Efficacy of Roflumilast Foam, 0.3%, in Patients With Seborrheic Dermatitis

3/10/23, 21:11 Efficacy of Roflumilast Foam, 0.
3%, in Patients With Seborrheic Dermatitis - PMC
JAMA Dermatology
JAMA Dermatol. 2023 Jun; 159(6): 613–620. PMCID: PMC10157502

Published online 2023 May 3. doi: 10.1001/jamadermatol.2023.0846: PMID: 37133856
10.1001/jamadermatol.2023.0846
Efficacy of Roflumilast Foam, 0.3%, in Patients With Seborrheic Dermatitis

A Double-blind, Vehicle-Controlled Phase 2a Randomized Clinical Trial
Matthew J. Zirwas, MD, 1 , 2 , 3 Zoe D. Draelos, MD, 4 Janet DuBois, MD, 5 Leon H. Kircik, MD, 6 , 7 , 8 , 9
Angela Y. Moore, MD, 10 , 11 Linda Stein Gold, MD, 12 Javier Alonso-Llamazares, MD, PhD, 13 Michael Bukhalo, MD, 14
Suzanne Bruce, MD, 15 Kimmie Eads, MSN, 16 Lawrence J. Green, MD, 17 Scott T. Guenthner, MD, 18 , 19
Laura K. Ferris, MD, PhD, 20 Seth B. Forman, MD, 21 Steven E. Kempers, MD, 22 Edward Lain, MD, 23
Charles W. Lynde, MD, 24 , 25 , 26 David M. Pariser, MD, 27 , 28 Darryl P. Toth, MD, 29 , 30 Paul S. Yamauchi, MD, PhD, 31 ,
32
Robert C. Higham, MPAS, 33 David Krupa, MS, 33 Patrick Burnett, MD, PhD, 33 and David R. Berk, MD 33
1
Dermatologists of the Central States, Bexley, Ohio
2
Probity Medical Research, Bexley, Ohio
3
Ohio University, Bexley
4
Dermatology Consulting Services, High Point, North Carolina
5
DermResearch, Inc, Austin, Texas
6
Icahn School of Medicine at Mount Sinai, New York, New York
7
Physicians Skin Care, PLLC, Louisville, Kentucky
8
Indiana Medical Center, Indianapolis
9
Skin Sciences, PLLC, Louisville, Kentucky
10
Arlington Center for Dermatology, Arlington Research Center, Arlington, Texas
11
Baylor University Medical Center, Dallas, Texas
12
Henry Ford Medical Center, Detroit, Michigan
13
Driven Research LLC, Coral Gables, Florida
14
Arlington Dermatology, Rolling Meadows, Illinois
15
SBA Dermatology, Houston, Texas
16
The Indiana Clinical Trials Center, PC, Plainfield
17
George Washington University School of Medicine, Rockville, Maryland
18
The Dermatology Center of Indiana, PC, Plainfield
19
The Indiana Clinical Trials Center, PC, Plainfield
20
University of Pittsburgh, Department of Dermatology, Pittsburgh, Pennsylvania
21ForCare Medical Center, Tampa, Florida
22
Minnesota Clinical Study Center, Fridley
23
Sanova Dermatology, Austin, Texas
24University of Toronto, Toronto, Ontario, Canada
25
Lynde Centre for Dermatology, Markham, Ontario, Canada
26
Probity Medical Research, Markham, Ontario, Canada
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10157502/?report=printable 1/19
3/10/23, 21:11 Efficacy of Roflumilast Foam, 0.3%, in Patients With Seborrheic Dermatitis - PMC
27
Eastern Virginia Medical School, Norfolk
28Virginia Clinical Research, Inc, Norfolk
29
XLR8 Medical Research, Windsor, Ontario, Canada
30
Probity Medical Research, Windsor, Ontario, Canada
31David Geffen School of Medicine at UCLA, Los Angeles, California
32
Dermatology Institute & Skin Care Center, Inc, Santa Monica, California
33
Arcutis Biotherapeutics, Inc, Westlake Village, California
Corresponding author.
Article Information
Accepted for Publication: March 1, 2023.
Published Online: May 3, 2023. doi:10.1001/jamadermatol.2023.0846
Open Access: This is an open access article distributed under the terms of the CC-BY-NC-ND License. © 2023 Zirwas
MJ et al. JAMA Dermatology.
Corresponding Author: Matthew J. Zirwas, MD, Dermatologists of the Central States, Probity Medical Research, and
Ohio University, 2359 E Main St, Bexley, OH 43209 ([email protected]).
Author Contributions: Dr Zirwas had full access to all of the data in the study and takes responsibility for the integrity
of the data and the accuracy of the data analysis.
Concept and design: Alonso-Llamazares, Bukhalo, Lain, Lynde, Yamauchi, Higham, Burnett, Berk.
Acquisition, analysis, or interpretation of data: Zirwas, Draelos, DuBois, Kircik, Moore, Stein Gold, Bruce, Eads, Green,
Guenthner, Ferris, Forman, Kempers, Lain, Lynde, Pariser, Toth, Yamauchi, Higham, Krupa, Burnett, Berk.
Drafting of the manuscript: Moore, Stein Gold, Green, Lain, Toth, Higham, Burnett.
Critical revision of the manuscript for important intellectual content: Zirwas, Draelos, DuBois, Kircik, Moore, Alonso-
Llamazares, Bukhalo, Bruce, Eads, Green, Guenthner, Ferris, Forman, Kempers, Lain, Lynde, Pariser, Toth, Yamauchi,
Higham, Krupa, Burnett, Berk.
Statistical analysis: Lynde, Krupa, Berk.
Obtained funding: Draelos.
Administrative, technical, or material support: Bukhalo, Bruce, Forman, Lain, Yamauchi, Higham, Burnett, Berk.
Supervision: Kircik, Moore, Alonso-Llamazares, Green, Lain, Burnett, Berk.
Conflict of Interest Disclosures: Dr Zirwas reported being a consultant and investigator for Arcutis Biotherapeutics
(no payment for this work in particular, but was an investigator in this trial) during the conduct of the study; grants from
Amgen and UCB; and personal fees from AbbVie, Dermavant, EPI Health, Galderma, Genentech/Novartis, Incyte,
L’Oréal, Lilly, Pfizer, Regeneron, and Sanofi outside the submitted work. Dr Draelos reported grants from Arcutis
Biotherapeutics during the conduct of the study and outside the submitted work. Dr DuBois reported grants from Arcutis
Biotherapeutics during the conduct of the study; grants from AbbVie, AiViva, Allergan, Almirall, AnaptysBio, Bausch
Health, Biofrontera, Bristol Myers Squibb (BMS), Caliway Biopharmaceuticals Co, Cara Therapeutics, Croma-Pharma
GmbH Austria, Dermata Therapeutics, DermBiont, Dr Reddy, Endo Pharmaceuticals, Evommune, Galderma USA, Leo
Laboratories (LEO Pharma), Merck, Palvella Therapeutics, RAPT Therapeutics, and Therapeutics Inc outside the sub-
mitted work. Dr Moore reported grants from Arcutis Biotherapeutics outside the submitted work. Dr Stein Gold reported
grants and personal fees from Arcutis Biotherapeutics during the conduct of the study; grants from Dermavant, AbbVie,
and Lilly; and personal fees from Dermavant, LEO Pharma, Ortho, Pfizer, outside the submitted work. Dr Alonso-
Llamazares reported having participated as a principal investigator in the clinical trials of Arcutis Biotherapeutics related
to roflumilast on this work and others and serving on the speakers bureau of Arcutis Biotherapeutics on roflumilast. Dr
Bukhalo reported grants from Arcutis Biotherapeutics during the conduct of the study; and grants from Johnson &
Johnson, Alumis, AbbVie, Eli Lilly, Ventyx, and Galderma outside the submitted work. Dr Bruce reported grants from
Arcutis Biotherapeutics during the conduct of the study; grants from Mindera, AbbVie, Dr Reddy, Ortho Dermatologics,
Biofrontera, Alumis, Janssen, Timber, Castle, Pfizer, Incyte, Eli Lilly, Concert, AnaptysBio, Galderma, Amgen, Dermira;
and personal fees from AbbVie outside the submitted work. Ms Eads reported grants from Arcutis Biotherapeutics (clini-
cal trial fees as a study investigator) during the conduct of the study. Dr Green reported grants from Arcutis
Biotherapeutics, personal fees from Arcutis Biotherapeutics (adviser and speaker), grants from Dermavant, personal
fees from Dermavant (adviser and speaker), grants from EPI, personal fees from EPI (adviser), and personal fees from
Orthoderm (adviser) outside the submitted work. Dr Guenthner reported grants from Arcutis Biotherapeutics (clinical
trial fees as a study investigator) during the conduct of the study; and speaking and consulting fees from Arcutis
Biotherapeutics outside the submitted work. Dr Ferris reported grants from Arcutis Biotherapeutics during the conduct of
the study; grants from BMS, Amgen, Janssen, Dermavant, UCB, Eli Lilly, AbbVie, and Nimbus; personal fees from
Arcutis Biotherapeutics, BMS, Janssen, Dermavant, Sun Pharma, and AbbVie outside the submitted work. Dr Lain re-
ported personal fees from BMS, Dermavant, Arcutis Biotherapeutics, Eli Lilly, Pfizer, Incyte, Ortho Dermatologics,
Galderma, AbbVie, and EPI Health outside the submitted work. Dr Lynde reported honoraria from Arcutis
Biotherapeutics (consulting, principal investigator, advisory board) during the conduct of the study; honoraria (advisory
board, consulting, speaking, principal investigator) from AbbVie, Amgen, Arcutis Biotherapeutics, Bausch Health, BMS,
Celgene, Dermavant, Eli Lilly, Galderma, Incyte, Innovaderm, Janssen, LEO Pharma, Merck, Novartis, Pfizer, Sanofi,
Sandoz, Sun Pharma, UCB, and Viatris; and other (principal investigator) from Fresenius Kabi and Kyowa Kirin outside
the submitted work. Dr Pariser reported grants from Arcutis Biotherapeutics during the conduct of the study. Dr
Yamauchi reported grants from Arcutis Biotherapeutics during the conduct of the study; and grants from Amgen,
AbbVie, Lilly, Janssen, LEO Pharma, Pfizer, Regeneron, Sanofi, Dermavant, EPI Health, Novartis, Incyte, and Sun
Pharma outside the submitted work. Mr Higham reported personal fees from Arcutis Biotherapeutics (employee and
shareholder) during the conduct of the study and outside the submitted work. Mr Krupa reported personal fees from
Arcutis Biotherapeutics (employee) during the conduct of the study. Dr Burnett reported other from Arcutis
Biotherapeutics (employee) during the conduct of the study. Dr Berk reported personal fees from Arcutis
Biotherapeutics (employee, with various compensation including salary, equity, options, and bonus; shareholder) during
the conduct of the study; in addition, Dr Berk had a patent for publication No. 20220211730 issued and a patent for pub-
lication No. 20220175743 issued. No other disclosures were reported.
Funding/Support: This work was supported by Arcutis Biotherapeutics, Inc.
Role of the Funder/Sponsor: The sponsor, Arcutis Biotherapeutics, Inc, was involved in the design and conduct of the
study; collection, management, analysis, and interpretation of the data; and preparation and review of the manuscript
but did not control the decision to publish the data or to which journal the manuscript was submitted.
Data Sharing Statement: See Supplement 4.
Additional Contributions: The authors thank the patients and their families for participation in this trial. Medical writing
support was provided by James Borwick and Christina McManus, PhD, for Alligent Biopharm Consulting, which was
supported by Arcutis Biotherapeutics, Inc.
Received 2022 Oct 10; Accepted 2023 Mar 1.
Copyright 2023 Zirwas MJ et al. JAMA Dermatology.
This is an open access article distributed under the terms of the CC-BY-NC-ND License.
This randomized clinical trial assesses the safety and efficacy of roflumilast foam, 0.3%, in adults
with seborrheic dermatitis affecting the scalp, face, or trunk.
Key Points
Question
What is the efficacy and safety of once-daily roflumilast foam, 0.3%, in adult patients with sebor‐
rheic dermatitis?
Findings
In this randomized clinical trial that included 226 patients with seborrheic dermatitis, 73.8% of
roflumilast-treated patients achieved Investigator Global Assessment success at week 8 compared
with 40.9% in the vehicle group, a statistically significant difference. Roflumilast was well tolerated,
with the rate of adverse events similar to that of the vehicle.
Meaning
These phase 2a data demonstrate that once-daily roflumilast foam, 0.3%, may be a viable nons‐
teroidal topical treatment of seborrheic dermatitis.
Abstract
Importance
Current topical treatment options for seborrheic dermatitis are limited by efficacy and/or safety.
Objective
To assess safety and efficacy of roflumilast foam, 0.3%, in adult patients with seborrheic dermatitis
affecting the scalp, face, and/or trunk.
Design, Setting, and Participants
This multicenter (24 sites in the US and Canada) phase 2a, parallel group, double-blind, vehicle-
controlled clinical trial was conducted between November 12, 2019, and August 21, 2020.
Participants were adult (aged ≥18 years) patients with a clinical diagnosis of seborrheic dermatitis
for a 3-month or longer duration and Investigator Global Assessment (IGA) score of 3 or greater
(at least moderate), affecting 20% or less body surface area, including scalp, face, trunk, and/or
intertriginous areas. Data analysis was performed from September to October 2020.
Interventions
Once-daily roflumilast foam, 0.3% (n = 154), or vehicle foam (n = 72) for 8 weeks.
Main Outcomes and Measures
The main outcome was IGA success, defined as achievement of IGA score of clear or almost clear
plus 2-grade improvement from baseline, at week 8. Secondary outcomes included IGA success at
weeks 2 and 4; achievement of erythema score of 0 or 1 plus 2-grade improvement from baseline
at weeks 2, 4, and 8; achievement of scaling score of 0 or 1 plus 2-grade improvement from base‐
line at weeks 2, 4, and 8; change in Worst Itch Numeric Rating Scale (WI-NRS) score from baseline;
and WI-NRS success, defined as achievement of 4-point or greater WI-NRS score improvement in
patients with baseline WI-NRS score of 4 or greater. Safety and tolerability were also assessed.
Results
A total of 226 patients (mean [SD] age, 44.9 [16.8] years; 116 men, 110 women) were randomized
to roflumilast foam (n = 154) or vehicle foam (n = 72). At week 8, 104 (73.8%) roflumilast-treated
patients achieved IGA success compared with 27 (40.9%) in the vehicle group (P < .001).
Roflumilast-treated patients had statistically significantly higher rates of IGA success vs vehicle at
week 2, the first time point assessed. Mean (SD) reductions (improvements) on the WI-NRS at
week 8 were 59.3% (52.5%) vs 36.6% (42.2%) in the roflumilast and vehicle groups, respectively
(P < .001). Roflumilast was well tolerated, with the rate of adverse events similar to that of the ve‐
hicle foam.
Conclusions and Relevance
The results from this phase 2a randomized clinical trial of once-daily roflumilast foam, 0.3%,
demonstrated favorable efficacy, safety, and local tolerability in the treatment of erythema, scaling,
and itch caused by seborrheic dermatitis, supporting further investigation as a nonsteroidal topi‐
cal treatment.
Trial Registration
ClinicalTrials.gov Identifier: NCT04091646
Introduction
Seborrheic dermatitis (SD) is a chronic inflammatory skin condition that affects patients of all
ages, with a global prevalence of 5% or greater.1,2,3,4 Cardinal features are erythematous, scaly,
pruritic patches and plaques, with a yellowish, greasy appearance, affecting areas with abundant
sebaceous glands, often accompanied by dyspigmentation in patients with darker skin.4,5
Seborrheic dermatitis can have deleterious effects on quality of life, particularly in patients with
more severe disease.6
Treatment options for seborrheic dermatitis include topical antifungals, corticosteroids, and
sulfur/sulfacetamide; topical calcineurin inhibitors are also used off label.4,7 Coal tar is less com‐
monly used and is associated with safety concerns.1 Treatments are available as creams, lotions,
ointments, foams, shampoos, gels, and solutions/topical suspensions.4,7,8 Corticosteroids are ef‐
fective, but should not be used long term due to risk of atrophy, telangiectasia, acne, rosacea, and
ocular toxic effects when used on the eyelid.9 Topical calcineurin inhibitors are not approved by
the US Food and Drug Administration to treat seborrheic dermatitis; however, efficacy and safety
have been assessed in patients with severe facial seborrheic dermatitis.10,11 Topical calcineurin in‐
hibitors are associated with short-term warmth and burning sensations, and labeling includes a
warning for rare cases of lymphoma and skin cancer, although clinical data do not suggest higher
risk compared with the general population.9 Scalp seborrheic dermatitis is often treated with
shampoos containing antifungal agents, selenium sulfide, or zinc pyrithione.4,7,8
Nonpharmacologic treatments, such as prescription nonsteroidal medical device creams, may also
be useful to treat erythema, scaling, and itching associated with seborrheic dermatitis.12
Phosphodiesterase (PDE) 4 inhibition may be effective for seborrheic dermatitis based on its ca‐
pacity to suppress proinflammatory cytokines implicated in seborrheic dermatitis pathophysiol‐
ogy by elevating cyclic adenosine monophosphate levels.5,13 Limited evidence from case reports
and a small clinical trial supported efficacy of the topical PDE4 inhibitor crisaborole and the oral
PDE4 inhibitor apremilast, both used off label, for treatment of seborrheic dermatitis.14,15,16
Roflumilast is a selective, highly potent PDE4 inhibitor with between 25- and more than 300-fold
greater potency than crisaborole or apremilast in vitro.17 An oral formulation of roflumilast is ap‐
proved for treatment of chronic obstructive pulmonary disease.13,17,18 Topical roflumilast is under
investigation for long-term management of various dermatologic conditions, including atopic der‐
matitis, scalp psoriasis, and chronic plaque psoriasis (approved July 29, 2022, by the US Food and
19,20,21,22
Drug Administration). We present results of a phase 2a randomized clinical trial of roflu‐
milast foam, 0.3%, for once-daily treatment of seborrheic dermatitis on scalp and nonscalp
locations.
Methods
Study Design
This was a parallel-group, double-blind, vehicle-controlled randomized clinical trial of once-daily

roflumilast foam, 0.3%, for treatment of seborrheic dermatitis, conducted at 24 sites in the US and
Canada. The study protocol and statistical analysis plans are in Supplements 1 and 2. Eligible pa‐
tients were adults (aged ≥18 years) with clinical diagnosis of seborrheic dermatitis of a 3-month
or greater duration, Investigator Global Assessment (IGA) score of 3 or greater, and affecting 20%
or less body surface area (BSA), including the scalp, face, trunk, and/or intertriginous areas (eFig‐
ure 1 in Supplement 3). Patients had to discontinue topical antifungals, corticosteroids, topical cal‐
cineurin inhibitors, sulfur-based treatments, medical devices, crisaborole, azelaic acid, or metron‐
idazole 2 or more weeks before randomization (additional excluded medications are in eTable 1 in
Supplement 3). Nonmedicated emollients, moisturizers, and sunscreens were allowed once daily
as normally used by patients and applied 3 or more hours after application of the investigational
product to untreated areas only.
Patients were randomized in a 2:1 ratio to roflumilast foam, 0.3%, or a vehicle foam. Assignment
to treatment group was based on an interactive response technology system using a computer-
generated randomization list generated by an unblinded statistician not involved in the trial and
stratified by study site and baseline disease severity. The study design included an initial screening
period (up to 4 weeks), randomization, 8-week treatment phase, and follow-up phase of 1 week.
At week 8, patients who met eligibility requirements were given the option to enroll in an open-la‐
bel, single-arm, long-term safety extension of the current trial.
Roflumilast foam is uniquely formulated to contain 0.3% roflumilast in an emollient, water-based

(65% water) foam without fragrances, propylene glycol, polyethylene glycol, isopropyl alcohol, or
ethanol. The foam has a propellant that dissipates rapidly when applied. Vehicle foam was identi‐
cal to roflumilast foam, 0.3%, without the active ingredient. Each patient received blinded, uniquely
numbered kits, each containing 2 blinded, 60-g canisters of the assigned product. The number of
kits dispensed to each patient was based on BSA involvement.
Study staff instructed patients how to apply the treatment foam at the randomization (baseline)
visit. Investigational product was applied to seborrheic dermatitis lesions as a thin film and
rubbed in thoroughly but gently until the product disappeared. The foam was self-administered
once daily, in the evening 20 or more minutes before going to bed, except when treatment was ap‐
plied at the study site on day 0 and week 2. For scalp lesions, treatment was applied when the skin
and hair were dry, with special attention given to ensure the treatment was applied to scalp skin
and not rubbed off on hair. Patients were to maintain treatment for the duration of the trial re‐
gardless of whether treatable areas of seborrheic dermatitis cleared. The study was conducted in
accordance with ethical principles set forth in the Declaration of Helsinki and International
Council for Harmonisation tripartite guideline. Written informed consent was obtained from all
patients at screening prior to trial enrollment. This study followed the Consolidated Standards of
Reporting Trials (CONSORT) reporting guideline.
End Points
The primary efficacy end point was IGA success, defined as achievement of IGA score of clear (0)
or almost clear (1) plus 2-grade improvement from baseline (scale: 0 [clear] to 4 [severe]; eTable
2 in Supplement 3) at week 8. As baseline included patients with moderate (3) and severe (4) dis‐
ease, the end point is referred to as IGA score of 0 or 1, as the 2-grade improvement is required
to meet the end point. Secondary end points included IGA success at weeks 2 and 4; achievement
of overall assessment of erythema score of 0 or 1 (scale: 0 [none] to 3 [severe]) plus 2-grade im‐
provement from baseline (erythema success); achievement of overall assessment of scaling score
of 0 or 1 (scale: 0 [none] to 3 [severe]) plus 2-grade improvement from baseline (scaling suc‐
cess); change from baseline on the Worst Itch Numeric Rating Scale (WI-NRS; scale 0 [no itch] to
10 [worst imaginable itch]); and WI-NRS success, defined as achievement of a 4-point or greater
WI-NRS score improvement from baseline in patients with baseline score of 4 or greater. Safety
end points included incidence of adverse events (AEs), clinical laboratory parameters, changes in
vital signs, Patient Health Questionnaire depression scale (PHQ-8), and Columbia–Suicide Severity
Rating Scale (C-SSRS). Local tolerability at application sites was assessed by investigators (prior to
study drug application) and patients (recall of their experience 10-15 minutes after application of
study drug) at baseline and weeks 4 and 8. Hypopigmentation and hyperpigmentation were as‐
sessed by investigators at each visit on 4-point scales (scale: 0 [none] to 3 [severe]). Demographic
information was collected for each patient, including gender, age, race, and ethnicity according to
categories required by regulatory agencies.
Statistical Analysis
A sample size of 184 participants provided approximately 90% power to detect an active re‐
sponse of 58.5% or greater, assuming 159 participants completed the study and vehicle response
of 30%, based on 2-group χ2 test of equal proportions (without continuity correction), using a 2-
sided α of .10. The intention-to-treat (ITT) population included all randomized patients, while the
modified ITT (mITT) population included all randomized patients except patients who missed the
week-8 IGA assessment due to COVID-19 disruption. The primary efficacy end point was analyzed
using a Cochran-Mantel-Haenszel (CMH) test stratified by study site and baseline disease severity.
Statistical significance was concluded at the 10% significance level (2-sided). The primary efficacy
analysis was based on the mITT population and repeated for the ITT population. Missing IGA
scores were imputed using multiple imputation for CMH test.
Secondary end points of IGA success (weeks 2 and 4), erythema success, scaling success, and WI-
NRS success were analyzed using the CMH test, similar to the primary end point. Change and per‐
centage change from baseline in WI-NRS score were analyzed using analysis of covariance with in‐
dependent variables of treatment, study site, baseline IGA, and baseline value of the respective
scale. All secondary efficacy analyses were performed using the mITT and ITT populations except
WI-NRS success, which was based on the subset of the ITT population with baseline WI-NRS score
of 4 or greater. Percentage of patients satisfying response criteria and the treatment difference in
percentage were estimated with observed data, and 95% CIs were calculated using the Wilson
method. Analyses were performed using SAS, version 9.4 (SAS Institute).
Results
A total of 328 patients were screened, and 226 patients (mean [SD] age, 44.9 [16.8] years; 116
men, 110 women) were randomized to roflumilast foam (n = 154) or vehicle foam (n = 72;
Figure 1). Most patients (208 of 226 [92.0%]) completed the study. Only 2 (1.3%) roflumilast-
treated patients discontinued due to AEs, compared with 1 (1.4%) vehicle-treated patient.
Additionally, 2 patients (1.3%) missed the IGA assessment at week 8 due to COVID-19 disruption
and were excluded from the mITT population (n = 224).
Treatment groups were well balanced for demographic and baseline disease characteristics (
Table 1). More than 90% of patients had moderate severity of seborrheic dermatitis (IGA score of
3) at baseline, approximately 90% had a moderate score for erythema, and slightly more than
80% had a moderate score for scaling. Mean WI-NRS scores were slightly less than 6 in both
groups. Mean percentage BSA affected was 3.3% in the roflumilast group and 3.0% in the vehicle
group. More roflumilast-treated patients than vehicle-treated patients presented with facial in‐
volvement (64.9% vs 50.0%).
Efficacy
For the primary end point of IGA score of 0 or 1 at week 8, a statistically significant higher num‐
ber of roflumilast-treated patients (104 [73.8%]) achieved IGA success compared with vehicle-
treated patients (27 [40.9%]; absolute difference, 32.8% [95% CI, 18.5%-45.7%]; P < .001;
Figure 2). The small number of patients with severe disease at baseline showed similar results,
with 6 of 10 roflumilast-treated patients achieving IGA score of 0 or 1 vs 0 of 3 vehicle-treated pa‐
tients. At week 8, 50 (35.5%) roflumilast-treated patients achieved IGA of clear, and 54 (38.3%)
achieved IGA of almost clear, compared with 10 (15.2%) and 17 patients (25.8%), respectively, in
the vehicle group. Differences in percentages of patients achieving IGA score of 0 or 1 at week 2
(the first posttreatment assessment) and week 4 were statistically significant in favor of roflumi‐
last (week 2: 33.8% vs 14.7%; absolute difference, 19.1% [95% CI, 6.6%-29.3%]; P = .003; week 4:
56.6% vs 28.4%; absolute difference, 28.3% [95% CI, 14.0%-40.5%]; P < .001; Figure 2).
A statistically significant increase in percentages of patients achieving erythema success was found
among roflumilast-treated patients compared with vehicle-treated patients (week 2: 22.5% vs
5.9%; absolute difference, 16.6% [95% CI, 6.4%-24.8%]; week 4: 35.7% vs 10.4%; absolute differ‐
ence, 25.2% [95% CI, 13.1%-34.9%]; week 8: 44.7% vs 21.2%; absolute difference, 23.5% [95%
CI, 9.6%-35.0%]; P ≤ .006 for all time points; eFigure 2 in Supplement 3). A statistically significant
increase in the percentage of roflumilast-treated patients achieving an erythema score of 0 was
also observed at all time points (week 2: 16.6% vs 5.9%; absolute difference, 10.7% [95% CI,
1.0%-18.3%]; week 4: 32.2% vs 10.4%; absolute difference, 21.7% [95% CI, 9.8%-31.3%]; week 8:
43.3% vs 19.7%; absolute difference, 23.6% [95% CI, 9.9%-34.9%]; eFigure 2 in Supplement 3).
Patients treated with roflumilast foam, 0.3%, demonstrated a greater mean (SD) change from
baseline erythema score at weeks 2, 4, and 8 (−1.0 [0.73], −1.3 [0.73], and −1.4 [0.78], respec‐
tively) compared with that observed in vehicle-treated patients (−0.4 [0.65], −0.7 [0.67], and −0.8
[0.85], respectively; P < .001 for each week).
Similar results were observed for scaling success, with statistically significant differences favoring
roflumilast at all time points (week 2: 26.5% vs 14.7%; absolute difference, 11.8% [95% CI, −0.3%
to 21.8%]; week 4: 41.3% vs 21.0%; absolute difference, 20.4% [95% CI, 6.8%-31.8%]; week 8:
56.0% vs 27.2%; absolute difference, 28.8% [95% CI, 14.4%-41.0%]; P ≤ .08; eFigure 3 in
Supplement 3). A statistically significant increase in percentages of roflumilast-treated patients
achieving a scaling score of 0 occurred at all time points (week 2: 22.5% vs 8.8%; absolute differ‐
ence, 13.7% [95% CI, 2.8%-22.4%]; week 4: 37.8% vs 14.9%; absolute difference, 22.8% [95% CI,
10.0%-33.3%]; week 8: 49.6% vs 24.2%; absolute difference, 25.4% [95% CI, 11.3%-37.3%]; eFig‐
ure 3 in Supplement 3). Patients treated with roflumilast foam, 0.3%, demonstrated a greater
mean (SD) change from baseline scaling score at weeks 2, 4, and 8 (−1.0 [0.77], −1.3 [0.76], and
−1.5 [0.75], respectively) compared with vehicle-treated patients (−0.6 [0.78], −0.8 [0.81], and
−1.0 [0.83], respectively; P < .001 for each week).
Patients receiving roflumilast experienced greater improvements in WI-NRS score compared with
those receiving the vehicle foam. At week 2, mean (SD) change from baseline in the roflumilast
group was −3.0 (2.8), a 47.2% (51.7%) decrease, vs −1.7 (2.1) with vehicle, a 30.9% (40.1%) de‐
crease. Change at week 4 in the roflumilast group was −3.5 (2.7), a reduction of 56.7% (44.6%),
and −1.9 (2.2), a reduction of 35.7% (39.9%), for the vehicle group. At week 8, mean (SD) change
was −3.7 (2.8) for the roflumilast group and −2.0 (2.4) for the vehicle group, reductions of 59.3%
(52.5%) and 36.6% (42.2%), respectively (P < .001). The percentage of patients who achieved WI-
NRS success was greater in the roflumilast group at weeks 2, 4, and 8 (Figure 3). At week 8, 73
(64.6%) roflumilast-treated patients achieved WI-NRS success compared with 18 (34.0%) vehicle-
treated patients (absolute difference, 30.6% [95% CI, 14.4%-44.6%]).
For all efficacy analyses, outcomes for the ITT population were similar to those for the mITT
population.
Safety
Roflumilast foam was well tolerated with a low rate of AEs (Table 2). Incidence of AEs was slightly
higher in the roflumilast group compared with the vehicle group (37 of 154 [24.0%] vs 13 of 72
[18.1%]). Of 37 AEs reported in the roflumilast group, 35 were mild or moderate, while 2 were se‐
vere (hyperkalemia, migraine), both of which were considered unrelated to treatment (eTable 3 in
Supplement 3). For the vehicle-treated group, 11 of the 13 AEs were mild or moderate, and the re‐
maining 2 were severe (increased alanine aminotransferase level, anemia). Only 3 (1.9%) AEs in
the roflumilast-treated group (application site pain, diarrhea, and insomnia) and 3 (4.2%) in the
vehicle-treated group (application site pain, insomnia, and application site dysesthesia) were con‐
sidered related to treatment by the investigator. Overall, only 3 patients had AEs of application site
pain: 2 (1.4%) in the roflumilast-treated group and 1 (1.3%) in the vehicle-treated group.
Two (1.3%) patients in the roflumilast group discontinued treatment due to AEs. One patient expe‐
rienced both migraine (considered unrelated to treatment) and moderate application site pain,
both of which resolved. The second patient discontinued due to dyspnea, which also resolved and
was considered not treatment related. One (1.4%) patient in the vehicle group discontinued due to
application site dysesthesia. No serious AEs or deaths occurred.
No clinically meaningful differences between groups were observed in changes in vital signs, PHQ-
8, or C-SSRS, and laboratory values did not indicate any safety concerns. Investigator-assessed lo‐
cal skin irritation was rated as no evidence of irritation in 98% or greater of evaluations in both
groups. On patient-rated local tolerability of roflumilast, scores were low (favorable) and similar
to vehicle at all time points. Over 95% of patients reported no or mild sensation after applying rof‐
lumilast foam at week 4 and week 8, similar to vehicle.
Most patients were classified as having no hyperpigmentation or hypopigmentation at any visit. At

baseline, both hyperpigmentation and hypopigmentation were disproportionately more common
in non-White patients (hypopigmentation: 9 of 39 [23.1%]; hyperpigmentation: 7 of 41 [17.1%])
than in White patients (hypopigmentation: 2 of 180 [1.1%]; hyperpigmentation: 7 of 180 [3.9%]).
Most patients with hypopigmentation at baseline (11 of 226 [4.9%]; 7 mild, 4 moderate) experi‐
enced full resolution (6 of 11; 54.5%) by week 8. Similarly, most patients with hyperpigmentation
at baseline (14 of 226 [6.8%]; 10 mild, 4 moderate) experienced full resolution (11 of 14; 78.5%)
by week 8. At week 8, new instances of hypopigmentation (n = 0) and hyperpigmentation (n = 3, all
in White patients) were uncommon.
Discussion
This phase 2a randomized clinical trial assessed efficacy of a topical PDE4 inhibitor foam in pa‐
tients with seborrheic dermatitis. Once-daily treatment with roflumilast foam, 0.3%, resulted in
consistent improvements from baseline for key signs and symptoms of seborrheic dermatitis.
Significantly more roflumilast-treated patients than vehicle-treated patients achieved the primary
end point, IGA success, at week 8, with superiority achieved by the first postbaseline assessment
at week 2. It is notable that 35.5% of patients achieved an IGA status of clear.
Similar results were observed for the secondary end point of WI-NRS success, as nearly two-
thirds of roflumilast-treated patients who had baseline WI-NRS score of 4 or greater achieved a 4-
point or greater improvement at week 8. This success rate for improvement in itch is noteworthy
considering that the baseline WI-NRS score was relatively high and because itch is a major com‐
plaint among patients with seborrheic dermatitis.6,23
The high rate of response in vehicle-treated patients suggests the vehicle, which has a number of
unique properties, has beneficial effects on seborrheic dermatitis. Roflumilast foam, 0.3%, is for‐
mulated with a water-based emollient vehicle nearly identical to the vehicle for roflumilast cream,
0.3%. This vehicle performed generally similarly to a leading ceramide-containing moisturizer
across most assessments in a double-blinded, intraindividual study in patients with asteatotic
eczema.24 Additionally, the unique emulsifier used does not act as a surfactant at skin tempera‐
ture, and thus is not able to extract lipids from the skin.25 While the mechanism is speculative at
this point, these results suggest the potential importance of the skin barrier in patients with seb‐
orrheic dermatitis.
Roflumilast foam, 0.3%, was well tolerated and demonstrated a favorable safety and tolerability
profile. Rates of treatment-related treatment-emergent AEs, serious AEs, and AEs leading to dis‐
continuation were low and generally comparable with vehicle. Few patients reported stinging,
burning, application site reactions, or application site pain with either roflumilast or vehicle treat‐
ment. The tolerability profile demonstrates emollient properties of the vehicle formulated without
excipients known to cause irritation, such as propylene glycol. This is important because of high
rates of application site pain with the only other topical PDE4 inhibitor (crisaborole), which is ap‐
proved for atopic dermatitis and has rates of application site pain between 13.8% and
31.7%.26,27,28 The low rates of application site pain in the current study suggest this is not a gen‐
eral feature of PDE4 inhibition. Additionally, in a trial evaluating efficacy and tolerability of
tacrolimus, 1%, ointment in patients with severe facial seborrheic dermatitis, approximately 47%
of patients reported burning.10 Local tolerability issues and adverse effects associated with other
topical treatments of seborrheic dermatitis, such as corticosteroids, antifungals, and off-label use
of calcineurin inhibitors, may limit their duration and usage.
The current standard of care for seborrheic dermatitis is to use multiple agents (usually an anti‐
fungal and anti-inflammatory).4 In addition to an anti-inflammatory effect, roflumilast inhibits
yeast PDE activity, suggesting a possible additional antifungal effect.29
Limitations
A limitation of this study was the 8-week treatment period. A second limitation is the relatively
small patient population enrolled in the current trial. A phase 3 randomized clinical trial (n = 457)
should provide additional information about efficacy and safety of once-daily roflumilast foam,
0.3%, in patients with seborrheic dermatitis. Third, the number of patients with severe seborrheic
dermatitis was small.
Conclusions
In this randomized clinical trial, nonsteroidal, once-daily roflumilast foam, 0.3%, demonstrated ef‐
ficacy and safety results with favorable local tolerability in the treatment of erythema, scaling, and
itch caused by seborrheic dermatitis. These results suggest roflumilast foam, 0.3%, has the poten‐
tial to help address the unmet need for an effective, cosmetically tolerable, treatment for sebor‐
rheic dermatitis.
Notes
Supplement 1.
Trial Protocol
Supplement 2.
Statistical Analysis Plan
Supplement 3.
eTable 1. Excluded Medications and Treatments
eTable 2. Investigator Global Assessment (IGA) scale
eTable 3. Treatment Emergent Adverse Events by Severity
eFigure 1. Study Design
eFigure 2. Percentage of Patients Achieving Erythema Success and Erythema score of None (mITT Population)
eFigure 3. Percentage of Patients Achieving Scaling Success and Scaling Score of None (mITT Population)
Supplement 4.
Data Sharing Statement
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Figures and Tables
Figure 1.
Patient Flow Diagram
mITT indicates modified intention-to-treat.
Table 1.
Baseline Demographic and Disease Characteristics (Safety Population)
Characteristic Patients, No. (%)
Roflumilast foam, 0.3% (n = 154) Vehicle foam (n = 72)
Age, mean (SD), y 45.3 (17.0) 44.2 (16.3)
Gender
Female 78 (50.6) 32 (44.4)
Male 76 (49.4) 40 (55.6)
Ethnicity
Hispanic or Latino 29 (18.8) 16 (22.2)
Not Hispanic or Latino 125 (81.2) 56 (77.8)
Race
American Indian or Alaska Native 1 (0.6) 0
Asian 7 (4.5) 1 (1.4)
Black or African American 17 (11.0) 6 (8.3)
Native Hawaiian or Other Pacific Islander 0 0
White 123 (79.9) 62 (86.1)
Othera 1 (0.6) 2 (2.8)
>1 Race 5 (3.2) 1 (1.4)
BSA affected, mean (SD), % 3.3 (2.51) 3.0 (2.11)
Baseline IGA (scale: 0-4)
3 (Moderate) 141 (91.6) 69 (95.8)
4 (Severe) 13 (8.4) 3 (4.2)
Baseline erythema (scale: 0-3)
2 (Moderate) 135 (87.7) 66 (91.7)
3 (Severe) 19 (12.3) 6 (8.3)
Baseline scaling (scale: 0-3)
2 (Moderate) 130 (84.4) 58 (80.6)
3 (Severe) 24 (15.6) 14 (19.4)
WI-NRS
Mean (SD) 5.8 (2.7) 5.7 (2.3)
Median (range) 6 0 (0-10) 6 0 (0-10)
Abbreviations: BSA, body surface area; IGA, Investigator Global Assessment; WI-NRS, Worst Itch Numeric Rating Scale.
a
Patients selected “other” when the patient did not feel that their race fit within 1 of the selected categories. The 3 patients
entered the following into the free-text field: mixed race, Arabic, Trinidadian.
Figure 2.
Percentage of Patients Achieving IGA Successa
a
Investigator Global Assessment (IGA) success = clear or almost clear (on a scale of 0 [completely clear] to 4 [severe]).
Error bars indicate 95% CIs.
Figure 3.
Percentage of Patients Achieving WI-NRS Success Among Patients With Baseline WI-NRS Score of 4 or Greatera
a
Worst Itch Numeric Rating Scale (WI-NRS) success = 4-point improvement from baseline WI-NRS score. Error bars indi‐
cate 95% CIs.
Table 2.
Adverse Events
Characteristic Patients, No. (%)
Roflumilast foam, 0.3% (n = 154) Vehicle foam (n = 72)
Any TEAE 37 (24.0) 13 (18.1)
Any treatment-related TEAE 3 (1.9) 3 (4.2)
Any serious AE 0 0
Discontinued study due to AEa 2 (1.3) 1 (1.4)
Most common TEAEs (>1.5% in any group), preferred term
Contact dermatitis b 3 (1.9) 2 (2.8)
Insomnia 3 (1.9) 1 (1.4)
Nasopharyngitis 3 (1.9) 0
Abbreviations: AE, adverse event; TEAE, treatment-emergent adverse event.
a
Adverse events leading to discontinuation were application site pain, migraine, and dyspnea in the roflumilast-treated
group and application site dysesthesia in the vehicle-treated group.
b
Contact dermatitis was reported to be unrelated to treatment in all cases, and no cases caused interruption of drug
application; 2 cases were reported as “poison ivy rash” by investigators.

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3/10/23, 21:11 Efficacy of Roflumilast Foam, 0.

3%, in Patients With Seborrheic Dermatitis - PMC

JAMA Dermatol. 2023 Jun; 159(6): 613–620. PMCID: PMC10157502

Accepted for Publication: March 1, 2023.

Published Online: May 3, 2023. doi:10.1001/jamadermatol.2023.0846

Statistical analysis: Lynde, Krupa, Berk.

Obtained funding: Draelos.

Supervision: Kircik, Moore, Alonso-Llamazares, Green, Lain, Burnett, Berk.

Funding/Support: This work was supported by Arcutis Biotherapeutics, Inc.

Data Sharing Statement: See Supplement 4.

Received 2022 Oct 10; Accepted 2023 Mar 1.

Copyright 2023 Zirwas MJ et al. JAMA Dermatology.

Design, Setting, and Participants

Main Outcomes and Measures

Conclusions and Relevance

ClinicalTrials.gov Identifier: NCT04091646

This was a parallel-group, double-blind, vehicle-controlled randomized clinical trial of once-daily

Roflumilast foam is uniquely formulated to contain 0.3% roflumilast in an emollient, water-based

Most patients were classified as having no hyperpigmentation or hypopigmentation at any visit. At

Statistical Analysis Plan

eTable 1. Excluded Medications and Treatments

eTable 2. Investigator Global Assessment (IGA) scale

eTable 3. Treatment Emergent Adverse Events by Severity

eFigure 1. Study Design

Data Sharing Statement

1. Berk T, Scheinfeld N. Seborrheic dermatitis. P T. 2010;35(6):348-352. [PMCID: PMC2888552] [PubMed: 20592880]

26. Eucrisa (crisaborole). Package insert. Pfizer Inc; April 2020.

Figures and Tables

Patient Flow Diagram

mITT indicates modified intention-to-treat.

Baseline Demographic and Disease Characteristics (Safety Population)

Characteristic Patients, No. (%)

Roflumilast foam, 0.3% (n = 154) Vehicle foam (n = 72)

Age, mean (SD), y 45.3 (17.0) 44.2 (16.3)

Female 78 (50.6) 32 (44.4)

Male 76 (49.4) 40 (55.6)

Hispanic or Latino 29 (18.8) 16 (22.2)

Not Hispanic or Latino 125 (81.2) 56 (77.8)

American Indian or Alaska Native 1 (0.6) 0

Asian 7 (4.5) 1 (1.4)

Black or African American 17 (11.0) 6 (8.3)

Native Hawaiian or Other Pacific Islander 0 0

White 123 (79.9) 62 (86.1)

Othera 1 (0.6) 2 (2.8)

>1 Race 5 (3.2) 1 (1.4)

BSA affected, mean (SD), % 3.3 (2.51) 3.0 (2.11)

Baseline IGA (scale: 0-4)

3 (Moderate) 141 (91.6) 69 (95.8)

4 (Severe) 13 (8.4) 3 (4.2)

Baseline erythema (scale: 0-3)

2 (Moderate) 135 (87.7) 66 (91.7)

3 (Severe) 19 (12.3) 6 (8.3)

Baseline scaling (scale: 0-3)

2 (Moderate) 130 (84.4) 58 (80.6)

3 (Severe) 24 (15.6) 14 (19.4)

Mean (SD) 5.8 (2.7) 5.7 (2.3)

Median (range) 6 0 (0-10) 6 0 (0-10)

Percentage of Patients Achieving IGA Successa

Characteristic Patients, No. (%)