) 10.3 (0.6-20.1)
P value d .153 .031 .038

NRS baseline is defined as the last measurement before day 1. One patient from the placebo group (20-004), 2 from the serlopitant 1-mg
group (04-003 and 12-010), and 1 from the serlopitant 5-mg group (12-014), although part of the ITT population were removed from the
analysis. Patient 20-004 was randomized in error and did not receive study medication, patient 04-003 did not receive an e-diary during
screening and had no baseline data, and patients 12-010 and 12-014 did not complete any e-diary information after screening.
CI, Confidence interval; e-diary, electronic diary; ITT, intention-to-treat; LS, least-squares; NRS, numeric rating scale.
*Model 1 included a parameter for each combination of dose and week and a random effect for patient.
y
Placebo group is the reference.
J AM ACAD DERMATOL Yosipovitch et al 891.e10
VOLUME 78, NUMBER 5

Supplemental Table VII. Change from baseline in overall DLQI score using linear mixed-effects model (cell
means)dITT population by treatment week
Serlopitant
Week Parameter Placebo (n = 63) 0.25 mg (n = 64) 1 mg (n = 65) 5 mg (n = 64)
Model I: cell means*
0 LS means 44.4 41.0 44.5 45.9
Standard error 2.6 2.6 2.6 2.6
Pairwise LS mean difference (95% CI)y d 3.3 ( 3.9 to 10.6) 0.1 ( 7.3 to 7.2) 1.6 ( 8.8 to 5.7)
P value d .368 .982 .674
1 LS means 31.4 24.3 26.9 28.9
Standard error 2.7 2.7 2.6 2.6
Pairwise LS mean difference (95% CI)y d 7.1 ( 0.3 to 14.5) 4.5 ( 2.8 to 11.8) 2.6 ( 4.8 to 9.9)
P value d .061 .230 .493
2 LS means 26.2 22.0 21.1 21.9
Standard error 2.7 2.7 2.6 2.7
Pairwise LS mean difference (95% CI)y d 4.2 ( 3.2 to 11.6) 5.1 ( 2.2 to 12.5) 4.3 ( 3.1 to 11.7)
P value d .264 .170 .256
4 LS means 24.6 18.1 16.3 19.7
Standard error 2.7 2.7 2.7 2.7
Pairwise LS mean difference (95% CI)y d 6.5 ( 0.9 to 14.0) 8.3 (0.9-15.8) 4.9 ( 2.6 to 12.3)
P value d .087 .028 .201
6 LS means 20.6 14.9 13.7 16.4
Standard error 2.7 2.7 2.7 2.7
Pairwise LS mean difference (95% CI)y d 5.6 ( 1.8 to 13.1) 6.8 ( 0.6 to 14.3) 4.2 ( 3.3 to 11.7)
P value d .138 .073 .277
10 LS means 20.2 15.8 17.9 16.2
Standard error 2.7 2.7 2.7 2.7
Pairwise LS mean difference (95% CI)y d 4.5 ( 3.0 to 12.0) 2.3 ( 5.2 to 9.8) 4.0 ( 3.5 to 11.6)
P value d .241 .543 .295

CI, Confidence interval; DLQI, Dermatology Life Quality Index; ITT, intention-to-treat; LS, least squares.
*Model 1 included a parameter for each combination of dose and week and a random effect for patient.
y
Placebo group is the reference.