Efficacy and Safety of Calcipotriene Plus Betamethasone Dipropionate Aerosol Foam in Patients With Psoriasis Vulgaris: a Randomized Phase III Study (PSO-FAST)

December 2015 | Volume 14 | Issue 12 | Original Article | 1468 | Copyright © December 2015


Craig Leonardi MD,a Jerry Bagel MD,b Paul Yamauchi MD,c David Pariser MD,d Zhenyi Xu MD,e Martin Olesen MD,e* Marie Louise østerdal MSc,e and Linda Stein Gold MDf

aSaint Louis University School of Medicine, St Louis, MObPsoriasis Treatment Center of Central New Jersey, East Windsor, NJ cDavid Geffen School of Medicine at UCLA, Los Angeles, CAdEastern Virginia Medical School and Virginia Clinical Research, Inc., Norfolk, VAeLEO Pharma A/S, Ballerup, DenmarkfHenry Ford Health System, Detroit, MI*LEO Pharma employee at time of study

Abstract
INTRODUCTION: An innovative aerosol foam formulation of calcipotriene 0.005% (Cal) plus betamethasone dipropionate 0.064% (BD) designed to improve treatment outcomes.OBJECTIVE: To compare the efficacy and safety of Cal/BD aerosol foam with aerosol foam vehicle in patients with psoriasis.DESIGN: Phase III, double-blind, randomized PSO-FAST (Cal/BD foam in PSOriasis vulgaris, a Four-week, vehicle-controlled, efficacy And Safety Trial) study recruited patients with ≥ mild severity psoriasis of the trunk and/or limbs from 27 US outpatient sites (NCT01866163). Patients were randomized (3:1) to Cal/BD foam or vehicle once-daily for 4 weeks. Primary outcome: proportion of patients at week 4 who achieved treatment success according to physician’s global assessment. Secondary outcomes: modified (excluding head) psoriasis area and severity index (mPASI) and patient's assessment of itch (visual analog scale). Safety was monitored by adverse events/calcium homeostasis.RESULTS: 426 patients enrolled between June and October 2013 (Cal/BD foam, n=323; vehicle, n=103). At week 4, significantly more patients using Cal/BD foam achieved treatment success versus vehicle (53.3 versus 4.8%; OR 30.3, 95% CI 9.7,94.3; P < .001) and mean mPASI score was significantly lower for patients using Cal/BD foam than vehicle (2.0 versus 5.5; adjusted difference –3.3, P <.001). Significantly greater itch relief was observed for patients using Cal/BD foam than vehicle (P = .010 at day 3, P < .001 from day 5). Adverse drug reactions were reported in 10 Cal/BD foam patients (3.1%) and two vehicle patients (1.9%); events occurred in one patient each except application site pain (Cal/BD foam, two patients; vehicle, one patient). There were no clinically significant changes in calcium homeostasis.CONCLUSIONS: Cal/BD foam was efficacious, achieved rapid itch relief and was well tolerated in patients with body psoriasis. This innovative aerosol foam formulation is expected to become a valuable treatment option. J Drugs Dermatol. 2015;14(12):1468-1477.

INTRODUCTION

Psoriasis vulgaris is a chronic inflammatory disease characterized by scaly plaques of thickened skin.1,2 The World Health Organization views psoriasis as a disabling, painful disease associated with multiple comorbidities, including cardiovascular disease, psoriatic arthritis and metabolic syndrome.3–6 These physical and other psychological comorbidities2 impair health-related quality of life (HRQoL).7
Guidelines recommend the topical use of corticosteroids and vitamin D3 analogs as first-line treatment for psoriasis, either as separate products (used in combination) or as a fixed combination treatment.8,9 The vitamin D3 analog calcipotriene and the corticosteroid betamethasone dipropionate in fixed combination formulations have superior efficacy compared with their individual components.10,11 In addition, the fixed combination has a more favorable tolerability profile versus monotherapy as local skin reactions typically associated with calcipotriene treatment appear to be attenuated by the addition of betamethasone dipropionate. Additionally, the presence of calcipotriene may increase the steroid effect within the combination, without compromising the tolerability profile.10 The once-daily fixed combination also offers improved convenience over the twice-daily applications required for the respective monotherapies,12 which can improve adherence.13 Topical suspension and ointment formulations of this fixed combination (Taclonex®/Daivobet®/Dovobet®) are established first-line treatments for psoriasis vulgaris.14
 
An innovative alcohol-free aerosol foam formulation of the fixed combination calcipotriene 0.005% (Cal) plus betamethasone dipropionate 0.064% (BD), incorporating a non-skin-drying emollient vehicle, has been developed to improve treatment for patients with psoriasis vulgaris. Early-phase exploratory studies have shown increased active ingredient penetration into pig ear skin with Cal/BD aerosol foam, along with significantly higher steady-state levels of Cal and BD than Cal/BD ointment.15 In a clinical psoriasis plaque test model, Cal/BD aerosol foam had greater antipsoriatic effect than Cal/BD ointment.16 Phase II clinical studies have demonstrated efficacy for Cal/BD aerosol foam as well as a favorable tolerability profile.17,18 No clinically relevant impacts on the hypothalamic–pituitary–adrenal axis or calcium metabolism were exhibited in patients with extensive psoriasis receiving Cal/BD doses at the upper limit of topical exposure.19
To confirm the favorable efficacy and safety profile seen in Phase II trials, the Phase III PSO-FAST trial was performed to compare the Cal/BD aerosol foam with vehicle when applied once daily for up to 4 weeks in patients with psoriasis vulgaris.20

MATERIALS AND METHODS

Patients

Eligible patients were ≥18 years of age, with a clinical diagnosis of psoriasis vulgaris of the trunk and/or limbs (of ≥mild severity, according to the physician's global assessment of disease severity [PGA; also referred to as investigator's global assessment], and of a ≥6-month duration) and were amenable to topical therapy with ≤90 g/week trial medication. Patients had between 2 and 30% of their body (ie, trunk and limbs) surface area affected by the disease, with a modified (excluding the head, which was not treated) psoriasis area and severity index (mPASI) score of ≥2. Each patient also had a target lesion of ≥5 cm at its longest axis, scoring ≥1 (range 0–4) for each of redness, thickness, and scaliness, and ≥4 in total, assessed by the physician.
Patients were excluded if they had received the following prior to randomization: etanercept within 4 weeks, adalimumab or infliximab within 8 weeks, ustekinumab within 16 weeks, other biologics within 4 weeks or 5 half-lives (whichever was longer), systemic treatments with a possible effect on psoriasis within 4 weeks, psoralen combined with ultraviolet A therapy within 4 weeks, ultraviolet B therapy within 2 weeks, or topical antipsoriatic treatment within 2 weeks. Other exclusion criteria were planned excessive exposure of the treated area to sunlight, planned initiation or change to concomitant medication that could affect psoriasis, current diagnosis of guttate, erythrodermic, exfoliative or pustular psoriasis, or other inflammatory skin disorders, any skin infections or manifestations, such as herpes or ichthyosis, disorders of calcium metabolism associated with hypercalcemia, severe renal insufficiency or severe hepatic disorders, or hypersensitivity to any component of the investigational products.

Study Design

PSO-FAST (Cal/BD aerosol foam in PSOriasis vulgaris, a Four-week, vehicle-controlled, efficacy And Safety Trial) was a Phase III, multicenter (US), double-blind, vehicle-controlled, 4-week study. Patients previously treated with antipsoriatic treatments or other relevant treatments (according to the eligibility criteria) underwent a washout period of up to 4 weeks prior to the start of treatment. Patients were randomized (3:1) to Cal/BD aerosol foam or aerosol foam vehicle once daily for up to 4 weeks.
Treatment assignment was performed by the site investigator using a central interactive web response system in accordance with a preplanned computer-generated randomization schedule, which was stratified by site. Patients who were clear of psoriasis at weeks 1 or 2 (according to the physician) were permitted to stop treatment but continue in the trial; if psoriasis reappeared, treatment was reinitiated. The institutional review boards of all investigational sites approved the protocol. This study was conducted according to Good Clinical Practice guidelines and the principles of the Declaration of Helsinki. All patients provided written informed consent prior to enrollment. The ClinicalTrials.gov identifier is NCT01866163.

Study Objectives and Endpoints

The primary objective was to evaluate the efficacy of Cal/BD aerosol foam versus vehicle after up to 4 weeks of treatment, in adult patients with psoriasis vulgaris. The secondary objective, safety, was monitored throughout the trial by incidence of adverse events (AEs) and by calcium homeostasis parameters. The primary efficacy endpoint was the proportion of patients at week 4 who achieved treatment success, defined as clear or almost clear (for patients with ≥moderate disease at baseline) or clear (for patients with mild disease at baseline), according to PGA. Secondary efficacy endpoints were mean mPASI at weeks 1 and 4. PASI50 and PASI75, defined as the proportion of patients with a ≥50% or ≥75% reduction in mPASI score, were
 
also determined as tertiary endpoints. For Patient's Global Assessment of disease severity (PaGA), treatment success was defined as clear or very mild.

ASSESSMENTS

All physician and patient assessments were performed at each visit (baseline and weeks 1, 2, and 4). Patients performed self-assessments (results were recorded within patient diaries) on days 3 and 5. Severity of psoriasis was evaluated according to PGA, using a five-point scale (clear, almost clear, mild, moderate, severe).21 Extent and severity of clinical signs were assessed to determine an mPASI score; each area (arms, trunk, and legs) was assessed separately.22 Extent of disease was evaluated by percentage involvement (no involvement, <10%, 10–29%, 30–49%, 50–69%, 70–89%, 90–100%) and severity of clinical signs (redness, thickness, scaliness) was assessed using a five-point scale (0=none, 1=mild, 2=moderate, 3=severe, 4=very severe). A target lesion, selected at baseline by the investigator was used to evaluate the change from baseline in severity of clinical signs at week 4.
PaGA was evaluated using a five-point scale (clear, very mild, mild, moderate, severe). Patients assessed the maximal intensity of itch over 24 hours before each visit and itch-related sleep loss during the night prior to each visit (and days 3 and 5), according to a visual analog scale (VAS, range 0–100 mm).
Safety was assessed by evaluating vital signs, AEs and adverse drug reactions (ADRs; ie, AEs that were not specifically described as 'not related' by study investigators). Investigators and patients performed assessments of local safety and tolerability at the application site. Blood and urine samples were collected at baseline and at week 4 to evaluate albumin-corrected serum calcium levels and urinary calcium:creatinine ratios, respectively. Patients experiencing AEs possibly or probably attributed to study treatment or not assessable at week 4 were followed up approximately 14 days after their last planned visit; this was to include patients with albumin-corrected serum calcium levels above the reference range (reference range upper limit: 10.2 mg/dL) at the last planned visit.
table 1

Statistical Analysis

It was planned to include 400 patients in this study, with 3:1 randomization (Cal/BD:vehicle), in order to achieve 95% power at a 5% significance level. Sample size was based on completed Phase II trials, where approximately 4517 and 55%18 of patients using Cal/BD aerosol foam achieved treatment success at week 4, according to PGA, compared with 6% of patients using the vehicle.18 All endpoints were analyzed on an intent-to-treat (ITT) basis. All AEs and ADRs were assessed according to the Medical Dictionary for Regulatory Activities (MedDRA) Version 16.0.
Categorical outcomes were compared between treatment groups using the Cochran-Mantel-Haenszel method, adjusted for pooled centers. For continuous outcomes, analysis of covariance (ANCOVA) was used, adjusted for baseline and pooled centers. Missing values for the primary endpoint and secondary endpoints, and PASI50 and PASI75, were handled by applying multiple imputation techniques, assuming 'missing at random'. Sensitivity analyses were performed for the primary endpoint and outputs are presented as observed cases, non-responder imputation, and last observation carried forward. The remaining endpoints were analyzed using an observed cases approach. All significance tests are presented as two sided and confidence intervals (CI) with 95% degree of confidence.
All patients who received study medication were included in the full analysis set and analyzed for efficacy. All patients who received study medication, and for whom the presence or confirmed absence of AE was available, were included in the safety analysis set.

RESULTS

Patients

Between June 2013 and October 2013, 491 patients from 27 US centers were enrolled in this trial; of these, 426 patients (median age 51 years [range 18–87]) were randomized to Cal/BD aerosol foam (n = 323) or vehicle (n = 103) and included in the full (ITT) and safety analysis sets. Patient demographics and baseline characteristics were balanced between treatment groups and were representative of the target patient population (Table 1). This trial was completed by 97% of the patients randomized to
 
table 2
treatment; of the 14 patients who withdrew, eight were lost to follow-up (Fig 1). Overall, 76.2% of patients using Cal/BD aerosol foam and 86.3% of patients using vehicle were fully compliant to treatment, an additional 16.9 and 12.7% of patients, respectively, missed ≤10% of all applications.

Efficacy

Investigator assessments By week 4, 53.3% of 323 patients using Cal/BD aerosol foam achieved treatment success (according to PGA) compared with 4.8% of 103 patients using vehicle (odds ratio [OR] 30.3; 95% CI 9.7, 94.3; P < .001; multiple imputation applied for missing data; Fig 2a). Similar findings were seen for sensitivity analyses (Table 2). Furthermore, greater proportions of patients using Cal/BD aerosol foam achieved treatment success at weeks 1 and 2 versus those using vehicle (week 1, 8.5 versus 1.0%; week 2, 26.4 versus 1.9%; multiple imputation).
Assessment by mPASI further demonstrated statistically significant and rapid improvement in disease extent and severity for patients using Cal/BD aerosol foam versus vehicle (Fig 2b). By week 1, mean mPASI score was significantly lower in patients using Cal/BD aerosol foam versus vehicle (mean mPASI score, 4.5 versus 6.2; adjusted mean difference –1.3; 95% CI –1.8, –0.8; P < .001; multiple imputation), corresponding to mean percentage changes in mPASI from baseline of –38.2% (Cal/BD aerosol foam) versus –19.6% (vehicle). By week 4, these differences increased, with mean mPASI scores of 2.0 for patients using Cal/BD aerosol foam versus 5.5 for vehicle (adjusted mean difference –3.3; 95% CI –3.9, –2.7; P < .001; multiple imputation), reflecting mean percentage changes in mPASI from baseline of –71.9 and –25.8%, respectively. At week 4, 82.3% of patients using Cal/BD aerosol foam achieved PASI50 compared with 28.0% using vehicle (OR 13.9; 95% CI 7.6, 25.7; P < .001; multiple imputation; Fig 2c); similarly, significantly more patients using Cal/BD aerosol foam achieved PASI75 at week 4 versus vehicle (52.9 versus 8.2%, respectively; OR 14.9; 95% CI 6.5, 34.0; P < .001; multiple imputation; Fig 2d). In addition, week 4 assessment of target lesion clinical sign severity (redness, thickness, scaliness) found that signs completely disappeared in 32.6, 57.5 and 70.0%
 
table 3
of patients, respectively, using Cal/BD aerosol foam versus 3.0, 4.0 and 18.2% using vehicle (Fig 3).
Patient-reported outcomes At week 4, treatment success rates according to PaGA mirrored those of investigators, with treatment success achieved in significantly more patients using Cal/BD aerosol foam versus vehicle (65.2 versus 22.2%; OR 7.9; 95% CI 4.4, 14.1; P < .001; observed cases). Furthermore, for patients using Cal/BD aerosol foam, the proportion with severe disease (according to PaGA) decreased from 18.9% (61/323) at baseline to 1.3% (4/313) by week 4; a decrease from 21.4% (22/103) to 10.1% (10/99) was observed with vehicle.
Patients reported significant and rapid reduction in itch with Cal/BD aerosol foam (Fig 4a). Itch relief (according to VAS) was observed by the first assessment (day 3), and decreases in itch score were significantly greater with Cal/BD aerosol
 
table 4
foam versus vehicle (mean change in VAS score, –22.9 versus –18.7; adjusted mean difference, –6.4; 95% CI –11.3, –1.6; P = .010; observed cases). Itch relief with Cal/BD aerosol foam was significantly greater at all assessed time points. Among patients with any reported itch at baseline (96.2% of patients overall), 36.8% of patients using Cal/BD aerosol foam reported a 70% reduction in itch at day 3, a significantly greater proportion than with vehicle (24.0%; OR 1.9; 95% CI 1.1, 3.2; P = .018; observed cases). By end of treatment, itch relief continuously improved and remained significantly better with Cal/BD aerosol foam (mean change in VAS score, –41.8 versus –25.1; adjusted mean difference, –20.4; 95% CI –25.2, –15.6; P < .001; observed cases). At week 4, 83.5% of patients using Cal/BD aerosol foam achieved a 70% reduction in their itch; statistically significantly greater than vehicle (40.6%; OR 7.0; 95% CI 4.2, 11.7; P < .001; observed cases; Fig 4b).
The reduction in itch-related sleep loss at day 3 versus baseline was also significantly greater with Cal/BD aerosol foam than vehicle (mean change in VAS score, –10.8 [Cal/BD], –7.5 [vehicle]; adjusted mean difference –6.0; 95% CI –10.4, –1.5; P = .009; observed cases). This statistically significant difference was maintained throughout the rest of the study (week 4 mean change in VAS score, –20.5 [Cal/BD], –13.2 [vehicle]; adjusted mean difference –11.9; 95% CI –16.0, –7.7; P < .001; observed cases; Fig 4c). Among patients with any itch-related sleep loss at baseline (79.8% of patients overall), a 70% reduction in itch-related sleep loss at day 3 was reported by 35.5% in the Cal/BD aerosol foam group versus 22.9% in the vehicle group (OR 1.9; 95% CI 1.0, 3.4; P = .035), increasing to 70.8% by week 4 versus 39.8%, respectively (OR 4.0; 95% CI 2.3, 6.9; P < .001; observed cases; Fig 4d).

Safety and tolerability

The mean duration of treatment was 4.0 weeks in the Cal/BD aerosol foam group and 4.1 weeks in the vehicle group, covering the full treatment period and reflecting the high completion rate. The mean amount of Cal/BD aerosol foam used per week was similar to the vehicle (29.8 g versus 32.1 g).
In total, 78 AEs were reported during this trial; incidence was similar between treatment groups (Cal/BD, 51 patients [15.8%]; vehicle, 12 patients [11.7%]); most events were mild or moderate in severity. The most common AEs were nasopharyngitis (six patients [1.9%], all in Cal/BD aerosol foam group) and application-site pain (Cal/BD, three patients [0.9%]; vehicle, two patients [1.9%]; Table 3). Fifteen ADRs were reported in 12 patients (Cal/BD, 10 patients [3.1%]; vehicle, two patients [1.9%]); all events were observed in one patient each except application-site pain (Cal/BD, 2 patients [0.6%]; vehicle, one patient [1.0%]; Table 3). Five severe AEs were reported; these were all in Cal/BD aerosol foam patients and were single occurrences of cellulitis, edema peripheral, bipolar disorder, substance-induced psychotic disorder and rebound psoriasis. Two of these events (bipolar disorder and substance-induced psychotic disorder) were reported as serious AEs. No other serious AEs were
 
table 5
reported. There were no withdrawals due to AEs. Local safety and tolerability reactions were few and occurred with similar frequency in the two treatment groups; most were mild or moderate in severity. The most frequently reported local reactions at week 4 were burning/pain (Cal/BD, seven patients [2.2%]; vehicle, four patients [4.0%]), erythema (Cal/BD, six patients [1.9%]; vehicle, two patients [2.0%]), and dryness (Cal/BD, three patients [1.0%]; vehicle, three patients [3.0%]).
No clinically significant changes in mean albumin-corrected serum calcium or urinary calcium:creatinine ratio were seen in either treatment group. Three patients in the Cal/BD aerosol foam group developed albumin-corrected serum calcium levels above the normal range at week 4. In all three patients, albumin-corrected serum calcium levels rose from normal at baseline (9.6, 9.0, and 9.5 mg/dL) to high at week 4 (10.3, 10.5, and 10.4 mg/dL), although the week 4 levels were only slightly above the upper limit of the reference range (10.2 mg/dL). One of the cases was reported as a mild AE. Albumin-corrected serum calcium levels in all three patients returned to normal or low at follow-up.

DISCUSSION

This Phase III study assessed the efficacy and safety of Cal/BD aerosol foam in adult patients with psoriasis vulgaris. Over 4 weeks, this innovative formulation provided rapid improvement in disease status, while maintaining the favorable tolerability profile seen with established fixed combination Cal/BD topical suspension and ointment formulations.
table 6
 
In this large, vehicle-controlled 4-week study of patients with mild-to-severe psoriasis, a treatment success rate (according to PGA) of 53.3% and a PASI75 response rate of 52.9% were achieved. These results are similar to the 45 and 55% treatment success rates reported in two earlier Phase II studies of Cal/BD aerosol foam.17,18 Furthermore, patient perception of Cal/BD aerosol foam treatment success (according to PaGA) was high (65.2%) and similar to that reported by the investigators. In this study, the fixed combination Cal/BD aerosol foam was not tested against any of its individual active components; however, a randomized, Phase II trial has shown Cal/BD aerosol foam to be more efficacious than
table 7
 
either individual active component separately, when in the aerosol foam vehicle.17
Itch is a common and distressing aspect of psoriasis23 causing discomfort and is often associated with sleep loss, which can negatively impact on patient daily productivity.24 A rapid and effective improvement in patient-reported itch was demonstrated in this study, with 83.5% of patients using Cal/BD aerosol foam achieving a 70% reduction in itch by week 4. There are few therapeutic options available to minimize itch in patients with psoriasis and this level of itch reduction is desirable in new treatments. This trial also demonstrated itch alleviation led to significant reductions in sleep loss, with 70.8% of patients using Cal/BD aerosol foam reporting a 70% reduction in itch-related sleep loss by week 4. Alleviation of itch can therefore significantly improve HRQoL and is an important feature of symptom relief with Cal/BD aerosol foam.
The tolerability profile of Cal/BD aerosol foam was consistent with the fixed combination topical suspension and ointment formulations seen in previous studies.12,25,26 Incidence of AEs and ADRs in this study was low (15.8 and 3.1%, respectively, for Cal/BD aerosol foam). Likewise, local safety and tolerability reactions were infrequent and usually mild-to-moderate. There were no clinically significant changes in mean albumin-corrected serum calcium or urinary calcium:creatinine ratio seen in either treatment group. As such, the good tolerability profile of the topical suspension and ointment formulations was maintained with this innovative vehicle. Cal/BD aerosol foam may be a beneficial treatment option for those patients who are candidates for therapy with a superpotent steroid, but desire a therapeutic safety profile similar to that of a less potent steroid.
Nonadherence is a universal and complex challenge in medicine,27 which is influenced by a number of factors, including mode of administration, efficacy and patient education.28,29 Adherence impacts the effectiveness in the 'real-life' setting of topical treatments for psoriasis and other chronic disorders.30–32 While topical therapies remain the mainstay of psoriasis treatment,33 the choice of vehicle can have considerable impact on treatment adherence. Patients with psoriasis are less willing to comply with topical treatment regimens if they find application to be cumbersome and time-consuming,28,29 and comparisons of treatment vehicles have shown that patients prefer more cosmetically elegant formulations that are convenient and easy-to-use, thereby minimizing impact on daily life.34,35 The innovative Cal/BD aerosol foam was developed to improve patient experience with topical psoriasis treatment and provides a highly effective treatment delivered in a more acceptable non-skin-drying emollient vehicle that fits with greater ease into daily life. This new formulation has the potential for greater patient acceptability, leading to improved effectiveness in the real-life setting.
In conclusion, in this study including patients with all disease severities, the fixed combination Cal/BD aerosol foam was efficacious and well tolerated in patients with psoriasis of the body; the response to treatment was rapid and with significant itch relief. Cal/BD aerosol foam is expected to be a valuable treatment option for psoriasis vulgaris.

DISCLOSURES

All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr. Leonardi has been a consultant for LEO Pharma (relevant to this manuscript) and Abbvie, Amgen, Dermira, Eli Lilly, Janssen, Sandoz, UCB, Pfizer (not relevant to this manuscript), received honoraria from Abbvie, Amgen, Dermira, Eli Lilly, Sandoz, UCB, Pfizer, Celgene, Novartis (not relevant to this manuscript), and has participated in speakers bureaus for Abbvie and Celgene (not relevant to this manuscript). Dr. Bagel has been a consultant, has participated in speakers bureaus, has been an investigator for LEO Pharma (relevant to this manuscript), and has no other relevant disclosures. Dr. Yamauchi has received grants from LEO Pharma (relevant to this manuscript), Amgen, Celgene, Galderma USA, Janssen-Ortho Inc, Lilly ICOS LLC, Pfizer Inc. (not relevant to this manuscript), honoraria from LEO Pharma (relevant to this manuscript), Abbvie, Amgen, Baxter, Galderma USA, Janssen-Ortho Inc, Lilly ICOS LLC, Novartis Pharmaceuticals Corp., Pfizer Inc. (not relevant to this manuscript). Dr. Pariser has received grants from LEO Pharma (relevant to this manuscript), and has no other relevant disclosures. Dr. Xu, and Ms Østerdal are employees of LEO Pharma. Dr. Olesen was an employee of LEO Pharma at the time of this study (relevant to this manuscript) and is now an employee of Novo Nordisk A/S (not relevant to this manuscript). Dr. Stein Gold has been a consultant for LEO Pharma, Pfizer, Novartis, Lilly, Galderma, Valeant (relevant to this manuscript), Taro, Activis, Allergan (not relevant to this manuscript), has received honoraria from LEO Pharma, Pfizer, Novartis, Lilly, Galderma, Valeant (relevant to this manuscript), Taro, Activis, Allergan (not relevant to this manuscript), and has participated in speakers bureaus for LEO Pharma, Pfizer, Novartis, Lilly, Galderma, Valeant (relevant to this manuscript), Taro, Activis, Allergan (not relevant to this manuscript).

ACKNOWLEDGMENTS

Author Contributions: Dr. Leonardi 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. Study concept and design: Leonardi, Olesen. Analysis and interpretation of data: Leonardi, Bagel, Yamauchi, Pariser, Xu, Olesen, Østerdal, Stein Gold. Drafting of the manuscript: Leonardi, Bagel, Yamauchi, Pariser, Xu, Olesen, Østerdal, Stein Gold (see funding/support). Critical revision of the manuscript for important intellectual content: Leonardi, Bagel, Yamauchi, Pariser, Xu, Olesen, Østerdal, Stein Gold. Statistical analysis: Østerdal. Study supervision: Leonardi, Olesen, Xu.
 
Funding/Support: This study was sponsored and funded by LEO Pharma. We would like to thank all study investigators. We would also like to thank Richard Bennett, from LEO Pharma, for clinical trial management. Additionally, we thank Carly Hayes, PhD, from Mudskipper Business Ltd, who provided medical writing support funded by LEO Pharma.
Role of the Funder/Sponsor: LEO Pharma had a role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review or approval of the manuscript; and decision to submit the manuscript for publication. LEO Pharma also provided administrative, technical, and material support for this trial.

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AUTHOR CORRESPONDENCE

Craig Leonardi MDcraig.leonardi@centralderm.com
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