Combination of Topical Heparin and Levomenol in the Treatment of Atopic Dermatitis: A SCORing Atopic Dermatitis (SCORAD) Analysis

Abstract

Background/Objectives: A prior placebo-controlled, double-blind clinical study demonstrated the superiority of a topical combination of heparin and levomenol over the control and single active constituents. The effect on pruritus and the total SCORAD index were used to evaluate efficacy, but not the effect on the individual SCORAD items. This analysis investigates the overall efficacy of the treatment and the relative contributions of heparin and levomenol to symptom relief in atopic dermatitis, including the effects on the affected body area and its implications for sleeplessness. Methods: The ITT group (combination group A: n = 79; levomenol group B: n = 80; heparin group C: n = 78; placebo group D: n = 41) of the previously published study was re-analysed. Results: The combination significantly improved symptoms such as erythema, edema/papulation, excoriations, and skin dryness compared to the control after eight weeks of treatment. No significant differences were observed for oozing/crust and lichenification among the active groups. Levomenol and heparin exhibited significant advantages over the control for erythema and excoriations, while heparin improved edema/papulation significantly. The inflamed body area significantly decreased using the combination or single active constituents, and sleeplessness significantly improved with the combination or with heparin alone compared to the control. Conclusions: These findings highlight the efficacy of the combination and individual active constituents in addressing specific symptoms of atopic dermatitis, providing insights into their therapeutic effects. The combination’s advantage over the control is most evident in improving excoriations, skin dryness, inflamed skin area, and sleeplessness, justifying its documented use as an intervention in the early stages of atopic dermatitis episodes.

1. Introduction

Atopic dermatitis is typically characterized by eczema, dry skin, and agonizing itching. Treatment recommendations are based on the severity of these symptoms in a stepwise approach: the first level consists of basic skin care (emollients) with the aim of counteracting skin dryness. When basic skin care alone is no longer sufficient, topical corticosteroids (TCSs) and/or topical calcineurin inhibitors (TCIs) may have to be applied. In severe cases of atopic dermatitis in adults, the treatment guidelines recommend the addition of systemic therapies, e.g., immunosuppressants including glucocorticosteroids, biologics, and Janus kinase inhibitors [1,2].

A German therapeutic S2k guideline also considers the use of antipruritic agents [3], provided that the corresponding therapeutic approaches are based on clinical evidence from controlled studies. Such evidence has been given for a topical combination product with heparin and levomenol as the active constituents in a clinical placebo-controlled trial [4], followed by a four-arm placebo-controlled trial performed to demonstrate the advantage of the combination over the two single active ingredients in terms of a reduction in pruritus and the SCORing Atopic Dermatitis (SCORAD) index [5,6]. The SCORAD index was introduced in 1993 by the European Task Force on Atopic Dermatitis [7] and is a widely accepted clinical tool for the assessment of the symptoms and extent of atopic dermatitis.

In a recent survey by Schmidt, it was discovered that dermatologists frequently prescribe the topical combination of heparin and levomenol in pediatric treatment, highlighting their primary concern to minimize the regular use of corticosteroids [8].

The formulation of a cream intended to treat itchy skin conditions with heparin and levomenol was originally based on research findings indicating the anti-inflammatory, anti-allergic, wound-healing, and anti-eczematic properties of heparin [9,10,11]. Levomenol, also known as (-)-α-bisabolol, is renowned for its potent anti-inflammatory characteristics, making it a prevalent constituent in skin-care products [12,13]. This topical combination, approved as a medicinal product in Germany, Austria, Switzerland, and the Czech Republic, has a long history of safe clinical use.

The superiority of the combination of heparin and levomenol over the control and over the single active constituents has already been demonstrated under controlled conditions. The superiority referred to the relief of pruritus and to the total SCORAD index [5]. However, the nuanced impact of heparin and levomenol on the individual symptoms contributing to the SCORAD index calculation has not been previously explored. The SCORAD index comprises three essential parts: (a) assessment of the afflicted skin area; (b) assessment of the severity of six individual observations related to the skin, including (1) erythema, (2) edema/papulation, (3) excoriations, (4) oozing/crust, (5) lichenification, and (6) skin dryness, the intensity of which is rated on a scale from 0–3 points [14]; and (c) the subjective assessment of pruritus and sleeplessness. While these parameters were recorded in the previously published study, they were not individually presented [5]. This post hoc analysis re-examined the original patient data, aiming to identify the differential impact of heparin and levomenol, both individually and in combination, on the specific symptoms building the SCORAD index in atopic dermatitis.

2. Methods

2.1. Study Design

The dataset of a previously published four-arm double-blind study [5] was re-examined to assess the specific impact of topical levomenol, heparin, and their combination on individual parameters of the SCORAD index. The trial, registered under EudraCT No. 2005-002951-41, received approval by the Czech drug authorization authority (SUKL) and the ethics committees responsible for the study centers. Involving 278 patients with atopic dermatitis, the study randomized participants in four groups: Group A (79 patients) received a medicinal product containing the active ingredients levomenol and heparin (in Germany authorized as Sensicutan^® by Harras Pharma Curarina, batch No. 1/0708); groups B (80 patients) and C (78 patients) were treated with an otherwise identically composed cream with only levomenol or heparin as active constituents, respectively; and group D (41 patients) were allocated to treatment with an identical cream without active constituents (control). Levomenol was used at a concentration of 0.3 g/100 g cream, and heparin with 20,000 IU/100 g cream. Manufactured by Gehrlicher Pharmazeutische Extrakte GmbH (Eurasburg, Germany), all four creams were undistinguishable in appearance and odor. Excipients of the cream base were almond oil, middle-chain triglycerides, tetradecane-1-ol, cetyl and stearyl alcohol, citric acid, collagen peptides, vitamin E, dexpanthenol, polyethylene glycol myristil, cetyl and stearyl ethers, and water, preserved by sorbic acid and salicylic acid. This composition was identical for all four treatment groups. The corresponding medications were applied to the affected eczematous skin areas twice daily over a period of 8 weeks [5].

There was no specific severity of the disease defined as an inclusion criterion, and no stratification by severity had been planned. The major exclusion criterion was the absence of treatment with corticosteroids, therefore more severe and advanced episodes were not part of the study. This was reflected in starting values of 59.4 ± 18.8 mm on a visual analogue scale for itching, and of 42.5 ± 13.6 points for SCORAD [5]. Further exclusion criteria were the absence of other potentially interfering skin diseases and the current use of systemic or topical medication for the treatment of pruritus.

Six skin-related symptoms—erythema, edema/papulation, excoriations, oozing/crust, lichenification, and dryness of unaffected skin—were evaluated on a 4-point rating scale of absent (0), mild (1), moderate (2), and severe (3). Furthermore, the SCORAD rating included the percentage of inflamed body area, along with assessment of pruritus and sleeplessness assessed by patients on a visual analogue scale (VAS). The obtained SCORAD values were considered a secondary non-confirmatory study parameter, with pruritus serving as the primary confirmatory parameter [5]. It is noteworthy that pruritus was already analyzed as the primary efficacy parameter in the original study.

The authors received explicit authorization to reuse the datasets of the original study for this analysis.

2.2. Within-Group Analyses of Individual SCORAD Parameters

In this evaluation, we assessed the effect of the two active constituents, their combination, and the control group on the individual parameters of the SCORAD index. This included the percentage of inflamed body area, the six skin-related symptoms, and the assessment of sleeplessness from baseline to study termination (week 8).

2.3. Statistics

SPSS v.16.0 was used as the statistical software (SPSS Inc., Chicago, IL, USA). Initially, the change in severity of each SCORAD item was assessed within groups using the Wilcoxon signed-rank test for paired samples. Subsequently, an intergroup analysis evaluated the improvement of SCORAD parameters from “severe” or “moderate” to “mild” or “absent” after eight weeks of treatment. The statistical significance of the shift in severity of symptoms between treatment groups and comparisons with the control was calculated using the Chi square test or Fisher’s exact test, as appropriate, after rejecting the hypothesis that the frequency of changes in effect severity was equal across all four treatment groups. Furthermore, the statistical significance of improvements in sleep loss related to symptoms of atopic dermatitis and the percentage of inflamed body area were analyzed within treatment groups. For this study, we computed the Spearman’s correlation coefficient to assess the relationship between the reduction in the inflamed area and the impact on sleep loss and pruritus. An additional analysis of covariance was conducted to compare the three active treatment groups with the control group.

3. Results

The intent-to-treat group (ITT) of the original study with 278 patients was used for the calculations. While there were four drop-outs (one from the heparin group and three from the control group), the calculations with the per-protocol group (PP, n = 274) did not yield a different outcome from that observed in the ITT population [5]. Consequently, for this reassessment, the analysis was conducted with the full ITT population. It is of note that no adverse effects were detected, and the overall tolerability was excellent.

Although patients up to the age of 60 years could have been included in the study, the average age was only 30.6 ± 16.3 years. A total of 27.3% of the study participants were under the age of 18 years. A subgroup analysis comparing children in the age groups of 0–6 years and 7–12 years did not detect statistically significant age-related differences in the response of the study participants to treatment [5]. Similarly, no other age-related differences in the efficacy rating were found or suspected (not published in [5]).

3.1. SCORAD Parameters Part A: Inflamed Body Area

At baseline, the inflamed body area reached an average size of 24.9 ± 18.0%. The percentage of inflamed body area varied among the treatment groups at baseline (

Table 1. Inflamed body area by treatment group in percent (%).

Treatment Group	n	Baseline	Week 4	Week 8
Combination	79	29.38 ± 18.96	16.90 ± 10.82	10.78 ± 10.10
Improvement vs. baseline			12.48 ± 12.21	18.59 ± 16.14
Improvement vs. control			5.27 ± 1.38	7.77 ± 1.48
p value vs. control			p = 0.0002	p = 3.2 × 10−5
Levomenol	80	25.55 ± 18.43	20.64 ± 15.49	15.53 ± 11.97
Improvement vs. baseline			4.91 ± 7.06	10.03 ± 10.55
Improvement vs. control			1.14 ± 1.02	3.80 ± 1.25
p value vs. control			p = 0.27 (n.s.)	p = 0.003
Heparin	78	23.08 ± 15.97	17.55 ± 12.07	13.31 ± 9.29
Improvement vs. baseline			5.53 ± 6.57	9.77 ± 10.56
Improvement vs. control			2.29 ± 0.84	4.18 ± 1.19
p value vs. control			p = 0.01	p = 0.001
Control	41	19.29 ± 16.77	17.34 ± 14.91	15.7 ± 14.35
Improvement vs. baseline			1.95 ± 3.14	3.54 ± 3.98

n.s.: not significant.

). However, noticeable developments were observed across all groups during the course of treatment. While the inflamed body area decreased after week 4 for all active treatments, statistical significance was not reached in the case of levomenol compared to the control. By the end of the two-month treatment period, a further decrease in the percentage of inflamed body area was evident, proving statistically significant for the combination and both single active constituents when compared to the control. Notably, the overall effect of the two single active constituents was observed to be additive (Figure 1, Table 1).

3.2. SCORAD Parameters Part B: Severity and Improvement of Skin-Related Symptoms

At baseline, the occurrence of the six skin symptoms comprising part B of the SCORAD index varied. Erythema, edema/papulation, excoriations, and skin dryness exhibited the highest occurrence at a severity level classified as “moderate” or “severe”, whereas oozing/crust and lichenification were not primary concerns for the patients at baseline (Supplementary Table S1).

The improvement in the severity of all six symptoms within the groups was statistically significant (p < 0.0001) for the active treatment groups, and also partially within the control group. The control group exhibited no significant effect on edema/papulation and lichenification. However, it showed significant effects on all other skin-related symptoms (Figure 2A–F, Supplementary Table S1).

The intragroup analysis lacks insights into the relative effect strength of the four treatments on individual symptoms. To address this, a secondary analysis examined the number of patients experiencing a shift in symptom severity from “severe” or “moderate” to “mild” or “absent”; this was followed by a statistical comparison of the three active treatment groups with the control group. Across all six skin-related symptoms, the combination group consistently demonstrated the highest percentage of patients experiencing an improvement, followed by the levomenol and heparin groups. With the exception of lichenification, the control group exhibited a comparatively lower efficacy (Figure 3).

Table 2. Percentage of improvements from “severe” or “moderate” to “mild” or “absent” and statistical comparison with the control after eight weeks of treatment (n: total number of patients per treatment group; N: number of patients showing the symptom with “severe” or “moderate” severity at baseline; n.s.: not significant).

Treatment Group	n	Erythema	Edema/Papulation	Excoriations	Oozing/Crust	Lichenification	Skin Dryness
Combination	79	100.0%	100.0%	100.0%	100.0%	100.0%	90.4%
		n = 66 (83.5%)	n = 24 (30.4%)	n = 58 (73.4%)	n = 14 (17.7%)	n = 15 (19.0%)	n = 52 (65.8%)
		p < 0.0001	p = 0.016	p = 0.0001	n.s. (p > 0.05)	n.s. (p > 0.05)	p = 0.001
Levomenol	80	97.2%	95.0%	77.8%	92.9%	81.8%	65.4%
		n = 71 (88.8%)	n = 20 (25.0%)	n = 45 (56.3%)	n = 14 (17.5%)	n = 11 (13.8%)	n = 52 (65.0%)
		p = 0.001	p = 0.06 (n.s.)	p = 0.003	n.s. (p > 0.05)	n.s. (p > 0.05)	n.s. (p > 0.05)
Heparin	78	90.6%	100.0%	86.0%	100.0%	100.0%	74.0%
		n = 53 (68.0%)	n = 16 (20.5%)	n = 43 (55.1%)	n = 14 (18.0%)	n = 6 (7.7%)	n = 50 (64.1%)
		p = 0.05	p = 0.03	p = 0.0002	n.s. (p > 0.05)	n.s. (p > 0.05)	n.s. (p > 0.05)
Control	40	73.1%	50.0%	36.8%	87.5%	100.0%	53.8%
		n = 26 (63.4%)	n = 4 (9.8%)	n = 19 (46.3%)	n = 8 (19.5%)	n = 2 (4.9%)	n = 26 (63.4%)

shows the population of each subgroup and the statistical comparisons with the control. No significant differences were found when comparing any active group with the control for the symptoms of oozing/crust and lichenification.

The combination treatment demonstrated superior efficacy in addressing erythema, edema/papulation, excoriations, and skin dryness, with significant advantages over the control group. Both single active constituents showed significant improvements over the control group for erythema and excoriations. Notably, levomenol had a better effect on erythema compared to heparin, whereas heparin had a better effect on edema/papulation. Regarding the treatment of dryness in unaffected surrounding skin, the effects of the two single active constituents vs. the control were not statistically significant, while the combination yielded a significant effect (Figure 3, Table 2).

3.3. SCORAD Parameters Part C: Sleeplessness

After week 4, the assessment of patient-reported sleep loss on a VAS did not show any statistically significant differences between any of the active groups and the control. However, the scenario changed over the further course of treatment: significance compared to the control was reached after week 8 in the combination and heparin groups, though not yet in the levomenol group. Notably, at baseline, sleep loss was more pronounced in the active treatment groups than in the control group (

Table 3. Sleep loss assessed on a visual analogue scale (VAS) in mm VAS (n.s.: not significant).

Treatment Group	n	Baseline	Week 4	Week 8
Combination	79	14.42 ± 13.21	8.85 ± 4.84	5.99 ± 3.40
Improvement vs. baseline			5.57 ± 10.87	8.43 ± 12.34
Improvement vs. control			1.20 ± 0.71	3.03 ± 0.69
p value vs. control			p = 0.09 (n.s.)	p = 2.4 × 10−6
Levomenol	80	10.84 ± 11.22	9.69 ± 8.80	8.69 ± 7.85
Improvement vs. baseline			1.15 ± 4.26	2.15 ± 6.00
Improvement vs. control			0.02 ± 0.71	0.85 ± 0.70
p value vs. control			p = 0.97 (n.s.)	p = 0.23 (n.s.)
Heparin	78	13.99 ± 12.88	10.92 ± 10.20	8.06 ± 7.58
Improvement vs. baseline			3.06 ± 8.05	5.92 ± 9.36
Improvement vs. control			0.57 ± 1.16	2.15 ± 0.94
p value vs. control			p = 0.62 (n.s.)	p = 0.024
Control	41	7.98 ± 8.30	7.44 ± 6.43	7.54 ± 6.23
Improvement vs. baseline			0.54 ± 5.73	0.44 ± 4.68

). Despite this, the effect was evident and again approximately additive for the two active constituents (Figure 4, Table 3).

3.4. Correlation Between Pruritus/Inflamed Area and Pruritus/Sleep Loss

The positive and statistically significant effect on pruritus was previously demonstrated in the initial publication [5]. As anticipated, the Spearman’s correlation coefficient for all tests fell within the range of 0.5 after week 8, affirming that the decrease in pruritus aligns in parallel with the reductions in inflamed skin area and sleep loss. This correlation was statistically significant (p < 10⁻¹⁴), confirming the expected relation between the symptoms of pruritus and inflamed body area, as well as pruritus and sleep loss. The data suggest that a decrease in pruritus corresponds to a reduction in inflamed body area and improved sleep.

4. Discussion and Conclusions

Levomenol and heparin contribute distinctively to the overall efficacy of a combination of both active constituents in the treatment of atopic dermatitis. As already expected from clinical experience with the application of the medicinal product, erythema, edema/papulation, excoriations, and skin dryness responded best to the treatment with the combination. The statistically significant improvement in pruritus correlated with reduced inflamed body area and enhanced sleep, aligning with the known anti-inflammatory and anti-allergic effects of levomenol [15,16] and heparin [17,18,19,20]. Levomenol had a better effect on erythema than heparin, which may be attributed to its potent anti-inflammatory activity, while heparin excelled in addressing edema, suggesting diverse biological pathways.

No significant difference was observed for oozing/crust and lichenification parameters vs. control. This does not negate the possibility of an effect. It is essential to recognise that the baseline prevalence of patients reporting these symptoms was relatively low (especially in the control group), indicating insufficient representation. Furthermore, it may be a process where improvement cannot be seen within eight weeks of treatment. Exploring these parameters in a study involving more patients in more advanced stages might yield a different outcome. This observation aligns with the typical prescription pattern of the medicinal product in the early stages of acute atopic dermatitis episodes [8]. The available clinical data suggest that the medicinal product may prevent the progression of symptoms toward oozing/crust formation and lichenification [4,5,6].

The treatment guidelines for atopic dermatitis recommend skin-care products as a baseline measure [3]. Basic skin care ought to improve the condition of dry skin. It is therefore not surprising that the control preparation significantly improved skin dryness to an extent where the treatment with the creams with the single active constituents did not provide better results. However, the effect of the combination of levomenol and heparin was statistically significant compared to the control, justifying its use and providing additional benefit for the prevention and treatment of episodes of atopic dermatitis.

Heparin had a better effect on sleep loss compared to levomenol. Remarkably, after one month of treatment, their combined effect exceeded mere summation, and by the end of eight weeks, the combination’s effect was more than additive. The anticipated direct association between sleep loss and pruritus and the conjecture that the anti-inflammatory effects of levomenol might give this substance an advantage over heparin were not evident. In contrast, after eight weeks, both single active constituents had similar effects on excoriations and on the inflamed body area, with the combination remaining considerably more potent. The effect of heparin on the inflamed body area manifested earlier than that of levomenol.

The limitations of this study are the relatively small patient numbers in the analysed subgroups, especially those patients with symptoms related to the more advanced stages in episodes of atopic dermatitis. This is mainly due to the authorized use of the study medication in the early phases of episodes. Overall, however, the combination of levomenol and heparin offers notable advantages in treating atopic dermatitis. The combination’s effects make it suitable for early intervention during episodes of atopic dermatitis, a fact substantiated by documented clinical trials [4,5]. Moreover, its proven efficacy in clinical trials suggests its applicability not only in the early stages of atopic dermatitis episodes but also, potentially, in more advanced stages, such as when it is used in conjunction with a TCS or TCI. Furthermore, the combination of heparin and levomenol can be used for relapse prophylaxis and proactive therapy, which can extend the TCS- or TCI-free interval or reduce their use. Current experience suggests that this form of therapy may reduce the requirement for immunosuppressants such as corticosteroids and calcineurin inhibitors [8].

The main advantages of combining topical levomenol and heparin for the treatment of atopic dermatitis are the distinct effects on pruritus, erythema, excoriations, and general skin dryness, as well as reductions in inflamed body area and in symptom-related sleeplessness. The proven efficacy of the combination suggests that it is eligible for use in early interventions in episodes of atopic dermatitis and possibly also in more advanced stages, e.g., in combination with a TCS or TCI.