Key Points
Question
Is once-daily roflumilast foam, 0.3%, safe and effective in adolescents and adults with psoriasis of the scalp and body?
Findings
In this randomized clinical trial including 432 patients, significantly greater proportions of patients treated with roflumilast vs vehicle achieved Scalp−Investigator Global Assessment (S-IGA; 66.4% vs 27.8%) and Body−IGA (45.5% vs 20.1%) success (clear/almost clear plus ≥2-grade improvement from baseline) at week 8. Roflumilast and vehicle had favorable local tolerability profiles and low rates of adverse events.
Meaning
These results demonstrate that once-daily roflumilast foam, 0.3%, may provide a monotherapy topical treatment option for patients with psoriasis of the scalp and body.
Abstract
Importance
Current topical treatments for scalp psoriasis are limited by formulation, efficacy, and/or safety.
Objective
To assess safety and efficacy of roflumilast foam, 0.3%, in patients with psoriasis of the scalp and body.
Design, Setting, and Participants
This was a phase 3 double-blinded, vehicle-controlled randomized clinical trial conducted between August 24, 2021, and June 3, 2022, at 49 sites in Canada and the US. Eligible participants were 12 years and older with plaque psoriasis affecting up to 25% of the scalp and body, at least 10% of the scalp, and up to 20% of nonscalp areas, with a minimum Scalp−Investigator Global Assessment (S-IGA) score of 3 (moderate), and minimum Body−IGA (B-IGA) score of 2 (mild). Data analyses were performed from September 9 to December 30, 2022.
Interventions
Once-daily roflumilast foam, 0.3%, or vehicle for 8 weeks.
Main Outcomes and Measures
Coprimary end points were S-IGA and B-IGA success (clear [0] or almost clear [1] plus ≥2-grade improvement) at week 8. Secondary end points included S-IGA success at weeks 2 and 4, change in Scalp Itch−Numeric Rating Scale (SI-NRS), and SI-NRS and Worst Itch−NRS (WI-NRS) success (≥4-point improvement in patients with baseline score of ≥4). Safety and tolerability were also assessed.
Results
A total of 432 patients (mean [SD] age, 47.3 [14.8] years; 243 women [56.3%]) were randomized to roflumilast foam (n = 281) or vehicle (n = 151). At week 8, 66.4% of the roflumilast group achieved S-IGA success vs 27.8% of the vehicle group (P < .001); and 45.5% of the roflumilast group achieved B-IGA success compared with 20.1% of the vehicle group (P < .001). Rates for S-IGA success at week 2 and SI-NRS and WI-NRS success at weeks 2, 4, and 8 were significantly higher for roflumilast vs vehicle. Improvements in SI-NRS were greater for the roflumilast vs the vehicle group as early as the first assessment (24 hours after the first application). Both study groups had low rates of adverse events and favorable tolerability profiles.
Conclusions and Relevance
This randomized clinical trial found that roflumilast foam, 0.3%, improved signs and symptoms of psoriasis on the scalp and body, including pruritus, with low rates of adverse events in patients 12 years and older. These results demonstrate the potential of roflumilast foam, 0.3%, as monotherapy for patients with psoriasis of the scalp and body.
Trial Registration
ClinicalTrials.gov Identifier: NCT05028582
This randomized clinical trial assesses the safety and efficacy of roflumilast foam, 0.3%, in patients with psoriasis of the scalp and body.
Introduction
Plaque psoriasis is a chronic inflammatory skin disease that negatively affects quality of life for patients with limited or extensive disease involvement.1 The scalp is one of the most common sites of plaque psoriasis, with approximately half of patients with psoriasis reporting involvement of the scalp.2,3 Topical treatment of scalp psoriasis can be challenging, and patients with psoriasis affecting both the body and scalp may require polypharmacy to address different application considerations. Scalp psoriasis is complicated by the presence of hair, which affects application of topical agents,4,5,6 especially cream or ointment formulations. Often, these formulations are cosmetically unacceptable or are incompatible with hair care practices, resulting in reduced treatment adherence.6,7,8,9 Newer topical formulations, including foams, are more compatible with hair care practices and can be applied to both hair-bearing and non–hair-bearing skin. This versatility may improve treatment outcomes by increasing adherence.
Most patients with psoriasis report substantial itch, with itch of the scalp being a predominant and bothersome site.10 Patients describe psoriatic itch using terms such as stinging, pinching, tickling, crawling, and burning sensations, as well as a feeling of pain.10 In a survey of North American and European patients with plaque psoriasis, itch was the most bothersome symptom.3 The severity of itch does not always correlate with the severity of psoriasis; patients with mild psoriasis often report considerable itch.11 Compared with those without persistent itch, patients with plaque psoriasis who report persistent itch have significant increases in overall work impairment and reduced quality of life.12 In addition, patients with plaque psoriasis and moderate to severe itch report significantly more sleep disturbance than those with mild itch.12
Roflumilast is a selective, potent, phosphodiesterase 4 (PDE4) inhibitor, with greater affinity for PDE4 than 2 other PDE4 inhibitors approved for dermatologic conditions, apremilast and crisaborole. Roflumilast is approximately 25- to greater than 300-fold more potent in in-vitro assays than apremilast and crisaborole,13 with roflumilast more closely mimicking physiologic cyclic adenosine monophosphate binding to PDE4.14 Inhibition of PDE4 by roflumilast modulates inflammatory cytokines, many of which are implicated in the pathophysiologic mechanism of inflammatory skin diseases, including psoriasis. This modulation decreases expression of key proinflammatory cytokines, including type 1 (interferon-γ, tumor necrosis factor−α), type 2 (IL-4), and type 17 (IL-17, IL-23), and increases anti-inflammatory cytokines, such as IL-10.13,15 Furthermore, roflumilast inhibits sensory neuron activation, thereby reducing itch sensation, and normalizes keratinocyte activation and differentiation, potentially mitigating epidermal barrier dysfunction.16,17,18
Clinical data for roflumilast demonstrates its safety and efficacy as a once-daily cream or foam for long-term management of various dermatologic conditions, including chronic plaque psoriasis (cream, 0.3%), atopic dermatitis (cream, 0.15% and 0.05%), and seborrheic dermatitis (foam, 0.3%).19,20,21,22,23 Roflumilast foam, 0.3%, was adapted from the high-water content formulation (approximately 48% water) of roflumilast cream, 0.3%, and includes addition of a propellant. Roflumilast foam differs from other topical foam formulations because it contains excipients that maintain the skin barrier, are used in cosmetic products but are novel to prescription topical products, and ensure its suitability for a wide variety of skin and hair types.24 Additionally, roflumilast foam does not contain ethanol, isopropyl alcohol, propylene glycol, polyethylene glycol, formaldehyde-releasing agents, or fragrances that can irritate skin, damage hair, or lead to contact sensitization.25
In a phase 2b trial for psoriasis of the scalp and body,26 roflumilast foam, 0.3%, was well tolerated and improved patients’ psoriasis signs and symptoms, including pruritus. The objective of this phase 3 trial was to assess efficacy and safety of roflumilast foam, 0.3%, vs vehicle administered once daily for 8 weeks in adolescent and adult patients with psoriasis of the scalp and body.
Methods
This was a phase 3, parallel-group, double-blinded, vehicle-controlled randomized clinical trial of roflumilast foam, 0.3%, vs vehicle foam (the ARRECTOR trial). The trial was conducted in 49 centers across Canada and the US between August 24, 2021, and June 3, 2022. The trial protocol is available in Supplement 1, and the statistical analysis plan, in Supplement 2. The trial was conducted in accordance with the principles of the Tri-Council Policy Statement, the ethical principles set forth in the Declaration of Helsinki,27 and the International Council for Harmonization tripartite guideline regarding Good Clinical Practice.28
The trial protocol and informed consent form were approved by a local institutional review board or independent ethics committee at each study site before enrollment of patients. All patients (and/or a parent/guardian) provided written informed consent (and assent when applicable) before screening. This study followed the Consolidated Standards of Reporting Trials (CONSORT) reporting guideline.
Participants
Eligible patients were 12 years or older with plaque psoriasis affecting the scalp and body with a minimum Scalp−Investigator Global Assessment (S-IGA) score of 3 (moderate) and a minimum rest of the Body−Investigator Global Assessment (B-IGA) score of 2 (mild); both were measured on 5-point scales ranging from 0 (none) to 4 (severe). Total overall psoriasis involvement of scalp and nonscalp areas for all patients was to be 25% or less of body surface area (BSA), not including palms and/or soles, at baseline. Total nonscalp BSA affected by psoriasis for all patients was to be 20% or less; at least 10% of the scalp was to be affected by psoriasis. Demographic information was collected, and was either self- or parent-reported, depending on the patient’s age per the protocol.
Key exclusion criteria were planned excessive exposure of treated area(s) to natural or artificial sunlight, tanning bed, or other light-emitting diode; planned initiation or changes to concomitant medication that could, in the opinion of the investigator, affect psoriasis; and current diagnosis of nonplaque forms of psoriasis or drug-induced psoriasis. In addition, patients for whom discontinuation of their current psoriasis treatment was inadvisable were excluded.
Treatment Groups
Patients were randomized in a 2:1 ratio to roflumilast foam, 0.3%, or vehicle (Figure 1). Assignment to treatment group was based on an interactive response technology system using a computer-generated randomization list created by an unblinded statistician not involved in the trial and stratified by trial site and baseline S-IGA and B-IGA. Patients received uniquely numbered blinded kits according to trial group assignment. Roflumilast foam comprised 0.3% roflumilast in an emollient foam. Vehicle was identical to roflumilast foam, 0.3%, without the active ingredient.
Figure 1. CONSORT Flow Diagram of Study Participants.
The foam was applied to all affected body areas, including the face, scalp, palms, soles, genitals, and intertriginous regions, for 8 weeks. Patients or caregivers were shown how to apply the foam at the randomization visit (baseline). For scalp lesions, special attention was given to ensure adequate foam was applied to scalp skin and not exclusively to the hair. Patients were instructed to apply foam once daily in the evening to scalp and body psoriasis lesions identified and outlined by the investigator at baseline for the duration of the trial, regardless of whether treated areas of psoriasis cleared. Any new lesions were also to be treated. Additional details pertaining to trial treatments are provided in the eMethods in Supplement 3; prohibited medications and products are detailed in eTable 1 in Supplement 3.
Efficacy Assessments
The coprimary efficacy end points were S-IGA success and B-IGA success (defined as achievement of a score of clear [0] or almost clear [1] plus at least a 2-grade improvement from baseline) at week 8. For both S-IGA and B-IGA, success at weeks 2 and 4 and achievement of an S-IGA score of 0 at week 8 were additional end points (eFigure 1 in Supplement 3).
Assessments of pruritus were made using the Scalp Itch−Numeric Rating Scale (SI-NRS)29 and Worst Itch−Numeric Rating Scale (WI-NRS).30 Patients completed SI-NRS and WI-NRS daily, and recorded scores in the provided diary at home each evening by assessing itch during the preceding 24 hours on an 11-point scale (range, 0 [no itch] to 10 [worst imaginable itch]) starting 7 days before the baseline visit through week 8. SI-NRS was scored before WI-NRS, and it specifically asked the patient to report the itch of highest intensity during the past 24 hours on the scalp only; WI-NRS then asked the patient to report intensity of the worst itch overall during the same period. SI-NRS success and WI-NRS success were defined as achievement of at least a 4-point improvement from baseline in patients with baseline scores of 4 or greater; they were assessed at weeks 2, 4, and 8. For SI-NRS, change from baseline at 24 hours, 72 hours, and week 1 were also evaluated.
Other secondary end points included at least a 75% improvement in Psoriasis Scalp Severity Index (PSSI-75) at week 8; at least a 75% improvement in Psoriasis Area and Severity Index (PASI-75) at week 8; change from baseline in PASI at week 2; a score of 0 for the Psoriasis Symptom Diary (PSD) total score and items addressing itching (question 1), pain (question 9), and scaling (question 11) at week 8, as well as the change from baseline in PSD items related to itching, pain, and scaling aggregate score at week 8.
Safety Assessments
Safety analyses included all treatment-emergent adverse events (TEAEs), coded using MedDRA (the Medical Dictionary for Regulatory Activities), version 25.0. Additional assessments included investigator- and patient-rated local tolerability assessments; the PHQ-8 (Patient Health Questionnaire Depression Scale, 8 items31) or the PHQ-A (modified for adolescents32), and the C-SSRS (Columbia-Suicide Severity Rating Scale33).
Statistical Analysis
A sample size of up to approximately 420 patients provided greater than 99% power to detect an overall 35% difference between treatment groups in S-IGA success rates at week 8, and an overall 25% difference between treatment groups on B-IGA success rates at week 8 at α = .025 using a 2-sided stratified (B-IGA at randomization, S-IGA at randomization, and site) Cochran-Mantel-Haenszel test. All statistical analyses were performed using SAS, version 9.4 (SAS Institute), from September 9 to December 30, 2022. All efficacy analyses were performed on the intent-to-treat population with missing data imputed using multiple imputation. Information on statistical analyses and testing schemas are included in the eMethods and eFigure 1 in Supplement 3. All patients who were randomized and applied at least 1 dose of trial medication were included in the population analyzed for safety.
Results
Of 574 patients screened, 432 (mean [SD] age, 47.3 [14.8] years; 243 female [56.3%] and 189 male [43.7%]) were included and randomized to roflumilast foam (n = 281) or vehicle (n = 151) and included in the analysis. The trial was completed by 376 participants (87.0%). Self- or parent-reported demographic and baseline disease characteristics were generally similar between the roflumilast and vehicle groups (Table 1).
Table 1. Participants’ Demographic and Baseline Disease Characteristics, by Study Group.
| Characteristic | Study group, No. (%) | |
|---|---|---|
| Roflumilast foam, 0.3% | Vehicle | |
| Participants, No. | 281 | 151 |
| Age, mean (SD; range), y | 48.6 (14.9; 12-87) | 45.0 (14.3; 15-78) |
| Sex | ||
| Female | 152 (54.1) | 91 (60.3) |
| Male | 129 (45.9) | 60 (39.7) |
| Racea | ||
| American Indian or Alaska Native | 0 | 3 (2.0) |
| Asian | 26 (9.3) | 4 (2.6) |
| Black or African American | 12 (4.3) | 6 (4.0) |
| Native Hawaiian or other Pacific Islander | 3 (1.1) | 1 (0.7) |
| White | 225 (80.1) | 129 (85.4) |
| Multiracial | 4 (1.4) | 1 (0.7) |
| Other | 11 (3.9) | 7 (4.6) |
| Ethnicitya | ||
| Hispanic or Latino | 48 (17.1) | 28 (18.5) |
| Not Hispanic or Latino | 224 (79.7) | 121 (80.1) |
| Not reported | 9 (3.2) | 2 (1.3) |
| Fitzpatrick skin type | ||
| I-III | 202 (71.9) | 116 (76.8) |
| IV-VI | 79 (28.1) | 35 (23.2) |
| BSA affected, mean (SD; range), % | 6.1 (4.3; 0.6-23.0) | 6.0 (4.3; 1.0-22.0) |
| Scalp involvement area, mean (SD; range), % | 34.4 (25.0; 3.0-100.0)b | 36.0 (25.8; 10.0-100.0) |
| Psoriasis involvement | ||
| Elbows and/or knees | 199 (70.8) | 109 (72.2) |
| Elbows | 182 (64.8) | 103 (68.2) |
| Knees | 123 (43.8) | 54 (35.8) |
| Face | 98 (34.9) | 59 (39.1) |
| Genitalia | 47 (16.7) | 28 (18.5) |
| Previous scalp and body psoriasis-specific medical history | ||
| Topical corticosteroid use | 299 (81.5) | 125 (82.8) |
| Inadequate response, intolerance, or contraindication | 165 (58.7) | 88 (58.3) |
| Topical vitamin D derivative use | 50 (17.8) | 27 (17.9) |
| Inadequate response, intolerance, or contraindication | 36 (12.8) | 17 (11.3) |
| S-IGA | ||
| 3 (Moderate) | 239 (85.1) | 131 (86.8) |
| 4 (Severe) | 42 (14.9) | 20 (13.2) |
| B-IGA | ||
| 2 (Mild) | 76 (27.0) | 43 (28.5) |
| 3 (Moderate) | 191 (68.0) | 99 (65.6) |
| 4 (Severe) | 14 (5.0) | 9 (6.0) |
| Other assessment scores | ||
| SI-NRS, mean (SD) | ||
| Daily | 5.9 (2.8) | 6.1 (2.5) |
| Weekly | 5.8 (2.6) | 6.1 (2.3) |
| WI-NRS, mean (SD) | ||
| Daily | 5.6 (2.8) | 5.5 (2.8) |
| Weekly | 5.7 (2.6) | 5.5 (2.6) |
| PASI, mean (SD; range) | 6.7 (3.6; 1.4-23.2) | 6.0 (3.3; 1.6-18.0) |
| PSSI, mean (SD; range) | 21.4 (11.1; 8-72) | 22.2 (11.0; 8-54) |
| PSD total score, mean (SD; range) | 73.4 (40.2; 0-159) | 75.2 (36.9; 1-158) |
Abbreviations: B-IGA, Body−Investigator Global Assessment; BSA, body surface area; PASI, Psoriasis Area and Severity Index; PSD, Psoriasis Symptoms Diary; PSSI, Psoriasis Scalp Severity Index; S-IGA, Scalp−Investigator Global Assessment; SI-NRS, Scalp Itch−Numeric Rating Scale; WI-NRS, Worst Itch−Numeric Rating Scale.
Self- or parent-reported; other included any other race or ethnicity or unreported.
A protocol deviation allowed 1 patient to enter the trial with less than 10% involvement of the scalp.
Efficacy
Significantly greater proportions of patients treated with roflumilast, 0.03%, vs vehicle achieved the coprimary efficacy end points of S-IGA success (66.4% vs 27.8%; proportion difference, 37.1% [97.5% CI, 25.7%-48.6%]; P < .001) and B-IGA success (45.5% vs 20.1%; proportion difference, 24.8% [97.5% CI, 13.6%-36.0%]; P < .001) at week 8 (Figure 2). Significantly greater proportions of the roflumilast group also achieved S-IGA success at weeks 2 (30.4% vs 11.7%; proportion difference, 18.5% [97.5% CI, 9.8%-27.1%]; P < .001) and 4 (53.8% vs 19.5%; proportion difference, 33.0% [97.5% CI, 22.2%-43.8%]; P < .001). Likewise, greater proportions of patients treated with roflumilast vs vehicle achieved B-IGA success at week 4 (32.8% vs 12.1%; proportion difference, 20.7% [97.5% CI, 11.3%-30.1%]; P < .001 [nominal]). Additionally, greater proportions of the roflumilast group achieved S-IGA of clear (40.0% vs 9.1%; proportion difference, 31.9% [97.5% CI, 22.4%-41.4%]; P < .001) and B-IGA of clear (27.8% vs 11.0%; proportion difference, 18.5% [97.5% CI, 9.5%-27.5%]; P < .001 [nominal]) at week 8. Photographs depicting changes in patient appearance are shown in Figure 3.
Figure 2. Proportions of Patients With S-IGA Success and B-IGA Success, by Week.
S-IGA success and B-IGA success were defined as score of clear (0) or almost clear (1) plus at least a 2-grade or greater improvement from baseline. Error bars represent 97.5% CIs; boxes indicate timing of coprimary end points of S-IGA and B-IGA success at week 8. B-IGA indicates Body−Investigator Global Assessment; S-IGA, Scalp−Investigator Global Assessment.
aNominal P value.
Figure 3. Response to Roflumilast Foam, 0.3%, in 2 Participants With Scalp Psoriasis, From Baseline to Week 8.
S-IGA indicates Scalp−Investigator Global Assessment, and SI-NRS, Scalp Itch−Numeric Rating Scale.
A significantly greater proportion of patients treated with roflumilast (50.1%) vs vehicle (16.8%) achieved PASI-75 at week 8 (P < .001; eTable 2 in Supplement 3). Similarly, a significantly greater proportion of those treated with roflumilast (70.9%) vs vehicle (31.3%) achieved PSSI-75 at week 8 (P < .001; eTable 2 in Supplement 3).
A significantly greater proportion of the roflumilast group than the vehicle group achieved SI-NRS success at week 2 (25.2% vs 8.0%; proportion difference, 17.3% [97.5% CI, 7.7%-26.8%]; P < .001), week 4 (46.2% vs 16.8%; proportion difference, 28.4% [97.5% CI, 16.1%-40.7%]; P < .001), and week 8 (65.3% vs 30.3%; proportion difference, 35.4% [97.5% CI, 22.3%-48.6%]; P < .001; eFigure 2A in Supplement 3). Additionally, a greater proportion of the roflumilast group achieved WI-NRS success at weeks 2 (23.3% vs 10.9%, proportion difference 16.1% [97.5% CI, 6.0%-26.2%]; P < .001 [nominal]), 4 (46.5% vs 18.1%, proportion difference 27.3% [97.5% CI, 14.5%-40.1%]; P < .001 [nominal]), and 8 (63.1% vs 30.1%, proportion difference 32.8% [97.5% CI, 18.6%-46.9%]; P < .001; eFigure 2B in Supplement 3). Early and sustained improvements in SI-NRS were observed in the roflumilast group compared with the vehicle group, with a statistically significance difference in SI-NRS recorded from as early as 24 hours in those using roflumilast (least-square mean change from baseline, –0.44 [97.5% CI, –0.71 to –0.17] vs –0.09 [97.5% CI, –0.42 to 0.24]; P < .02; eFigure 2C in Supplement 3). Improvement in the weekly average SI-NRS and WI-NRS was greater for the roflumilast group as early as week 1 (P < .05 [nominal]; eFigure 3 in Supplement 3).
The other patient-reported outcomes were also favorable for the roflumilast group compared with the vehicle group, with the least-squares mean change from baseline in PSD itching, pain, and scaling aggregate score at week 8 showing greater improvement in the roflumilast group than in the vehicle group (–10.9 [97.5% CI, –12.1 to –9.7] vs –5.8 [97.5% CI, – 7.3 to –4.2]; P < .001; eTable 2 in Supplement 3). In addition, at week 8, significantly greater proportions of patients treated with roflumilast vs vehicle achieved a PSD total score of 0 (19.6% vs 7.1%; P < .001), PSD scaling score of 0 (41.5% vs 13.6%; P < .001), PSD pain score of 0 (64.9% vs 40.3%; P < .001), and PSD itching score of 0 (31.7% vs 10.0%; P < .001; eTable 2 in Supplement 3).
Safety
TEAEs were reported for 26.7% of the roflumilast group and 16.6% of the vehicle group (Table 2). Of the 75 patients in the roflumilast group for whom TEAEs were reported, 72 had TEAEs that were mild or moderate. Of the 25 patients in the vehicle group for whom adverse events (AEs) were reported, 23 had mild or moderate AEs. Treatment-related adverse events were reported for 16 patients (5.7%) in the roflumilast group and 3 patients (2.0%) in the vehicle group. Treatment-emergent serious adverse events (SAEs) were reported for 2 patients (0.7%) in the roflumilast group and 1 patient (0.7%) in the vehicle group. The incidence of AEs leading to discontinuation of the trial were low and similar between the roflumilast (1.8%) and vehicle (1.3%) groups. Investigator-rated local tolerability was similar between roflumilast and vehicle groups, with investigators reporting no evidence of irritation for at least 99.2% of all patients at all time points. Patient-rated local tolerability was also similar between roflumilast and vehicle (eFigure 4 in Supplement 3); at least 94.4% of patients reported no or mild sensation on local tolerability assessments at all time points. Depression and suicidal ideation or behavior were not associated with either treatment group based on protocol-specified validated instruments administered by the investigators at each study visit.
Table 2. Treatment-Emergent Adverse Events (TEAEs) Among Roflumilast Foam, 0.03%, vs Vehicle Groups.
| Category | Study group, No. (%) | |
|---|---|---|
| Roflumilast foam, 0.3% | Vehicle | |
| Participants, No. | 281 | 151 |
| Participants with ≥1 TEAE, by type | ||
| TEAE | 75 (26.7) | 25 (16.6) |
| Treatment-related TEAE | 16 (5.7) | 3 (2.0) |
| Treatment-emergent SAEa | 2 (0.7) | 1 (0.7) |
| TEAE leading to trial withdrawal | 5 (1.8) | 2 (1.3) |
| TEAE leading drug discontinuation | 7 (2.5) | 2 (1.3) |
| Most common TEAEs (≥1% of either group) | ||
| Headache | 13 (4.6) | 3 (2.0) |
| Diarrhea | 9 (3.2) | 4 (2.6) |
| COVID-19 | 8 (2.8) | 4 (2.6) |
| Nausea | 6 (2.1) | 0 |
| Nasopharyngitis | 4 (1.4) | 2 (1.3) |
| Hypertension | 3 (1.1) | 2 (1.3) |
| Urinary tract infection | 2 (0.7) | 2 (1.3) |
| Upper respiratory tract infection | 3 (1.1) | 0 |
Abbreviations: SAE, serious adverse event; TEAE, treatment-emergent adverse event.
Included bipolar disorder (roflumilast; unrelated), gastritis (roflumilast; possibly related), joint dislocation, peripheral artery occlusion, and radius fracture (vehicle; all unrelated).
Discussion
Once-daily roflumilast foam, 0.3%, improved psoriasis across multiple efficacy end points in patients with psoriasis of the scalp and body when used as monotherapy. Investigator-reported outcomes (S-IGA, B-IGA, PASI, and PSSI) significantly improved with roflumilast compared with vehicle. Importantly, these improvements were also reflected in patient-reported outcomes (SI-NRS, WI-NRS, and PSD), suggesting clinical improvements observed in those treated with roflumilast may translate into clinically meaningful outcomes for patients. Of note, pruritus improved early, with significantly greater proportions of patients achieving SI-NRS success in the roflumilast group compared with the vehicle group. Significant improvement in pruritus with roflumilast as compared with vehicle was observed as early as 24 hours after treatment initiation. Early improvement in patient-reported outcomes is advantageous because patient satisfaction with therapy can enhance adherence to treatment, particularly when the areas affected by psoriasis are difficult to treat.7,8,34 In both study groups, patients experienced low rates of TEAEs, with few TEAEs leading to trial discontinuation. Roflumilast foam and vehicle had similar investigator- and patient-rated local tolerability assessments.
Results from the current trial are consistent with previous trials comparing roflumilast cream, 0.3%, with vehicle cream in patients with chronic plaque psoriasis. DERMIS-1 and DERMIS-219 demonstrated a statistically significantly greater proportion of patients treated with roflumilast cream achieving IGA success (clear or almost clear status plus at least a 2-grade improvement from baseline on a scale of none [0] to severe [4]) compared with vehicle. Foam formulations are intended to make application to the scalp and other hair-bearing areas easier; in the current trial, success in both investigator- and patient-reported outcomes supports the use of the foam formulation.34 In addition, using a single topical product suitable for both hair-bearing and non–hair-bearing regions is more convenient than using separate products for different body parts. The investigator- and patient-reported outcomes suggest that the foam formulation should help improve patient satisfaction, adherence to therapy, and quality of life.34,35
Limitations
The current trial has a few limitations. Only 2.3% of patients who participated were 17 years or younger. Trial duration was 8 weeks, so interpretation of the results was limited to this time frame, although durable efficacy has been demonstrated in long-term trials of roflumilast cream in patients with psoriasis.36 In addition, the lack of an active comparator prevented comparing efficacy of roflumilast foam with roflumilast cream or other currently available treatments.
Conclusions
The results of this phase 3 randomized clinical trial indicate that once-daily roflumilast foam, 0.3%, is uniquely formulated for hair-bearing areas to improve tolerance and adherence. Use of roflumilast foam was associated with significant improvements in both signs and symptoms of psoriasis of the scalp and body, consistent with outcomes previously observed with roflumilast cream, 0.3%, in patients with psoriasis.19 Roflumilast effectively reduced pruritus, a symptom associated with considerable burden to patients with psoriasis, with significantly greater improvements compared with vehicle observed within 24 hours after first application. Roflumilast foam was well tolerated with no new AEs, and low rates of AEs consistent with those reported with vehicle.
Trial Protocol
Statistical Analysis Plan
eMethods. Additional Methods
eTable 1. Excluded Medications and Treatments
eTable 2. Summary of Secondary End Points
eFigure 1. Primary and Secondary End Point Testing Schema
eFigure 2. Proportions of Patients With SI-NRS Success (A) and WI-NRS Success (B) at Weeks 2, 4, and 8, and LS Mean Change from Baseline in Daily SI-NRS (C)
eFigure 3. Improvement in Weekly SI-NRS (A) and WI-NRS (B) Scores
eFigure 4. Patient-Rated Local Tolerability
Data Sharing Statement
References
- 1.Barbieri JS, Gelfand JM. Patient-reported outcome measures as complementary information to clinician-reported outcome measures in patients with psoriasis. JAMA Dermatol. 2021;157(10):1236-1237. doi: 10.1001/jamadermatol.2021.3341 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Armstrong A, Young M, Seal MS, Higham RC, Greiling T. Treatment burden and the perspectives of patients with psoriasis using topical treatments: results from a national survey of adults with psoriasis in the United States. J Dermatolog Treat. 2024;35(1):2389174. doi: 10.1080/09546634.2024.2389174 [DOI] [PubMed] [Google Scholar]
- 3.Lebwohl MG, Bachelez H, Barker J, et al. Patient perspectives in the management of psoriasis: results from the population-based Multinational Assessment of Psoriasis and Psoriatic Arthritis Survey. J Am Acad Dermatol. 2014;70(5):871-81.e1, 30. doi: 10.1016/j.jaad.2013.12.018 [DOI] [PubMed] [Google Scholar]
- 4.Callis Duffin K, Mason MA, Gordon K, et al. Characterization of patients with psoriasis in challenging-to-treat body areas in the Corrona Psoriasis Registry. Dermatology. 2021;237(1):46-55. doi: 10.1159/000504841 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Egeberg A, See K, Garrelts A, Burge R. Epidemiology of psoriasis in hard-to-treat body locations: data from the Danish skin cohort. BMC Dermatol. 2020;20(1):3. doi: 10.1186/s12895-020-00099-7 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Dopytalska K, Sobolewski P, Błaszczak A, Szymańska E, Walecka I. Psoriasis in special localizations. Reumatologia. 2018;56(6):392-398. doi: 10.5114/reum.2018.80718 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Blakely K, Gooderham M. Management of scalp psoriasis: current perspectives. Psoriasis (Auckl). 2016;6:33-40. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Kivelevitch D, Frieder J, Watson I, Paek SY, Menter MA. Pharmacotherapeutic approaches for treating psoriasis in difficult-to-treat areas. Expert Opin Pharmacother. 2018;19(6):561-575. doi: 10.1080/14656566.2018.1448788 [DOI] [PubMed] [Google Scholar]
- 9.Mosca M, Hong J, Hadeler E, Brownstone N, Bhutani T, Liao W. Scalp psoriasis: a literature review of effective therapies and updated recommendations for practical management. Dermatol Ther (Heidelb). 2021;11(3):769-797. doi: 10.1007/s13555-021-00521-z [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Elewski B, Alexis AF, Lebwohl M, et al. Itch: an under-recognized problem in psoriasis. J Eur Acad Dermatol Venereol. 2019;33(8):1465-1476. doi: 10.1111/jdv.15450 [DOI] [PubMed] [Google Scholar]
- 11.Roblin D, Wickramasinghe R, Yosipovitch G. Pruritus severity in patients with psoriasis is not correlated with psoriasis disease severity. J Am Acad Dermatol. 2014;70(2):390-391. doi: 10.1016/j.jaad.2013.09.030 [DOI] [PubMed] [Google Scholar]
- 12.Griffiths CEM, Jo SJ, Naldi L, et al. A multidimensional assessment of the burden of psoriasis: results from a multinational dermatologist and patient survey. Br J Dermatol. 2018;179(1):173-181. doi: 10.1111/bjd.16332 [DOI] [PubMed] [Google Scholar]
- 13.Dong C, Virtucio C, Zemska O, et al. Treatment of skin inflammation with benzoxaborole phosphodiesterase inhibitors: selectivity, cellular activity, and effect on cytokines associated with skin inflammation and skin architecture changes. J Pharmacol Exp Ther. 2016;358(3):413-422. doi: 10.1124/jpet.116.232819 [DOI] [PubMed] [Google Scholar]
- 14.Wang J, Ho M, Bunick CG. Chemical, biochemical, and structural similarities and differences of dermatological cAMP phosphodiesterase-IV inhibitors. J Invest Dermatol. 2024;S0022-202X(24)02885-9. Published online November 27, 2024. doi: 10.1016/j.jid.2024.10.597 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Annunziato F, Romagnani C, Romagnani S. The 3 major types of innate and adaptive cell-mediated effector immunity. J Allergy Clin Immunol. 2015;135(3):626-635. doi: 10.1016/j.jaci.2014.11.001 [DOI] [PubMed] [Google Scholar]
- 16.Wakita H, Ohkuro M, Ishii N, Hishinuma I, Shirato M. A putative antipruritic mechanism of the phosphodiesterase-4 inhibitor E6005 by attenuating capsaicin-induced depolarization of C-fibre nerves. Exp Dermatol. 2015;24(3):215-216. doi: 10.1111/exd.12606 [DOI] [PubMed] [Google Scholar]
- 17.Das P, Mounika P, Yellurkar ML, et al. Keratinocytes: an enigmatic factor in atopic dermatitis. Cells. 2022;11(10):1683. doi: 10.3390/cells11101683 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Xu R, Feng S, Ao Z, et al. Long-acting β(2) adrenergic receptor agonist ameliorates imiquimod-induced psoriasis-like skin lesion by regulating keratinocyte proliferation and apoptosis. Front Pharmacol. 2022;13:865715. doi: 10.3389/fphar.2022.865715 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Lebwohl MG, Kircik LH, Moore AY, et al. Effect of roflumilast cream vs vehicle cream on chronic plaque psoriasis: the DERMIS-1 and DERMIS-2 randomized clinical trials. JAMA. 2022;328(11):1073-1084. doi: 10.1001/jama.2022.15632 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Gooderham M, Kircik L, Zirwas M, et al. The safety and efficacy of roflumilast cream 0.15% and 0.05% in patients with atopic dermatitis: randomized, double-blind, phase 2 proof of concept study. J Drugs Dermatol. 2023;22(2):139-147. doi: 10.36849/JDD.7295 [DOI] [PubMed] [Google Scholar]
- 21.Blauvelt A, Draelos ZD, Stein Gold L, et al. Roflumilast foam 0.3% for adolescent and adult patients with seborrheic dermatitis: a randomized, double-blinded, vehicle-controlled, phase 3 trial. J Am Acad Dermatol. 2024;90(5):986-993. doi: 10.1016/j.jaad.2023.12.065 [DOI] [PubMed] [Google Scholar]
- 22.Simpson EL, Eichenfield LF, Alonso-Llamazares J, et al. Roflumilast cream, 0.15%, for atopic dermatitis in adults and children: INTEGUMENT-1 and INTEGUMENT-2 randomized clinical trials. JAMA Dermatol. 2024;160(11):1161-1170. doi: 10.1001/jamadermatol.2024.3121 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Simpson EL, Eichenfield LF, Papp KA, et al. Long-term safety and efficacy with roflumilast cream 0.15% in patients aged ≥6 years with atopic dermatitis: a phase 3 open-label extension trial. Dermatitis. 2025. Published online January 10, 2025. doi: 10.1089/derm.2024.0418 [DOI] [PubMed] [Google Scholar]
- 24.Berk D, Osborne DW. Krafft temperature of surfactants in vehicles for roflumilast and pimecrolimus cream and effects on skin tolerability. J Invest Dermatol. 2022;142(8)(suppl):S101. doi: 10.1016/j.jid.2022.05.602 [DOI] [Google Scholar]
- 25.Zirwas MJ, Draelos ZD, DuBois J, et al. Efficacy of roflumilast foam, 0.3%, in patients with seborrheic dermatitis: a double-blind, vehicle-controlled phase 2a randomized clinical trial. JAMA Dermatol. 2023;159(6):613-620. doi: 10.1001/jamadermatol.2023.0846 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Kircik LH, Alonso-Llamazares J, Bhatia N, et al. Once-daily roflumilast foam 0.3% for scalp and body psoriasis: a randomized, double-blind, vehicle-controlled phase IIb study. Br J Dermatol. 2023;189(4):392-399. doi: 10.1093/bjd/ljad182 [DOI] [PubMed] [Google Scholar]
- 27.World Medical Association . World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects. JAMA. 2013;310(20):2191-2194. doi: 10.1001/jama.2013.281053 [DOI] [PubMed] [Google Scholar]
- 28.Dixon JR Jr. The International Conference on Harmonization Good Clinical Practice guideline. Qual Assur. 1998;6(2):65-74. doi: 10.1080/105294199277860 [DOI] [PubMed] [Google Scholar]
- 29.Wang Y, Coyne K, Sofen H, et al. Qualitative analysis and reproducibility assessment of the Scalp Itch Numeric Rating Scale among patients with moderate to severe plaque psoriasis of the scalp. J Dermatolog Treat. 2019;30(8):775-783. doi: 10.1080/09546634.2019.1577546 [DOI] [PubMed] [Google Scholar]
- 30.Naegeli AN, Flood E, Tucker J, Devlen J, Edson-Heredia E. The Worst Itch Numeric Rating Scale for patients with moderate to severe plaque psoriasis or psoriatic arthritis. Int J Dermatol. 2015;54(6):715-722. doi: 10.1111/ijd.12645 [DOI] [PubMed] [Google Scholar]
- 31.Johnson JG, Harris ES, Spitzer RL, Williams JB. The patient health questionnaire for adolescents: validation of an instrument for the assessment of mental disorders among adolescent primary care patients. J Adolesc Health. 2002;30(3):196-204. doi: 10.1016/S1054-139X(01)00333-0 [DOI] [PubMed] [Google Scholar]
- 32.Kroenke K, Strine TW, Spitzer RL, Williams JB, Berry JT, Mokdad AH. The PHQ-8 as a measure of current depression in the general population. J Affect Disord. 2009;114(1-3):163-173. doi: 10.1016/j.jad.2008.06.026 [DOI] [PubMed] [Google Scholar]
- 33.Posner K, Brown GK, Stanley B, et al. The Columbia-Suicide Severity Rating Scale: initial validity and internal consistency findings from three multisite studies with adolescents and adults. Am J Psychiatry. 2011;168(12):1266-1277. doi: 10.1176/appi.ajp.2011.10111704 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 34.Hong CH, Papp KA, Lophaven KW, Skallerup P, Philipp S. Patients with psoriasis have different preferences for topical therapy, highlighting the importance of individualized treatment approaches: randomized phase IIIb PSO-INSIGHTFUL study. J Eur Acad Dermatol Venereol. 2017;31(11):1876-1883. doi: 10.1111/jdv.14515 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 35.Del Rosso JQ, Kircik LH, Zeichner J, Stein Gold L. The clinical relevance and therapeutic benefit of established active ingredients incorporated into advanced foam vehicles: vehicle characteristics can influence and improve patient outcomes. J Drugs Dermatol. 2019;18(2s):s100-s107. [PubMed] [Google Scholar]
- 36.Stein Gold L, Adam DN, Albrecht L, et al. Long-term safety and effectiveness of roflumilast cream 0.3% in adults with chronic plaque psoriasis: a 52-week, phase 2, open-label trial. J Am Acad Dermatol. 2024;91(2):273-280. doi: 10.1016/j.jaad.2024.03.030 [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Trial Protocol
Statistical Analysis Plan
eMethods. Additional Methods
eTable 1. Excluded Medications and Treatments
eTable 2. Summary of Secondary End Points
eFigure 1. Primary and Secondary End Point Testing Schema
eFigure 2. Proportions of Patients With SI-NRS Success (A) and WI-NRS Success (B) at Weeks 2, 4, and 8, and LS Mean Change from Baseline in Daily SI-NRS (C)
eFigure 3. Improvement in Weekly SI-NRS (A) and WI-NRS (B) Scores
eFigure 4. Patient-Rated Local Tolerability
Data Sharing Statement