A daily regimen of a ceramide‐dominant moisturizing cream and cleanser restores the skin permeability barrier in adults with moderate eczema: A randomized trial

Abstract The dysfunctional skin barrier in eczema patients may be attributed to decreased levels of ceramides in the stratum corneum. The aim of this study was to determine whether a two‐part system consisting of a ceramide‐dominant physiological lipid‐based moisturizing cream and cleanser could ameliorate the signs and symptoms of moderate eczema in adults over 28 days compared to placebo. Assessments were conducted at baseline and every 7 days thereafter. Eczema area severity index score decreased significantly across all time points in both groups compared to baseline (P < .0001), however, this decrease was not significant between groups at day 28 (P = .7804). In contrast, transepidermal water loss and skin hydration significantly improved over time in the active group, while it either stayed the same or worsened in the placebo group (P = .0342 and P < .0001, respectively). There was no difference in the use of mometasone furoate as rescue medication over time between groups (P = .1579). Dermatology life quality index scores improved significantly in both groups (P < .0001), with no difference between groups (P = .5256). However, patient satisfaction was greater in the active compared to the placebo group for several parameters including relief of itch, dry skin, skin softness and smoothness (all P < .05). No patients withdrew from the study due to adverse events (AEs) and there were no serious AEs. The ceramide‐dominant moisturizing cream and cleanser safely restores skin permeability and improves the signs and symptoms of eczema in adults.

as water modulators and an integral part of the skins permeability barrier by forming multi-layered lamellar structures with cholesterol and free fatty acids between cells of the SC. 4 The abnormal barrier function in eczema results in increased transepidermal water loss (TEWL) leading to xerosis, and predisposes the skin to inflammatory processes evoked by irritants and allergens. 5,6 In addition to ceramide deficiency, changes in ceramide profiles including ceramide chain length have been linked with the impaired SC barrier function in eczema. 7,8 Eczema treatments have traditionally included topical corticosteroids and immunomodulators that do not target the underlying structural barrier abnormalities, and have clinically well-recognized undesirable side effects. 9 More recently it has been established that a crucial eczema management tool, including between episodes of flare ups, is the frequent use of an appropriate moisturizer. 10 However, most conventional moisturizers do not address the underlying lipid deficiency in eczematous skin. 11 Conventional moisturizers form a more superficial occlusive barrier on the skin whereas physiologic lipids, including ceramides, permeate the SC and are synthesized in the keratinocytes, processed in lamellar bodies, and secreted back into the SC to become a part of the dermal matrix. 12 As such, and coupled with an improved understanding of the etiology of eczema, new pharmacological approaches should focus on correcting the epidermal barrier dysfunction through the inclusion of specific SC lipids at the appropriate concentration in moisturizers. 13,14 The objective of this randomized, double-blind, placebo-controlled, single centre, comparative trial was to determine whether a two-part system consisting of a ceramide-dominant physiological lipid-based moisturizing cream and cleanser, could safely ameliorate the signs and symptoms of moderate eczema in adult patients compared to placebo over 28 days. Efficacy was determined through the evaluation of eczema area severity index (EASI), TEWL, and skin hydration. In addition, patients completed the dermatology life quality index (DLQI) survey as well as a patient satisfaction survey. Safety of the study products was also closely monitored.

| Study design
Patients meeting the inclusion criteria were randomly assigned to receive either the ceramide cream and ceramide cleanser or placebo cream and placebo cleanser according to a randomization schedule F I G U R E 1 Flow chart illustrating the progress of participants through the study generated using SAS statistical software (SAS Institute Inc.) blocked in groups of six ( Figure 1). The study products were filled into identical 350 mL pump pack containers and each assigned a randomization code to conceal their identity from participants and the physician allocating treatments and assessing outcomes. Data analysts were also blinded to the identification of each study group until the final efficacy analyses were complete.
Patients were instructed to massage the cleanser into wet skin across their whole body once daily, rinse with water and pat dry, for 28 days. Patients were also required to apply the cream liberally to their whole body, in particular eczema-prone areas, twice daily, morning and night for 28 days. One application of cream was required after daily body cleansing. In addition, patients were supplied with mometasone furoate 0.1% w/w (Zatamil Hydrogel; Ego Pharmaceuticals Pty. Ltd., Braeside, Victoria, Australia) to be used as rescue medication for the duration of the study in place of their usual topical corticosteroids or calcineurin inhibitors.

| Efficacy and safety assessments
The primary efficacy outcome was comparison of the treatments effects on symptom severity as assessed by EASI at day 28 compared The DLQI is a 10 item questionnaire focusing on how eczema affects overall life quality rated using a four point scale from "not at all" to "very much". 17 The patient satisfaction survey is a 9 item questionnaire which was designed to focus on eczema symptoms and satisfaction with the treatments, rated on the same scale.
Prior to measurements of skin biophysical properties, participants were required to equilibrate in a closed environment with a constant temperature (20 C ± 2 C) and humidity (45 to 55% RH 3 | RESULTS

| Study population
The intention-to-treat (ITT) population included all participants who were randomized and received at least one dose of the study products. The demographics and baseline characteristics of the ITT population are described in Table 2  respectively. Therefore, only results for the ITT population are presented. One participant found that she was pregnant during the course of the study, however, the pregnancy was deemed unlikely to significantly impact the efficacy results so the participant's data was included in the analysis.
Age and gender were approximately balanced between the two groups, and the majority of participants were either Asian or Caucasian. The most common skin allergies/sensitivities were to soaps, followed by food, perfumes, cosmetics, deodorants and sunscreen, which were well distributed between groups. Twenty-six participants did not report any allergies/sensitivities at baseline. The most common non-eczema conditions were hay fever/allergies, asthma and dandruff, which were also well distributed between groups.

| Efficacy assessment
Baseline EASI scores were matched between groups (P > .05), however the placebo group had slightly less variance in scores overall due to two outliers ( For the secondary efficacy outcomes, EASI scores significantly improved across visits in both groups (P < .0001; Figure 2), however, there were no differences in the change in EASI score between the active and placebo groups at any time point (all P > .05).
TEWL was similar in both groups at baseline (P > .05; Table 2). Baseline DLQI scores were similar in both groups (P > .05; Table 2). DLQI scores improved significantly over time in both groups (P < .0001; Figure 6), with no significant difference observed between groups (P = .7804). However, analysis of the patient satisfaction survey by cumulative logistic regression (Table 3) found that several questions were answered more positively in the active compared to the placebo group, including relief of itch on day 14 (P = .0255), relief of dry skin at both day 14 (P < .0001) and day 28 (P = .0033) and effects on skin softness and smoothness at day 14 (P = .0001) and day 28 (P = .0573).
The reduction of rash approached significance at day 14 (P = .0698).
No differences were found between groups for the reduction of redness and inflammation, treatment pleasantness, maintenance of healthy skin, ease of use and overall satisfaction (all P > .05).

| Safety assessment
There were a small number of AEs (22) (Table 1) which have different mechanisms of action.
Comprising a "triple moisturizing system", 20 ceramide cream and cleanser contain glycerin and sodium PCA as humectants to attract and hold water in the SC and epidermis, dimethicone and petrolatum as occludents to maintain the increased water content in the skin, and paraffinum liquidum, hexanediol and caprylyl glycol as emollients to smooth rough skin created by improperly desquamating corneocytes. 21 The benefits obtained through the use of these traditional moisturizing ingredients are further enhanced by additional ingredients targeted to assist in correcting the epidermal barrier dysfunction. 13 Ceramide cream and cleanser also contain ceramide EOP and ceramide NP, cholesterol and linoleic acid from safflower oil in a 3:1:1 M ratio. These ingredients must be delivered in the correct ratio to have a positive effect on the integrity of the skin barrier 22 since application in the incorrect ratio has been shown to impede barrier repair. 23 Ceramide EOP and ceramide NP were utilized as these ceramides have been demonstrated to be deficient in eczematous skin. 5 Furthermore, topical delivery of ceramides has also been shown to relieve itch. 24 In addition, the ceramide cream and cleanser also contain pyroglutamic acid (PCA), lactic acid and nicotinamide to promote and enhance the effects of ceramides.
PCA, which is a filaggrin breakdown product and part of the skin's natural moisturizing factor (NMF), is present as sodium PCA, the form of PCA most used in topical preparations, which helps to restore the hydration of the SC. 25 Lactic acid also forms part of the NMF, and together with nicotinamide have been shown to promote ceramide biosynthesis and thus further strengthen the skin barrier. 26,27 Similar outcomes to those observed in this study have been reported in the relatively few clinical studies examining the safety Similar results have been observed in adults and children using moisturizers containing synthetic pseudoceramides [34][35][36] or ceramide precursor lipids. 37,38 However, the nature of pseudoceramides and ceramide precursors may make them less efficacious in treating dry skin than ceramides. 20,24 This study demonstrates the importance of supporting the barrier function of eczematous skin and highlights the need for moisturizers and cleansers to be formulated specifically for eczema. A limitation of the study is that patients were not followed up after completion of the study to determine whether the skin barrier continued to improve. Furthermore, a change in EASI may have been observed if a longer study period was used. Similar studies of up to 8 weeks with a follow-up period may be useful in both adults and children with moderate eczema.

| CONCLUSION
This is the first study to show clinical evidence that a commercially available moisturizing cream and cleanser containing ceramides and other lipids in the appropriate physiological ratio, successfully and safely improves the signs and symptoms of moderate eczema in adults.

ACKNOWLEDGMENTS
The authors would like to thank Datapharm Australia Pty. Ltd.
(Drummoyne, New South Wales, Australia) for assistance in performing the statistical analysis.

DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author upon reasonable request.