Improved itch relief with new product formulation for topical treatment in patients with mild-to-moderate atopic dermatitis: results from an exploratory trial Back

Hans Stettler1*, Peter Kurka1, Rolf Dominicus2, Viktoria Pavel2, Marion Breuer2 and Holger Lenz1

1Bayer Consumer Care AG, Basel, Switzerland; 2Proinnovera GmbH, Muenster, Germany

Abstract

Background: Effective treatment of atopic dermatitis (AD) should restore barrier function, reduce inflammation and break the itch-scratch cycle. Bepanthen® Itch Relief Cream, a medical device with a physical mode of action, restores the skin barrier and relieves symptoms of irritation in patients with mild-to-moderate AD. An exploratory study was conducted to assess the efficacy and safety of a new formulation (investigational product; IP), compared with the commercial product (comparator) and no treatment (negative control).

Methods: Randomised test areas of 35 AD patients were simultaneously treated (twice daily for 28 days) with IP, comparator or no treatment. Exploratory variables were local SCORing Atopic Dermatitis (local SCORAD); intensity parameters of the local SCORAD index, transepidermal water loss (TEWL), erythema, skin hydration and pruritus.

Results: During treatment IP was superior to negative control for local SCORAD, TEWL, skin moisturisation and pruritus. IP and comparator were comparable except for itch relief where a significant difference in favour of IP was observed. Adverse effects were mild.

Conclusions: In patients with mild-to-moderate AD, the new formulation of Bepanthen® Itch Relief Cream was well-tolerated with comparable efficacy to comparator and significantly improved TEWL, skin hydration and itch relief compared with no treatment.

Key words: atopic dermatitis, Bepanthen, eczema, medical device

Introduction

Atopic dermatitis (AD) (also known as atopic eczema) is one of the most common inflammatory skin diseases [1]. It typically presents during childhood and recent studies estimate that 10–20 % of children in North West Europe and 1–3 % of adults in Europe are affected [2, 3].

Although the pathogenesis of AD is not fully understood, it is thought that genetic, immunological, lifestyle and local factors are involved [2, 3]. It has been shown however, that the characteristic symptoms of AD such as pruritus, erythema and lichenification [1] are due to disturbance of the natural skin barrier caused by lipid abnormalities, increased epidermal proliferation and abnormal differentiation [4]. This results in increased transepidermal water loss (TEWL), and dehydrated, extremely sensitive and vulnerable skin [4]. Disruption of the skin barrier also allows entry of irritants, micro-organisms and allergens into the deeper layers of the skin where they generate an immune response which exacerbates inflammation and pruritus. Scratching provides immediate but short relief for the patient, but further weakens and compromises the skin barrier, triggering the itch-scratch cycle [5].

Effective AD treatment therefore needs to restore barrier function to break the itch-scratch cycle and thereby reduce inflammation and pruritus. The European Task Force on Atopic Dermatitis/ European Academy of Dermatology and Venerology eczema task force recommend a step-wise approach to the management of AD [1]. In a recent advisory board meeting it was also suggested that a holistic AD treatment strategy should follow a step-wise management with topical corticosteroid/topical calcineurin inhibitors, barrier formulas and emollients [6]. Bepanthen® Itch Relief Cream (Bayer Consumer Care AG, Basel, Switzerland) is a medical device which provides a physical mode of action for the management of mild-to-moderate AD. Lamellar lipid structure binding ingredients integrate into the stratum corneum and regenerate barrier properties; emollients substitute lacking lipids and mechanically improve skin elasticity; and humectants (such as glycerin) enhance moisturisation of the stratum corneum and epidermis. Following a minor reformulation of Bepanthen® Itch Relief Cream an exploratory trial was conducted to assess the safety and efficacy of the new preparation in comparison to the commercial product (comparator) and untreated skin (negative control) in patients with mild-to-moderate AD.

Materials and methods

This investigator-blinded, three-arm, randomised pilot trial included male and female Caucasians aged 18–60 years with mild-to-moderate AD, defined as a SCORing Atopic Dermatitis (SCORAD) rating <50 (Table 1), and target lesions on one or both arms [7]. All patients had acute AD symptoms on each test area within the target lesions, with a local SCORAD rating of ≥3 and ≤12 and acute pruritus at baseline. Local SCORAD was defined as the sum of the six intensity parameters of SCORAD on a scale from 0 to 3: erythema, edema/papulation, excoriation, lichenification, oozing/crusts and dryness.

Table 1 SCORing Atopic Dermatitis index for classification of severity of eczema [15]

Patients using any AD treatment (including alternative treatment), drugs interfering with the immune system, inhaled corticosteroids, antiphlogistic drugs or ultraviolet therapy prior to enrolment were excluded. So were patients with any other skin disease, moles, tattoos, strong pigmentation or scars at the test area that would interfere with the clinical assessment. Pregnant or lactating women were also excluded from the study, and women of child-bearing potential had to use reliable contraception for at least 1 month prior to screening.

Target lesions could be either one lesion of sufficient size on one arm or two comparable lesions on both arms. Each target lesion was divided into two (two separate lesions) or three (one lesion) test areas (Fig. 1).

figure 1

If the patient had one target lesion (approximately 28 cm2) IP and comparator were applied to the same lesion in different but equivalent test areas according to a random list, leaving a third test area untreated for intra-individual comparison (Fig. 1).

Treatment was applied twice daily in the morning and evening over the course of 29 days, with the exception of Day 1 (evening only) and Day 29 (morning only), for a total of 56 applications.

The excipients of the two treatments are listed in Table 2.

Table 2 Excipients of treatments

All evaluations of the trial variables were performed on the pre-determined assessment areas. The primary efficacy variables were local SCORAD at visits 2–6 (Day 2, Day 4, Day 8 ± 1, Day

15 ± 1 and Day 29 ± 2, respectively); intensity items of the local SCORAD index at visits 2–6; TEWL as a measure for skin barrier function at visits 2–6; skin hydration as assessed by corneometry at visits 2–6; erythema as assessed by chromametry at visits 2–6; and patient-reported intensity of pruritus Days 1–29, reported using a visual analogue scale before application and approximately 30 min after application of test products.

Incidence and severity of adverse events (AEs) were assessed by investigators through evaluation of the patient diary at visits 2–6. Vital signs (blood pressure, heart rate and body temperature) were assessed at visit 2 and visit 6.

Statistical analysis

The study aimed to randomise 62 patients to achieve 50 evaluable patients.

Intra-individual comparisons were performed for the various baseline adjusted efficacy parameters after treatment with IP or comparator versus untreated areas. Intra- individual comparisons were also made between IP and comparator. Exploratory hypothesis tests used Wilcoxon’s signed rank test for TEWL, skin moisture, intensity of erythema and skin thickness. Local SCORAD and intensity of pruritus were assessed using paired t-tests. The area under the curve (AUC) was calculated for the efficacy variables and compared between treatments using the Wilcoxon signed rank test. When comparing the data of IP with untreated skin, hypotheses favouring IP were exploratively tested at one-sided significance level of 0.025. When comparing IP with comparator, explorative testing was performed at a two-sided significance level of 0.05.

The final trial protocol and informed consent documentation were approved by the respective Independent Ethics Committee (Ethikkommission der Ärztekammer Westfalen-Lippe und der Medizinischen Fakultät der WWU Münster) before the

start of the study. The study was conducted in compliance with the Declaration of Helsinki and International Conference on Harmonization Good Clinical Practice Guidelines. In addition, all local regulatory requirements were followed and all subjects provided written information consent prior to entering the study.

Results

Recruitment into the study was slow due to the specific require- ments for the target lesions, and so the decision was made to stop recruitment on 23 May 2014 after enrolment of 36 patients. Due to the late recruitment of some patients a seasonal influence on the severity of AD was anticipated and analysed separately. Thirty-five patients were randomised and 33 completed treatment; all 35 were included in the efficacy (full analysis set, FAS) and safety analyses. Baseline characteristics of these patients are summarised in Table 3.

Table 3 Patient baseline characteristics

Compliance was high; 34 of 35 patients had a compliance rate of ≥80 % and only three patients missed one or more applications.

Efficacy

At the end of treatment local SCORAD decreased for each test, with a non-significant improvement with IP and comparator versus negative control (Table 4).

Table 4 Local SCORAD

However, both IP and comparator showed a significant treatment effect when compared with negative control over the whole study duration (Fig. 2 and Table 5); P = 0.0243 and P = 0.01, respectively. The difference between the two treatments was non-significant; P = 0.7545.

Fig. 2. Changes in local SCORing Atopic Dermatitis for investigational product (IP) and comparator versus untreated atopic dermatitis lesions. AUC, area under the curve; IP, investigational product; ns, non- significant; SCORAD, SCORing Atopic Dermatitis.

Fig. 2. Changes in local SCORing Atopic Dermatitis for investigational product (IP) and comparator versus untreated atopic dermatitis lesions. AUC, area under the curve; IP, investigational product; ns, non- significant; SCORAD, SCORing Atopic Dermatitis.

Table 5 Treatment differences for efficacy variables

There was also a statistically significant difference in the reduction of TEWL between IP and negative control (P = 0.002) and comparator and negative control (P = 0.0095) at end of treatment. Again, the difference between IP and comparator was not significant (P = 0.3288). When compared over the whole study duration, the effects of treatment were even more significant; P < 0.0001 for IP versus negative control and P = 0.0112 for comparator versus negative control (Fig. 3 and Table 5).

Fig. 3. Changes in transepidermal water loss for investigational pro- duct (IP) and comparator versus untreated atopic dermatitis lesions AUC, area under the curve; ns, non-significant; TEWL, transepidermal water loss.

Fig. 3. Changes in transepidermal water loss for investigational pro- duct (IP) and comparator versus untreated atopic dermatitis lesions AUC, area under the curve; ns, non-significant; TEWL, transepidermal water loss.

Skin moisturisation was also significantly improved with IP and comparator versus negative control at the end of treatment and over the course of treatment (Fig. 4 and Table 5). Once again, the difference between IP and comparator was non-significant. There were minimal changes in erythema intensity over the course of the treatment and differences between treatment and negative control, and IP and comparator were not significant (Table 5).

Fig. 4. Changes in skin moisturisation for investigational product (IP) and comparator versus untreated atopic dermatitis lesions. AUC, area under the curve; IP, investigational product ns, non-significant.

Fig. 4. Changes in skin moisturisation for investigational product (IP) and comparator versus untreated atopic dermatitis lesions. AUC, area under the curve; IP, investigational product ns, non-significant.

Finally, both treatments were shown to have a fast effect on pruritus; at all visits (with the exception of comparator at visit the intensity of pruritus was higher before application than 30 min after application (Table 6). In addition, the intensity of pruritus decreased steadily at all visits during treatment with IP and was statistically superior to negative control (P = 0.0248). Over the course of the treatment the difference between comparator and negative control however, was not significant (P = 0.2415). IP was also superior to comparator with regards to pruritus intensity reduction (P = 0.0408).

Table 6 Pruritus intensity

The results for the single symptoms of local SCORAD are summarised in Table 5.

Safety

The treatment was well-tolerated. Thirty-three AEs in 20 patients were reported; 20 AEs in 14 patients were systemic and 13 AEs in eight patients were dermatological (two of the patients experienced both systemic and dermatological AEs). Eight of the dermatological AEs occurred within the test area or in the direct vicinity of the test area. Of the 33 AEs only five in three patients were judged to be related to treatment and all were dermatological including application-site pruritus and application-site urticaria.

All AEs were considered mild, none led to discontinuation from the trial, and the majority had resolved or were recovering by the end of the trial.

 

Discussion

The current study has shown that both IP and comparator had a positive effect on all efficacy parameters over the whole treatment period. In particular, IP and comparator improved parameters associated with the ability to restore an impaired skin barrier and provide itch relief, such as reduction of TEWL, and improved moisturisation and dryness. As expected, IP and comparator were equivalent for all parameters with the exception of pruritus intensity, which showed a significantly better treatment effect in favour of IP for momentary relief of pruritus and improved pruritus versus comparator. Treatment with both IP and comparator was generally well tolerated.

With both IP and comparator, an initial treatment effect versus untreated skin was observed for dryness as a SCORAD symptom but the difference in effect levelled off towards the end of treatment. Similar observations were made with comparator for oozing/crusts. These results may be due to the fact that although the study was planned to be conducted during the winter when AD is generally worse, the winter was unusually short and mild and recruitment was prolonged into spring and early summer, so there may have been general seasonal improvements in skin dryness and oozing/crusts in the untreated skin [1, 2]. By evaluating the entire treatment period rather than the final visit alone, the impact of spontaneous healing during the warmer spring months should have been taken into account. However, to explore the impact of seasonal variation further, the efficacy variables were also analysed for patients who terminated the study before 28 February 2014 versus patients who terminated the study after 28 February 2014. Overall, there were no clear differences in the treatment effects observed between the subgroups with the exception of local SCORAD which was significantly better for IP at end of treatment in the early seasonal participation population versus the late seasonal participation population and the total study population, highlighting the positive seasonal impact on AD.

In an earlier, similarly designed study 40 patients were treated daily for 28 days with either comparator or 1% hydrocortisone and then evaluated for local SCORAD, TEWL, erythema and skin hydration [8]. As with the current study, this study found a clear benefit of treatment over non-treatment, and there were no clinically significant differences in efficacy or safety between comparator and 1% hydrocortisone.

In both studies, each patient served as their own control and so the study design provided less variability of data compared with a parallel-group design study. In

addition, in order to allow both intra- and inter-individual comparisons of the products and negative control, the test areas were randomised and pre-defined. Studies have demonstrated how the three main components of Bepanthen® Itch Relief Cream reinforce the skin barrier and provide symptom relief. Lamellar lipids similar to those contained in the stratum corneum of healthy skin integrate into the stratum corneum to support barrier repair and stabilize TEWL[9]. Panthenol (also known as provitamin B5) hydrates the stratum corneum and decreases TEWL [10-12]. Glycerine, accumulates in the stratum corneum to ensure water retention and long-lasting hydration [13, 14].

This study has confirmed that the new formulation of Bepanthen® Itch Relief Cream was well tolerated and significantly improved TEWL, skin hydration and itch relief when compared with no treatment in patients with mild-to-moderate AD.

Conflict of interest

HS, PK and HL are employees of Bayer Consumer Care AG, Basel, Switzerland; VP and MB are employees of Proinnovera GmbH, Muenster, Germany; RD is a board-certified dermatologist with his own practice and works as a freelancer with Proinnovera GmbH, Muenster, Germany.

Author contributions

RD was responsible for the conduct of the trial, as well as analysis of the trial data and opinions, conclusions, and interpretation of the data.

VP, MB, HS, PK and HL were responsible for analysis of the trial data and opinions, con- clusions, and interpretation of the data.

Acknowledgements

Medical writing support was provided by Kerren Davenport of Prime Medica, Cheshire, UK, funded by Bayer.

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